Abstract Book of the 21th National Congress of Italian Association of Medical Oncology (AIOM)

INCIDENCE, REPRODUCTIVE AND DISEASE OUTCOMES OF PREGNANCY AFTER BREAST CANCER IN PATIENTS CARRYING A BRCA MUTATION: RESULTS FROM AN INTERNATIONAL COHORT STUDY

Lambertini M.¹, Ameye L.², Hamy A.³, Zingarello A.⁴, Poorvu P.D.⁵, Carrasco E.⁶, Grinshpun A.⁷, Han S.⁸, Rousset-Jablonski C.⁹, Ferrari A.¹⁰, Paluch-Shimon S.¹¹, Cortesi L.¹², Senechal C.¹³, Miolo G.¹⁴, Pogoda K.¹⁵, Pérez-Fidalgo A.¹⁶, De Marchis L.¹⁷, Del Mastro L.¹, Peccatori F.A.¹⁸, Azim Jr. H.A.¹⁹

¹IRCCS Policlinico San Martino - Università di Genova, Genova; ²Institut Jules Bordet, Brussels; ³Institut Curie, Paris; ⁴Institut Gustave Roussy, Paris; ⁵Dana-Farber Cancer Institute, Boston; ⁶Vall Hebron Institute of Oncology, Barcelona; ⁷Hadassah-Hebrew University Medical Center, Jerusalem; ⁸University Hospitals Leuven, Leuven; ⁹Leon Berard Cancer Center, Lyon; ¹⁰Fondazione IRCCS Policlinico San Matteo, Pavia; ¹¹Shaare Zedek Medical Centre, Jerusalem; ¹²Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena; ¹³Bergonie Institute, Bordeaux; ¹⁴Centro di Riferimento Oncologico di Avano (CRO) IRCCS, Aviano; ¹⁵Maria Sklodowska-Curie Institute–Oncology Center, Warsaw; ¹⁶INCLIVA University Hospital of Valencia, Valencia; ¹⁷“La Sapienza” University of Rome, Rome; ¹⁸European Institute of Oncology (IEO), Milan; ¹⁹Tecnologico de Monterrey, Monterrey

Background: Very limited data are available on the safety of pregnancy and reproductive outcomes in BRCA-mutated patients with prior breast cancer history. We report the results of the largest study to date addressing these questions.

Material and methods: This international, multicenter, hospital-based, retrospective cohort study included consecutive patients with invasive early breast cancer (stage I-III) diagnosed between January 2000 and December 2012 at the age of = 40 years and carrying a deleterious germline BRCA mutation. Primary endpoints were pregnancy rate and disease-free survival (DFS); overall survival (OS) and pregnancy outcomes were secondary endpoints. To account for guarantee-time bias, we performed two survival analyses: 1) Case-control approach matching pregnant and non-pregnant (1:3) patients for classic prognostic factors (each non-pregnant control had a disease-free interval =than the time elapsing between breast cancer diagnosis and date of pregnancy of the matched pregnant case); 2) Extended Cox model with occurrence of pregnancy as time-varying covariate including all patients.

Results: 1,252 BRCA-mutatedbreast cancer patients (811 BRCA1,430 BRCA2, 11BRCA1&2) were included from 30 centers worldwide, of whom 195 patients had a pregnancy (pregnancy rate = 16% [95% CI 14-18]) after a median 4.5 years (range 3.1-6.7 years) following breast cancer diagnosis. Pregnant patientswere younger and had more ER-negative tumors (all p<0.01). 16 (8.2%) and 20 (10.3%) patients had an induced and spontaneous abortion, respectively. Among the 150 (76.9%) patients who conceived (n = 170 babies), pregnancy complications and congenital anomalies were described in 13 (11.6%) and 2 (1.8%) cases, respectively.Median follow-up was 8.3 years (range 8.1-8.7 years). In the case-control analysis, pregnant patients had better DFS (HR 0.71; 95% CI 0.51-0.99; p = 0.045), with no difference in OS (HR 0.86; 95% CI 0.44-1.67; p = 0.65). Subgroup analysis suggested that the superior outcome was restricted to BRCA1-mutatedpregnant patients(p-interaction<0.01). Similar results were obtained in the second supportive analysis.

Conclusions: Pregnancy following breast cancer is safe in BRCA-mutated patients, particularly those with BRCA1-mutations, with no detrimental impact on maternal prognosis or fetal outcomes. These findings are of paramount importance for fertility counseling in young BRCA-mutated breast cancer patients.

ClinicalTrials.gov Identifier: NCT03673306

UPDATED RESULTS OF TRIBE2, A PHASE III, RANDOMIZED STRATEGY STUDY BY GONO IN THE FIRST- AND SECOND-LINE TREATMENT OF UNRESECTABLE mCRC

Rossini D.¹, Cremolini C.¹, Lonardi S.², Antoniotti C.¹, Pietrantonio F.³, Cordio S.S.⁴, Bergamo F.², Marmorino F.¹, Maiello E.⁵, Passardi A.⁶, Masi G.¹, Tamburini E.⁷, Santini D.⁸, Grande R.⁹, Zaniboni A.¹⁰, Granetto C.¹¹, Murgioni S.², Aprile G.¹², Boni L.¹³, Falcone A.¹

¹Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa; ²Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, IOV - IRCCS, Padua; ³Medical Oncology Department, Fondazione IRCSS - Istituto Nazionale dei Tumori, Milan; ⁴Oncologia Medica, Azienda Ospedaliera ARNAS Garibaldi, Catania; ⁵Oncology Unit, Hospital Casa Sollievo della Sofferenza-IRCCS, San Giovanni Rotondo (FG); ⁶ Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola; ⁷Department of Medical Oncology, Infermi Hospital, Rimini; ⁸Department of Medical Oncology, Campus Bio-Medico - University of Rome, Rome; ⁹Medical Oncology, Ospedale Fabrizio Spaziani-ASL Frosinone, Frosinone; ¹⁰Medical Oncology Unit, Poliambulanza Foundation, Brescia; ¹¹Oncologia Medica, Azienda Sanitaria Ospedaliera Santa Croce e Carle, Cuneo; ¹²Department of Oncology, San Bortolo General Hospital, ULSS8 Berica-East District, Vicenza; ¹³Clinical Trial Coordinating Center, AOU Careggi, Florence

Background: In the phase III TRIBE study FOLFOXIRI/bev significantly improved Response Rate (RR), PFS and OS when compared with FOLFIRI/bev as initial treatment of mCRC. However, the actual advantage by the triplet could be lower when compared with a pre-planned sequential strategy of doublets (FOLFOX, FOLFIRI). TRIBE2 (NCT02339116) is a phase III trial in which unresectable mCRC pts were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after PD (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). A pre-planned interim analysis showed a significant advantage for arm B in terms of PFS2, primary endpoint of the study, defined as the time from randomization to PD on any treatment given after first PD or death (PD2).

Methods: The study had 80% power to detect a HR for PFS2 of 0.77 in favor of arm B with an overall 2-sided-a error of 0.05 (0.0131 and 0.0455 for the interim and final analyses, planned at 303 and 466 PFS2 events, respectively). Secondary endpoints included RR, 1st-PFS, i.e. the time from randomization to the first evidence of PD or death (PD1), 2nd-PFS, i.e. the time from PD1 to PD2, and OS.

Results: From February 2015 to May 2017, 679 pts (arm A/B: 340/339) were enrolled in 58 Italian sites. Main pts’ characteristics were (arm A/B): right side 38%/38%, synchronous mets 89%/89%, RAS mutant 65%/63%, BRAF mutant 10%/10%. At a median follow up of 30.6 mos, 514 (arm A/B: 272/242) PD2, 594 (arm A/B: 303/291) PD1 and 408 (arm A/B: 217/191) OS events were collected. A significant advantage by upfront FOLFOXIRI/bev was confirmed in terms of PFS2 (19.1 vs 16.4 mos, HR 0.74, 95%CI 0.62-0.88, p<0.001), RR (62% vs 50%, OR 1.61, 95%CI 1.19-2.18, p = 0.002) and 1st-PFS (12.0 vs 9.8 mos, HR 0.75, 95%CI 0.63-0.88, p<0.001). A significant OS benefit for pts in arm B was also observed (27.6 vs 22.6 mos, HR: 0.81, 95%CI: 0.67-0.98, p = 0.033). Out of 594 pts with a PD1 event, 470 (79%, arm A/B: 251/219) received a treatment after PD. In the per-protocol analysis (N = 323), pts in arm B showed significantly longer 2nd-PFS (6.5 vs 5.8 mos, HR 0.76, 95%CI 0.59-0.97, p = 0.024).

Conclusions: Upfront FOLFOXIRI/bev followed by the pre-planned reintroduction of the same agents after PD provided a statistically significant and clinically relevant PFS2 and OS benefit when compared with the pre-planned sequential administration of FOLFOX/bev and FOLFIRI/bev in unresectable mCRC patients. A median OS of 27.6 mos was reached despite the high percentage of pts with poor prognostic features.

BENEFIT FROM LETROZOLE AS EXTENDED ADJUVANT THERAPY AFTER SEQUENTIAL ENDOCRINE THERAPY: A RANDOMIZED, PHASE III STUDY OF GRUPPO ITALIANO MAMMELLA (GIM)

Del Mastro L.¹, Mansutti M.², Bisagni G.³, Ponzone R.⁴, Durando A.⁵, Amaducci L.⁶, Fabi A.⁷, Frassoldati A.⁸, Michelotti A.⁹, Pazzola A.¹⁰, Valle E.¹¹, Sanna G.¹², Gori S.¹³, De Placido S.¹⁴, Garrone O.¹⁵, Donadio M.¹⁶, Bruzzi P.¹⁷, Bighin C.¹⁸, Lambertini M.¹⁹, Poggio F.¹⁸

¹Department of Medical Oncology, UO Oncologia Medica 2, Policlinico San Martino-IST - Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova; ²Department of Oncology-ASUI Udine University Hospital, Udine; ³Oncologia Medica Azienda USL/IRCCS di Reggio Emilia, Reggio Emilia; ⁴Gynecologic Oncology, Candiolo Cancer Institute Turin, Torino; ⁵Breast Unit, Città della Salute e della Scienza, ASO S. Anna Torino, Torino; ⁶Ospedale Faenza, Dipartimento Oncologico Area Vasta Romagna Faenza, Faenza; ⁷Division of Medical Oncology, “Regina Elena” National Cancer Institute Rome, Roma; ⁸Division of Oncology, Ferrara University Hospital, Ferrara; ⁹Medical Oncology, AOU Pisana, Ospedale S. Chiara, ITT Pisa, Pisa; ¹⁰Medical Oncology - Ospedale Civile SS. Annunziata, Sassari; ¹¹Oncologia Medica, Ospedale Oncologico “A. Businco”-AO Brotzu, Cagliari; ¹²Azienda Ospedaliera Universitaria di Sassari, Sassari; ¹³Oncology Unit, Ospedale Sacro Cuore-don Calabria, Negrar; ¹⁴Oncology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, Napoli; ¹⁵Breast Unit Medical Oncology S. Croce and Carle Hospital, Cuneo; ¹⁶Oncology Department Aou Città Della Salute e Della Scienza, Torino; ¹⁷IRCCS Ospedale Policlinico San Martino, Genova; ¹⁸Department of Medical Oncology, UO Oncologia Medica 2, Policlinico San Martino-IST, Genova; ¹⁹Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino & Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova

Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET with letrozole after tamoxifen.

Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635) was a prospective, randomized, phase III, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tamoxifen, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS) in both arms. Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n = 1030) or 5 years (n = 1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10.4 years (IQR range: 8.8-11.4). In the intention to treat (ITT) population the 8-year DFS was 82.2% (95% CI:79.5-84.9.) and 86.8% (95% CI:84.4-89.1) in the S and L arm, respectively. In a land-mark univariate Cox analysis, in which events occurred while patients in the 2 arms received the same therapy (i.e. 2/3 years after randomization) were excluded, the Hazard Ratio (HR) for DFS was 0.81 (95% CI 0.65-1.00; p = 0.051). This effect did not change in a multivariate Cox model that included nodal status, tumor size, grading, age and previous chemotherapy (HR 0.81; 95% CI 0.66-1.01; p = 0.06). Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in the S arm and 81 (8.3%) pts in the L arm (chi-square = 9.88; p = 0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively (p = 0.29, Fisher exact test).

Conclusions: After 2-3 years of adjuvant tamoxifen, extended treatment with 5 years of letrozole improved DFS compared to the standard duration of 2-3 years of letrozole.

CLINICAL RELEVANCE OF MUCINOUS AND POORLY DIFFERENTIATED COLON ADENOCARCINOMAS ON THE OUTCOME OF PATIENTS WITH STAGE II: A TOSCA SUBGROUP ANALYSIS

Rosati G.¹, Galli F.², Cantore M.³, Lonardi S.⁴, Banzi M.⁵, Zampino M.G.⁶, Pelliccioni S.⁷, Pella N.⁸, Ronzoni M.⁹, Antista M.¹⁰, Tamberi S.¹¹, Marchetti P.¹², Bozzarelli S.¹³, Marsico V.A.¹⁴, Bochicchio A.M.¹⁵, Artioli F.¹⁶, Labianca R.¹⁷, Galli F.², Bilancia D.¹, Bregni G.¹⁸

¹Ospedale San Carlo, Potenza; ²Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ³Azienda USL 1 di Massa e Carrara, Carrara; ⁴IRCCS Istituto Oncologico Veneto, Padova; ⁵Azienda USL-IRCCS, Reggio Emilia; ⁶IRCCS Istituto Europeo di Oncologia, Milano; ⁷Azienda Ospedaliera Marche Nord, Pesaro/Fano; ⁸Azienda Ospedaliera Universitaria S. Maria della Misericordia, Udine; ⁹Ospedale San Raffaele, Milano; ¹⁰Fondazione IRCCS INT, Milano; ¹¹Ospedale degli Infermi, Faenza; ¹²Ospedale Sant’Andrea, Università Sapienza e IRCCS Istituto Dermopatico dell’Immacolata, Roma; ¹³Istituto Clinico Humanitas IRCCS, Rozzano; ¹⁴Ospedale S. Giovanni Calibita Fatebenefratelli, Roma; ¹⁵Ospedale Oncologico Regionale CROB, Rionero in Vulture; ¹⁶Ospedale B. Ramazzini, Carpi; ¹⁷Cancer Center ASST Papa Giovanni XXIII, Bergamo; ¹⁸IRCCS San Martino-IST, Genova

Background: Although it has been proven for many years that adjuvant chemotherapy is the standard of care for stage III colon cancer (CC) after resection, there is no sufficient evidence that its role on stage II patients get the same benefit. ASCO and ESMO guidelines have identified inadequate sampling of lymph nodes, pT4 primary tumors, obstruction or perforation, lymphovascular and perineural invasion, and poorly differentiated tumors as negative prognostic factors supporting the clinicians in treating this subgroup of patients. However, the influence of histological subtypes on the risk of death or disease recurrence remains controversial.

Patients and methods: The phase III, multicenter, randomized TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. Objective of this sub-study was to investigate the role of the histological subtype [(mucinous adenocarcinoma (MUC) or non-mucinous adenocarcinoma (NMUC)] on the impact of the treatment duration in terms of relapse-free survival (RFS) and overall survival (OS) in the subgroup of patients with high-risk stage II and grade 3 CC.

Results: Out of 3,614 patients from 130 centres enrolled in the per-protocol population defined in the TOSCA trial, 85 MUC and 389 NMUC patients were included in this analysis. No statistical differences were found between 3 versus 6 months groups in both histological subgroups in terms of baseline characteristics, except for tumor side. After a median follow-up of 62 months, 60 progression/deaths and 38 deaths were observed. A significant interaction between treatment duration and histology was observed on both RFS (p = 0.027) and OS (p = 0.017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = 0.045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = 0.037) were detected for patients treated in the 3 months arm. No statistically significant differences were detected in the subgroup of patients with NMUC.

Conclusions: Both MUC and poorly differentiated subtypes identify unfavorable clinical characteristics. Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to clarify the possible negative effect of the histological subtype to improve the prognosis of these patients.

BEVACIZUMAB (BV) MAINTENANCE (M) AFTER FIRST-LINE CHEMOTHERAPY (CT) PLUS BV FOR METASTATIC COLORECTAL CANCER (mCRC) PATIENTS (pts): A META-ANALYSIS OF INDIVIDUAL PTS DATA (IPD) FROM 3 PHASE III STUDIES

Salvatore L.¹, Bria E.¹, Sperduti I.², Bensi M.¹, Hinke A.³, Hegewisch-Becker S.⁴, Aparicio T.⁵, Le Malicot K.⁶, Boige V.⁷, Koeberle D.⁸, Baertschi D.⁹, Dietrich D.⁹, Tortora G.¹, Arnold D.¹⁰

¹UOC Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy; ²Biostatistics, Regina Elena National Cancer Institute IRCCS, Roma, Italy; ³CCRC, Düsseldorf, Germany; ⁴HOPE -Hämatologisch-Onkologische Praxis Eppendorf, Hamburg, Germany; ⁵Department of Gastroenterology, Saint Louis Hospital, Paris, France; ⁶FFCD and INSERM U1231, Dijon, France; ⁷Digestive Oncology, Gustave Roussy, Villejuif, France; ⁸Claraspital, Basel, Switzerland; ⁹Swiss Group for Clinical Cancer Research, Bern, Switzerland; ¹⁰Asklepios Tumorzentrum Hamburg AK Altona, Hamburg, Germany

Background: Although CAIRO3 and AIO KRK 0207 trials have demonstrated the benefit of BV and fluoropyrimidine as M regimen after induction CT plus BV, the role of BV alone is not clear. Indeed, SAKK 41/06 and PRODIGE 9 trials failed to demonstrate the superiority of BV alone in comparison to no M, while AIO KRK 0207 showed the non-inferiority of BV alone vs combo M. Thus, in order to evaluate the magnitude of the eventual benefit of M with BV alone in comparison to no M, an IPD meta-analysis of randomized trials prospectively investigating such issue was performed

Patients and methods: Trials whereas mCRC pts were prospectively randomized to receive BV M or not were considered eligible. Primary end-points were Progression-Free and Overall Survival (PFS/OS), both from the start of induction and M. Univariate and multivariate analyses for PFS and OS were performed, with the following variables: baseline ECOG PS; age (> vs = 65 years); RAS and BRAF status; LDH and CEA baseline level; RR (PR or CR vs SD) during induction; induction CT (oxa- vs iri-based); resected primary tumor; primary tumor side; synchronous vs metachronous; adjuvant treatment; number of metastatic sites.

Results: IPD of 1,064 pts enrolled in the PRODIGE 9, AIO KRK 0207 and SAKK 41/06 trials were collected. Considering the different timing of randomization in PRODIGE 9 (at the start of induction) vs AIO KRK 0207 and SAKK 41/06 (at the start of M), IPD of pts not progressed during induction and starting M phase entered the analysis. 909 pts were included, 457 (50%) received BV M. Median PFS from induction start was 9.6 and 8.9 months in BV group vs no M group, respectively (HR 0.78; 95%CI: 0.68-0.89; p<0.0001). At the multivariate PFS analysis, BV M, resected primary tumor and number of m sites were significant. No difference in terms of OS between the two groups was observed.

Conclusions: This is the first IPD meta-analysis investigating the role of BV alone M vs no M after first-line induction CT plus BV in mCRC pts. Despite results demonstrated a significant PFS improvement in favor of BV M, the absolute benefit appears limited, and without a clear clinical relevance. Based on these findings, we can’t conclude that BV alone can be a M therapy option for the overall population, but we need to identify pts most likely to benefit from BV alone.

EFFICACY OF RETREATMENT WITH ANTI-EGFRS IN mCRC IS NOT PREDICTABLE BY CLINICAL FACTORS RELATED TO PRIOR LINES OF THERAPY: A MULTI-INSTITUTIONAL ANALYSIS

Zucchelli G.¹, Pagani F.², Pellino A.³, Dell’Aquila E.⁴, Liscia N.⁵, Bensi M.⁶, Germani M.M.⁷, Masi G.⁷, Moretto R.⁷, Santini D.⁴, Salvatore L.⁶, Scartozzi M.⁵, Lonardi S.⁸, Rossini D.⁷, Ongaro E.⁷, Vannini F.⁷, Colombo C.⁷, Falcone A.⁷, Pietrantonio F.⁹, Cremolini C.⁷

¹Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, PISA; ²Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; ³Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, IOV - IRCCS, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; ⁴Department of Medical Oncology, Campus Bio-Medico - University of Rome, Rome, Italy; ⁵Medical Oncology Department, University Hospital, University of Cagliari, Cagliari, Italy; ⁶Fondazione Policlinico Universitario A. Gemelli-IRCCS-UOC Oncologia Medica, Rome, Italy; ⁷Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; ⁸Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy; ⁹Medical Oncology Department, Fondazione IRCSS - Istituto Nazionale dei Tumori, Milan, Italy

Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1st-line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1st-line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need.

Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/BRAF wild-type status on tissue samples, who had received a 1st-line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1st-line; time from the last anti-EGFR administration to 1st-line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1st-line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1st-line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (=vs. < 18 mos).

Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.8 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.5 vs 5.0 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005).

Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.

TREATMENTS (TX) AFTER PROGRESSION TO FIRST-LINE FOLFOXIRI + BEVACIZUMAB (BEV) IN METASTATIC COLORECTAL CANCER (mCRC) PATIENTS (pts): A POOLED ANALYSIS OF TRIBE AND TRIBE-2 STUDIES BY GONO

Marmorino F.¹, Rossini D.¹, Lonardi S.², Santini D.³, Tomasello G.⁴, Aprile G.⁵, Moretto R.¹, Prete A.², Granetto C.⁶, Urbano F.⁷, Borelli B.¹, Zaniboni A.⁸, Randon G.⁹, Buonadonna A.¹⁰, Ritorto G.¹¹, Barbara C.¹², Latiano T.¹³, Bordonaro R.¹⁴, Antoniotti C.¹, Falcone A.¹, Cremolini C.¹

¹Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa; ²Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, IOV - IRCSS, Padova, Italy, Padova; ³Department of Medical Oncology, Campus Bio-Medico - University of Rome, Rome, Italy, Roma; ⁴Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy, Cremona; ⁵Medical Oncology Unit, ULSS8 Berica - East District, Vicenza, Italy, Vicenza; ⁶Oncologia Medica, Azienda Sanitaria Ospedaliera Santa Croce e Carle, Cuneo, Italy, Cuneo; ⁷Department of Radiological Science, Oncology and Patology, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy, Roma; ⁸Medical Oncology Unit, Poliambulanza Foundation, Brescia, Italy, Brescia; ⁹Medical Oncology Department, Fondazione IRCSS - Istituto Nazionale dei Tumori, Milan, Italy, Milano; ¹⁰Department of Clinical Oncology, Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy, Aviano; ¹¹SSD ColoRectal Cancer Unit Dipartimento di Oncologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy, Torino; ¹²UOC di Oncologia Medica, Ospedale di Livorno - Azienda USL Toscana Nord Ovest, Livorno, Italy, Livorno; ¹³Oncology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, San Giovanni Rotondo; ¹⁴Oncologia Medica, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy, Catania

Background: FOLFOXIRI + bev is regarded as a valuable option in the first-line tx of mCRC pts. A possible concern for the adoption is the feasibility and efficacy of tx after progression, and especially the reintroduction of the same agents used upfront. The aim of the study was to evaluate the efficacy of tx after progression among pts treated with first-line FOLFOXIRI + bev in the phase III TRIBE (NCT00719797) and TRIBE2 (NCT02339116) studies. The impact of the oxaliplatin and irinotecan free interval (OIFI), defined as the time from the last administration of oxaliplatin and irinotecan to disease progression, on the efficacy of tx after progression was also investigated.

Methods: Data about tx received after progression including 2^ndPFS (i.e. the time from 2^nd line tx start to disease progression or death) were collected. The efficacy of tx after progression according to the duration of the OIFI was explored. A cut-off value of 4 months was adopted

Results: Out of 586 pts treated with upfront FOLFOXIRI + bev, 520 progressed. Among 409 (79%) pts who received a tx after progression, 168 (41%) received FOLFOXIRI ± bev (Group A) and 241 (59%) received other tx (Group B), including FOLFOX or FOLFIRI ± bev or other agents not used in first line in 124 and 117 cases, respectively. Anti-EGFR moAbs were administered in 68 cases. Pts in Group A experienced significantly longer 2^nd PFS than pts in Group B (median 2^nd PFS: 6.1 vs 4.2, HR 0.76, 95%CI 0.62-0.94; p = 0.012). Pts with an OIFI ⩾ 4 mos (n = 279) had longer 2^nd PFS than those with an OIFI < 4 mos (n = 130) independently of the second-line tx (6.1 vs 3.7 mos: HR 0.54, 95% CI 0.42-0.69; p<0.001). In the subgroup of pts with an OIFI ⩾ 4 mos FOLFOXIRI ± bev (n = 125) was associated with longer 2^nd PFS compared to other tx (n = 154) (7.2 vs 5.5 mos; HR 0.75, 95% CI 0.58-0.97; p = 0.029). Conversely, in pts with an OIFI < 4 mos no significant difference was shown between Group A (n = 43) and B (n = 87) (4.4 vs 3.2; HR 0.94, 95% CI 0.65-1.36; p = 0.75).

Conclusions: Tx after progression to first-line FOLFOXIRI + bev were feasible. Pts with longer OIFI showed better 2^nd PFS and seemed to derive more benefit from the reintroduction of the triplet.

HOW TO DEAL WITH SECOND LINE DILEMMA IN METASTATIC COLORECTAL CANCER? A SYSTEMATIC REVIEW AND META-ANALYSIS

Galvano A.¹, Incorvaia L.¹, Badalamenti G.¹, Rizzo S.¹, Guarini A.¹, Cusenza S.¹, Castellana L.¹, Insalaco L.¹, Iacono F.¹, Gristina V.¹, Barraco N.¹, Calò V.¹, Cutaia S.¹, Castiglia M.¹, Fanale D.¹, Beretta G.², Marchiafava E.¹, Fulfaro F.¹, Bazan V.³, Russo A.¹

¹Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, A.O.U.P. “P. Giaccone” University Hospital, Palermo, Palermo; ²Humanitas Gavazzeni Research Hospital, Bergamo, Bergamo; ³Department of Biomedicine, Neuroscience and Advanced Diagnostics - BIND, University of Palermo, Palermo, Italy, Palermo

Background: Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy in combination with chemotherapy as second line for metastatic colorectal cancer (mCRC). However, there is still a paucity of evidence or guidelines suggesting the right sequential treatment in all RAS (KRAS/NRAS) wild type(wt) mCRC. Therefore, we aimed to evaluate the impact of these targeted therapies by reviewing literature data.

Methods: We used Cochrane, EMBASE and Medline databases to select phase III clinical trials containing efficacy and safety data about chemotherapy (CT) or CT + targeted agents combination (Anti-VEGF and Anti-EGFR) in second line mCRC setting. We performed direct comparisons to obtain pooled data for anti-VEGF + CT versus CT and anti-EGFR + CT versus CT comparisons. Then we performed indirect comparisons between anti-EGFR and Anti-VEGF. Outcomes were disease control rate (DCR), response rate (RR), progression-free survival (PFS), overall survival (OS) and most common G3-G5 toxicities.

Results: Eight eligible RCTs (6793 pts) were included: 5 studies compared anti-VEGF + CT and 3 anti-EGFR + CT combinations to CT. After direct comparisons, pooled indirect results showed significantly improved OS (HR 0.83, 95% CI 0.72 – 0.94) and DCR (HR 1.27, 95% CI 1.04 – 1.54) favouring anti-VEGF combinations in overall population; however, no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70 – 1.09). Additionally, anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31 – 0.96), showing a trend in all RAS wt patients (RR 0.63, 95% CI 0.48 – 0.83) too. Furthermore, no significant difference in PFS and DCR all RAS was registered. Anti-VEGF combination significantly increased the risk of asthenia difference (RR 1.34, 95% CI 1.03 – 1.75).

Conclusions: At our knowledge, our indirect comparisons between anti-VEGF and anti-EGFR combinations showed for the first time better OS and DCR for anti-VEGF combinations, whereas better RR is observed for anti-EGFR combinatory regimens, defining a role of both targeted agents in second line mCRC setting, according to mutational status, clinical conditions and toxicities.

RARE BRAF MUTATIONS (MTs) IN METASTATIC COLORECTAL CANCER (mCRC): A BI-INSTITUTIONAL RETROSPECTIVE ANALYSIS (REBUS STUDY)

Di Stefano B.¹, Calegari M.A.², Basso M.², Orlandi A.², Boccaccino A.², Lombardo F.³, Zurlo I.V.¹, Bensi M.¹, Camarda F.¹, Vivolo R.¹, Ribelli M.¹, Cocomazzi A.⁴, Martini M.⁴, Auriemma A.³, Pozzo C.², Bria E.², Salvatore L.², Tortora G.²

¹Università Cattolica del Sacro Cuore, Roma; ²Fondazione Policlinico Universitario A. Gemelli-IRCCS-UOC Oncologia Medica, Roma; ³Azienda Ospedaliera Universitaria Integrata, Verona; ⁴Fondazione Policlinico Universitario A. Gemelli-IRCCS-Istituto di Anatomia Patologica, Roma

Background: Recently, 3 classes of BRAF MTs have been described. BRAF V600 MTs, which identify mCRC with poor prognosis and not benefitting from anti-EGFR drugs, belong to class 1. Class 2 and 3 include BRAF non-V600 MTs, which occur in about 1-2% mCRC and are associated to favourable prognosis and specific clinicopathologic features. Class 2 and 3 differ in kinase activity and sensitivity to anti-EGFR: class 2 are activated and RAS-independent MTs; class 3 are kinase-dead and sensitive to inhibition of activated RAS. This study aims to retrospectively evaluate features and prognostic role of rare BRAF non-V600 compared to BRAF V600E MTs in mCRC pts treated at 2 Italian Institutions.

Methods: mCRC pts harboring BRAF MTs, assessed by means of NGS, pyrosequencing or RT-PCR, treated between Jan-13 and Dec-18 at 2 Italian Institutions, were retrospectively analyzed. Clinico-pathological and treatment characteristics and survival data were collected.

Results: 55 pts bearing BRAF MTs were identified. Of those, 46 (84%) harbored a V600E and 9 (16%) a non-V600 MT. Within the non-V600 group, 3 MTs (K601E, G469A, G469R) belonged to class 2, while 5 MTs (G466E, G466A, 2 D594G, D594N), belonged to class 3. One pt harboured a T599I MT, whose kinase activity is unknown. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided (p.017) and displayed a lower grade (p.045). In addition, non-V600 mCRC pts had a lower tumor burden (involving one metastatic site) (p.026) and underwent more frequently to resection of metastases with radical intent (77.7 vs 18%; p.000175). mOS was significantly longer in the non-V600 compared to the V600E group (61.3 vs 20.4 m; HR 0.41, 95%CI 0.18-0.93; p.05). No difference in activity and efficacy of anti-EGFR agents was observed between class 2 and 3.

Conclusions: Despite the small size of our retrospective analysis, the results were consistent with previous evidences. BRAF non-V600 MTs identified a subgroup of mCRC, differing both in terms of clinicopathologic characteristics and prognosis from BRAF V600 mCRC. Interestingly, the better prognostic features allowed more frequently radical resection of metastases, positively impacting on survival.

UPDATED RESULTS OF THE PHASE 2 TRUST TRIAL OF TOTAL NEOADJUVANT APPROACH IN LOCALLY ADVANCED RECTAL CANCER (LARC)

Masi G.¹, Vivaldi C.¹, Fornaro L.², Bergamo F.³, Marcucci L.⁴, Laliscia C.⁵, Pasqualetti F.⁵, Martignetti A.⁶, Castagna M.⁷, Alberti G.⁸, Boccaccino A.¹, Manfredi B.⁵, Balestri R.⁹, Musettini G.⁴, Cremolini C.¹, Daniel F.⁸, Puccini M.⁹, Galuppo S.¹⁰, Buccianti P.⁹, Falcone A.¹

¹Università di Pisa, Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa; ²Azienda Ospedaliera-Universitaria Pisana, UO Oncologia Medica 2, Pisa; ³Oncologia Medica 1, IOV - IRCCS, Padova; ⁴Azienda Toscana Nord Ovest, Oncologia Medica, Pontedera; ⁵Azienda Ospedaliera-Universitaria Pisana, UO Radioterapia, Pisa; ⁶Azienda Toscana Sud Est, Oncologia Medica, Poggibonsi; ⁷Università di Pisa, Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Pisa; ⁸Oncologia Medica 1, IOV - IRCCS; Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova; ⁹Azienda Ospedaliera-Universitaria Pisana, UO Chirurgia Generale, Pisa; ¹⁰Radioterapia, IOV - IRCCS, Padova

Background: Induction chemotherapy (CT) followed by chemoradiotherapy (CRT) represents a promising strategy in LARC. TRUST is a phase 2 trial in which LARC patients were treated with 6 cycles of induction with GONO FOLFOXIRI plus BV regimen followed by CRT plus BV and surgery with total mesorectal excision (TME). TRUST met its primary end-point with a 2-year disease-free survival (DFS) of 80.45% (Masi et al. EJC 2019). Neoadjuvant rectal (NAR) score is a composite short-term endpoint that seems to predict outcome in locally advanced rectal cancer treated with preoperative CRT. The aim of this analysis is to provide an update of DFS and overall survival (OS) at a longer follow up and to validate NAR score in TRUST cohort.

Materials and methods: NAR score was calculated as previously reported. The cT category of the NAR score formula was obtained from the MRI performed before induction chemotherapy. NAR was applied to 44 patients treated per-protocol. According to the score, patients were divided into low, intermediate, or high risk of relapse or death. For statistical analysis, we performed Kaplan-Meier curves, log-rank tests, and Cox regression analysis.

Results: 48 patients were included in per-protocol analysis; 45 completed CRT and 44 underwent surgery. After a median follow up of 60.6 months, 13 patients had experienced disease progression. Median DFS was not reached. Updated DFS at 2 and 3 years was 80.51% and 71.8%, respectively. Median OS was not reached and 3y-OS was 86.9%. Of the 44 patients undergoing surgery, NAR score was low (<8) in 22 patients (50%), intermediate (8-16) in 13 patients (29.5%) and high (>16) in 9 patients (20.5%). DFS was significantly better in patients with low NAR score (3y DFS: 95.4%) compared to those with intermediate (3y DFS: 54.5%, HR 0.133 [95% CI: 0.021-0.842]; p = 0.032) and high NAR score (3y DFS: 33.3%, HR 0.024 [95% CI: 0.004-0.145]; p<0.0001). The difference between intermediate and high NAR score in terms of DFS was not statistically significant (p = 0.097). Three-year OS was 100% in low NAR score compared to 84.6% (p = 0.09) in patients with intermediate and 75% (HR 0.093 [95% CI: 0.013-0.648]; p = 0.016) in those with high NAR score, respectively.

Conclusions: Effect of induction therapy with FOLFOXIRI plus BV followed by CRT plus BV seems promising at a longer follow up. We confirmed the prognostic role of NAR score in an independent cohort of patients treated with total neoadjuvant approach.

P53 EXPRESSION AND CLINICAL OUTCOME IN RAS/BRAF WILD TYPE METASTATIC COLORECTAL CANCER PATIENTS RECEIVING LATER-LINE IRINOTECAN-CETUXIMAB: A RETROSPECTIVE ANALYSIS

Lai E.¹, Loupakis F.², Ziranu P.¹, Schirripa M.³, Puzzoni M.¹, Demurtas L.¹, Liscia N.⁴, Pretta A.⁴, Mariani S.¹, Impera V.⁴, Soro P.¹, Musio F.¹, Camera S.⁴, Pusceddu V.¹, Astara G.¹, Giampieri R. ⁵, Zaniboni A.⁶, Fassan M.⁷, Lonardi S.⁸, Zagonel V.⁸, Scartozzi M.¹

¹Medical Oncology Unit, University Hospital and University of Cagliari, Italy, Cagliari; ²Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy, Padova; ³Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Padova; ⁴Medical Oncology, Sapienza-University of Rome, Italy; Medical Oncology Unit, University Hospital and University of Cagliari, Italy, Cagliari; ⁵Oncologia Clinica c/o Università Politecnica delle Marche, Dipartimento Scienze Cliniche e Molecolari - Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Italy, Ancona; ⁶Medical Oncology, Casa di Cura Poliambulanza, Brescia, Italy, Brescia; ⁷Department of Medicine and Surgical Pathology and Cytopathology Unit, University Hospital of Padova, Padova, Italy, Padova; ⁸Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy, Padova

Background: Preclinical and clinical data support that p53 might modulate the EGFR activity and as a consequence it might influence response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. In our study we evaluated the role of p53 expression in RAS/BRAF wild type (WT) metastatic colorectal (mCRC) patients (pts) receiving irinotecan-cetuximab by using a validation cohort.

Patients and methods: p53 immunohistochemical expression was retrospectively analysed in tumour samples of RAS/BRAF WT mCRC pts treated with second-third line irinotecan-cetuximab. Our aim was to evaluate the correlation between p53 expression and OS, PFS and RR. Statistical analysis was performed with the MedCalc package. Survival distribution was assessed by the Kaplan-Meyer method and comparison of survival curves was performed with log-rank test.

Results: Globally 120 RAS/BRAF WT mCRC pts were included in our analysis, 88 in the exploratory cohort and 32 in the validation cohort. 36/88 and 14/32 pts had p53 normal expression, whereas 52/88 and 18/32 showed p53 overexpression. In the exploratory cohort, RR was 61.1% in pts with p53 normal expression versus (vs) 3.8% in pts overexpressing p53 (p<0.0001); median OS (mOS) was 18 months in pts with normal p53 (95% CI 17-20) vs 8 months (95% CI 5.9-9; p<0.0001) and median PFS (mPFS) was 8 months in pts with p53 normal status (95% CI 6.98-8.10) vs 3 months in pts with abnormal p53 (95% CI 2.90-3.63; p<0.0001). These results were confirmed in the validation cohort: RR was 56.2% in pts with normal p53 and 43.7% in pts with abnormal p53 (p = 0.4830); mOS was 30.1 months in pts with p53 normal status (95% CI 22.42-53.31) vs 13.4 months in pts with p53 overexpression (95% CI 12.04-24.84; p = 0.03) and mPFS was 9.8 months in pts with normal p53 (95% CI 7.51-12.55) vs 7.9 months in pts with abnormal p53 (95% CI 5.32-8.21; p = 0.02).

Conclusions: In our study p53 normal expression was associated with better outcome in RAS/BRAF WT mCRC pts receiving irinotecan-cetuximab, as confirmed by the validation cohort. Further prospective studies are needed to validate the role of p53 in these pts and to investigate its cross-talk with EGFR.

METASTATIC COLORECTAL CANCER AND PIK3CA MUTATION: ASSOCIATION WITH CLINICO-PATHOLOGICAL FEATURES AND OUTCOME

Fanotto V.¹, Zucchelli G.², Germani M.M.², Rossini D.², Sensi E.³, Lupi C.³, Ugolini C.³, Antoniotti C.², Marmorino F.², Moretto R.², Boccaccino A.², Borelli B.², Conca V.², Ongaro E.⁴, Masi G.², Fontanini G.⁵, Falcone A.², Cremolini C.²

¹Department of Medicine (DAME), University of Udine, Udine; ²Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa; ³Unit of Pathology 3, Azienda Ospedaliero-Universitaria Pisana, Pisa; ⁴SOC Oncologia Medica e Prevenzione Oncologica, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano; ⁵Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Pisa

Background: Mutations in PIK3CA, an EGFR downstream effector, and the subsequent activation of AKT pathway plays an important role in colorectal carcinogenesis. Considering the frequent co-occurrence of PIK3CA and RAS mutations, conflicting data exist about its impact on prognosis of metastatic colorectal cancer (mCRC) patients (pts) and its predictive role to anti-EGFR therapy. However, PI3K inhibitors have been developed and are currently under investigation in mCRC.

Material and methods: Data from mCRC pts treated at Azienda Ospedaliero-Universitaria Pisana from 1 Jan 2005 to 31 Dec 2017, whose tumours had been analysed per clinical practice by means of MALDI-TOF MassArray were retrieved. Association between PIK3CA mutation and clinico-pathological features was analysed by χ2 test; OS curves were estimated with Kaplan-Meier method and compared by log-rank test.

Results: Tumours from 90 (17%) out of 542 pts included in the present analysis were PIK3CA mutated (mut), mostly in exon 9 (58.9%) or 20 (21.1%). Other mutations involved exon 1 (10%), 7 (3.3%), and 4 (2.2%); a double mutation was found in 4 pts: exon 1+20 (3.3%) and exon 1+7 (1.1%). Compared to PIK3CA wild-type (wt) tumours, mut ones were more often RAS mut (p = 0.006), MSI high (p = 0.008), and right-sided (p = 0.0004). Among 53 pts for whom PIK3CA status was available on both primary tumours and metastasis, the concordance was 92.4%. PIK3CA mutations were not associated with OS (36.4 vs 35.9 mos, HR 1.17, 95%CI 0.85-1.62, p = 0.3), with no difference among those affecting exon 9 and exon 20 (36.4 vs 27.5 mos, HR 0.77, 95%CI 0.39-1.54, p = 0.44). In RAS/BRAF wt (N = 188) and in RAS mut (N = 299) subgroup, no difference in terms of OS was reported between pts bearing PIK3CA mut and wt tumours (38.1 vs 44.4 mos, HR 1.22, 95%CI 0.60-2.48, p = 0.55 and 27.5 vs 34.4 mos, HR 1.26, 95%CI 0.85-1.86, p = 0.22, respectively), though PIK3CA mut had shorter OS. In BRAF mut subgroup (N = 54), PIK3CA mut pts had longer OS compared to PIK3CA wt (not reached vs 14.4 mo, HR 0.37, 95%CI 0.16-0.85, p = 0.09). Among 39 chemorefractory RAS/BRAF wt pts evaluable for response to an anti-EGFR agent, only 2 harboured exon 9 PIK3CA mutations and achieved stable disease.

Conclusions: PIK3CA mut tumours displayed specific clinico-pathological features and a strong concordance was found between primary tumours and paired metastases. Interestingly, a different impact on prognosis of PIK3CA mutation in RAS/BRAF wt, RAS mut or BRAF mut mCRC pts was observed and deserves validation.

IMPACT OF AGE AND GENDER ON SAFETY AND EFFICACY OF FIRST-LINE FOLFOXIRI/BEVACIZUMAB IN METASTATIC COLORECTAL CANCER: A POOLED ANALYSIS OF TRIBE AND TRIBE2 STUDIES

Moretto R.¹, Zucchelli G.², Marmorino F.², Rossini D.², Aprile G.³, Casagrande M.⁴, Lonardi S.⁵, Murgioni S.⁵, Dell’Aquila E.⁶, Tomasello G.⁷, Antoniotti C.², Urbano F.⁸, Ronzoni M.⁹, Zaniboni A.¹⁰, Manglaviti S.¹¹, Buonadonna A.¹², Ritorto G.¹³, Masi G.², Allegrini G.¹⁴, Falcone A.¹⁵, Cremolini C.¹⁵

¹Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa; ²Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa; ³Department of Oncology, San Bortolo General Hospital, ULSS8 Berica, Vicenza; ⁴Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Udine; ⁵Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova; ⁶Department of Medical Oncology, University Campus Biomedico, Roma; ⁷Oncology Department, ASST Ospedale di Cremona, Cremona; ⁸Department of Radiological Science, Oncology and Patology, Policlinico Umberto I, “Sapienza” University of Rome, Roma; ⁹Department of Oncology, IRCCS Ospedale San Raffaele, Milano; ¹⁰Medical Oncology Unit, Poliambulanza Foundation, Brescia; ¹¹Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; ¹²Medical Oncology Department, IRCCS, Aviano; ¹³SSD ColoRectal Cancer Unit Dipartimento Oncologia AOU Città della Salute e della Scienza, Torino; ¹⁴ Unit of Medical Oncology, Livorno Hospital, Azienda Toscana Nord Ovest, Livorno; ¹⁵ Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa

Background: FOLFOXIRI/bevacizumab (bev) is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 patients (pts) aged 18–70 years with ECOG-PS = 2 or between 71–75 years with an ECOG-PS = 0 were randomized to receive first-line FOLFOXIRI/bev or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bev. We aimed at assessing the effect of the intensification of the upfront chemotherapy (CT) (triplet versus doublets) in terms of safety and efficacy in pts aged<70 vs 70-75 years and in females vs males.

Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), CT-related and bev-related AEs were performed according to baseline age and gender.

Results: Among 1187 pts enrolled in TRIBE and TRIBE2 studies, 85% and 15% were aged<70 and 70-75 years respectively; 58% and 42% were males and females respectively. The benefit provided by the intensification of the upfront CT was independent of the age and gender subgroup in terms of both ORR (p for interaction >0.05 for age and gender) and PFS (p for interaction >0.05 for age and gender). In the safety population, the risk of overall and CT-related G3/4 AEs was increased with the triplet independently of age (p for interaction: 0.74 and 0.79) and gender (p for interaction: 0.63 and 0.33). Overall, pts aged 70-75 experienced a higher rate of overall G3/4 AEs (70% vs 57%, p<0.01) as compared with younger pts, and females had a significantly higher risk of overall G3/4 AEs compared with males (65% vs 55%, p<0.01). In the FOLFOXIRI/bev arm, elderly pts reported a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.02) and febrile neutropenia (16% vs 6%, p<0.01) than younger pts, while females had a higher risk to experience any grade of vomiting (50% vs 34%, p<0.01) and nausea (68% vs 59%, p = 0.03) as compared with males.

Conclusions: The activity and efficacy of FOLFOXIRI/bev are independent of gender and age, with a relative increase in the risk of overall and CT-related AEs similar among age and gender subgroups. However, elderly and females pts are more likely to experience AEs regardless of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bev, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluoruracil might be considered in this population. In females treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis.

DRUG HOLIDAYS FOR PATIENTS WITH METASTATIC COLORECTAL CANCER: ASSOCIATION TO OVERALL SURVIVAL

Garattini S.K.¹, Bonotto M.², Basile D.³, Porcu L.⁴, Ongaro E.⁵, Gerratana L.³, Cortiula F.⁶, Pelizzari G.⁷, Parnofiello A.⁸, Bertoli E.⁸, Cattaneo M.⁶, Lisanti C.⁷, Casagrande M.², Iacono D.², Cardellino G.G.², Buonadonna A.⁵, Aprile G.⁹, Pella N.², Puglisi F.⁷, Fasola G.²

¹ IRCCS CRO di Aviano-Oncologia Medica e Prevenzione Oncologica - Università di Udine, Dipartimento di Area Medica, Aviano (PN); ²Azienda Sanitaria Universitaria Integrata di Udine- Oncologia, Udine (UD); ³IRCCS CRO di Aviano-Oncologia Medica e Prevenzione Oncologica - Università di Udine, Dipartimento di Area Medica, Aviano (PN); ⁴IRCCS Istituto di ricerche farmacologiche Mario Negri- Laboratory Of Methodology For Clinical research-oncology, Milano (MI); ⁵IRCCS CRO di Aviano-Oncologia Medica e Prevenzione Oncologica, Aviano (PN); ⁶Azienda Sanitaria Universitaria Integrata di Udine- Oncologia- Università di Udine, Dipartimento di Area Medica, Udine (UD); ⁷IRCCS CRO di Aviano-Oncologia Medica e Prevenzione Oncologica- Università di Udine, Dipartimento di Area Medica, Aviano (PN); ⁸Azienda Sanitaria Universitaria Integrata di Udine- Oncologia - Università di Udine, Dipartimento di Area Medica, Udine (UD); ⁹ULSS8-Ospedale San Bortolo di Vicenza-Dipartimento Strutturale Oncologia Clinica Vicenza, Vicenza (VI)

Background: Patients with metastatatic colorectal cancer (mCRC) have improved their overall survival (OS), over the last decade. Patients with stable disease can currently undergo programmed temporary treatment discontinuations called drug holidays (DH), in order to limit toxicity. Since a full demonstration of OS benefit of continuous treatment over DH was not proven, we studied the real world association of DH to OS.

Patients and Methods: The study included 754 consecutive pts treated in first line for mCRC, at University Hospital of Udine and IRCCS CRO of Aviano from 1/1/2005 to 15/03/2017. A first line interruption of 56 or more days was considered a DH. We performed a uni- and multivariate Cox regression analyses to find association between DH and OS. Kaplan-Meier curves were used to estimate OS.

Results: Continuous treatment was given to 459 (60.9%) pts, while DH to 255 (33.8%) (5.3% missing data). Univariate analysis found associated to OS: KRAS (HR 1.39; 95%CI 1.17-1.66; p<0.001) and BRAF mutation (HR 1.39; 95%CI 1.02-1.90; p = 0.035), nodes (HR 1.92; 95%CI 1.49-2.46; p<0.001) peritoneum (HR 1.72; 95%CI 1.38-2.15; p<0.001), bone (HR 1.93; 95%CI 1.93; 1.02-3.64; pp = 0.043) and brain (HR 13.51; 95%CI 5.94-30.74; p<0.001) involvement, ECOG PS (1 vs 0: HR 1.84; 95%CI 1.35-2.50,p<0.001; 2 vs 0: HR 2.87; 95%CI 1.89-4.33, p<0.001), metastatic sites >1 (HR 1.61;95%CI 1.36-1.91; p<0.001), DH (HR 0.43; 95%CI 0.36-0.52; p<0.001), metastasectomy (HR 0.32; 95%CI 0.24-0.44; p<0.001), left sidedness (HR 0.70; 95%ICI 0.58-0.86; p<0.001), rectal tumor (HR 0.71; 95%CI 0.58-0.88; p = 0.002) and thermo-ablations (HR 0.34; 95%CI 0.25-0.47; p<0.001). After multivariate analysis, worst survival was associated to BRAF mutation (HR 1.82; 95%CI 1.15-2.87; p = 0.010); ECOG PS 1 (HR 2.08; 95%CI 1.29-3.35; p = 0.003) and 2 (HR 3.57; 95%IC 1.91-6.63; p<0.001). Better OS was associated to DH (HR 0.44; 95%CI 0.35-0.57; p<0.001), metastasectomy (HR 0.33; 95%CI 0.20-0.55; p<0.001), thermo-ablations (HR 0.44; 95%CI 0.28-0.70; p = 0.001) and left sidedness (HR 0.72; 95%CI 0.55-0.95; p = 0.018). After median follow-up of 68.6 months, median OS was 23.15 months. Interestingly, median OS was 35.3 months for DH and 18 months for continuous therapy.

Conclusions: In our study, DH seems to be an independent prognostic factor, suggesting that DH could be a safe treatment strategy in accurately selected patients.

OLD PATIENTS MANAGEMENT IN COLON-RECTAL CANCER POPULATION: A MONOCENTRIC EXPERIENCE

Balestra A.¹, Ballestrero A.¹, Tixi L.¹, Barbero V.¹, Zoppoli G.¹, Gallo M.¹, Stratta E.², Giannotti C.², Massobrio A.², Sparavigna M.², Alessandra A.², Scabini S.², Romairone E.², Murialdo R.¹

¹Department of Internal Medicine (Di.M.I.), University of Genoa and IRCCS AOU San Martino-IST, Genova; ²Oncologic Surgery and Implantable Systems Unit, Department of Emergency, IRCCS San Martino IST, Genova

Background: In patients (pts) aged over 70 years colon-rectal cancer (CRC) is the second cause of death. The Italian Society of Gerontology and Geriatrics (SIGG) proposes a new definition of old age for population due to prolongation of life expectancy. Now we can define as old people aged 75 years and over, in contrast with the previous threshold of 65 years. Unfortunately this part of population is poorly represented in clinical trials so data are poor. We report the experience of our oncology unit in the management of patients aged ⩾75 years underwent surgery for CRC.

Patients and Methods: We included 406 consecutive pts with diagnosis of CRC candidate for surgery (at least stage II) and evaluated in our institution between 2009 and 2018. Age of pts ranged from 75 to 92 years at the time of first visit. Patients were divided in two subgroups: group A (214 pts, aged 75-79) and group B (192 pts, aged = 80). Main subgroups characteristics are summarized in table below. 81 (38%) pts in group A and 72 (38%) in group B were candidate for adjuvant chemotherapy related to their tumor risk. From these 59 (73%) pts in group A received an adjuvant treatment versus 20 (10%) in the group B (p<0.0001). 27% vs 72% of pts in respectively group A and B didn’t perform adjuvant chemotherapy. The main causes of exclusion in group B were comorbidity/PS (71%) and patient refuse (25%). 52 (69%) out of 75 metastatic patients in group A started a first line treatment versus 22 (41%) out of 54 patients in group B (p = 0.0028). In the group B an higher proportion of patients didn’t start follow-up program: 31 (18%) in group A vs 68 (39%) in group B (p<0.0001).

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PATIENT CHARACTERISTICS	GROUP An. 214 (%)	GROUP Bn. 192 (%)
Gender M:F	129:91	108:88
Adjuvant chemo indication n. (%)	81 (38)	72 (38)
Adjuvant chemo performed n. (%)	59 (73)	20 (28)
Completed	45 (76)	15 (75)
Interrupted for toxicity	14 (24)	5 (15)
Metastatic patients n. (%)	75 (35)	54 (28)
Synchronous metastases	40 (53)	19 (35)
Metachronous metastases	35 (47)	35 (65)
First-line treatment performed	52 (69)	22 (41)
Follow-up not started	31 (18)	v

Conclusions: In old patient it’s important to consider comorbidities, PS and patient preferences in therapy decision making. Pts aged = 80 receive less adjuvant/ first line therapies and have a more drop-out in the follow-up respect younger counterpart. Age anyway remains an important factor to consider in decision-making.

AXL EXPRESSION IN PATIENTS WITH RAS WILD TYPE METASTATIC COLORECTAL CANCER IS PREDICTIVE OF POOR PROGNOSIS AND OF LACK OF EFFICACY OF BOTH ANTI-ANGIOGENIC AND ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR DRUGS

Cardone C.¹, Blauensteiner B.², Moreno-Viedma V.², Vitiello P.P.¹, Martini G.¹, Ciardiello D.¹, Simeon V.¹, Rachiglio A.M.³, Rizzi D.⁴, Maiello E.⁵, Latiano T.⁵, Cremolini C.⁶, Argilés G.⁷, Elez E.⁷, Falcone A.⁶, Tabernero J.⁷, Normanno N.⁸, Sibilia M.², Ciardiello F.¹, Martinelli E.¹

¹Università degli Studi della Campania “Luigi Vanvitelli”, Napoli; ²Medical University of Vienna, Vienna; ³National Cancer Institute ‘Fondazione Giovanni Pascale’ degli Studi della Campania, Napoli; ⁴GOIM office, Bari; ⁵Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo, S Giovanni Rotondo; ⁶Azienda Ospedaliero-Universitaria Pisana, Pisa; ⁷Vall d’Hebrón Institute of Oncology, Barcelona; ⁸National Cancer Institute ‘Fondazione Giovanni Pascale’, Napoli

Background: AXL receptor is a tyrosine kinase member of the TAM family, key mediator of epithelial to mesenchymal transition. AXL is overexpressed in several human cancers, including CRC (colorectal cancer).

Methods: AXL expression was evaluated by immunohistochemistry in tumor samples from 346 mCRC patients (pts) treated at three Institutions and enrolled in different clinical trials (CAPRI, MACBETH, MOMA, TRIBE2). In silico data of AXL RNA levels were obtained from GSE5851 dataset, including 80 pts with advanced mCRC treated with cetuximab in a later line.

Results: AXL expression in tumor was found in 61 out of 346 cases (18%), with no difference among RAS cohorts. In stroma, that was assessable in 334 samples, AXL was expressed in 268 cases (80%), with no difference in RAS groups.

In the RAS WT cohort, a worse mPFS was registered in AXL positive pts, whether treated with chemotherapy (CT) + anti-angiogenic agent [6.7 m (CI95% 8.9- 19.3) vs 14.1 m (CI95% 9.4– 13.0) p 0.007] or CT + anti-EGFR drug [6.2 m (CI95% 4.2- 8.2) vs 12.1 m (CI95% 10.6 – 13.6) p 0.012], whereas in RAS mutant pts no impact on PFS was observed. AXL expression in tumor cells correlated with worse mOS in both cohorts; notably, in RAS WT pts mOS was 19.9 m (CI95% 10.5- 29.2) vs 37.6 m (CI95% 31.1– 44.1) p 0.006.

AXL expression in stroma was associated with worse mOS in both cohorts [in RAS WT pts: 49.8m (CI95% 40.6 – 59.0) vs 33.5m (CI95% 29.3- 37.7) p 0.03; in RAS mutant: 35.5m (CI95% 24.2- 46.5) vs 24.7m (CI95% 21.8- 27.6) p 0.056)].

Intriguingly, taking into account AXL levels in both tumor and stroma, AXL double positive expression (+/+) correlated with shorter mOS; in particular, RAS WT pts (+/+) had a mOS of 19.9 m (CI95% 8.0- 31.7) vs (-/-) 50.1 m (CI95% 43.9- 56.2) p 0.004].

In silico analyses showed high AXL RNA levels in 50% of pts. Moreover, in this population treated with cetuximab in later line, in the KRAS exon2 WT cohort (N = 43) AXL high pts had worse mPFS [1.9 m (CI95% 1.7 -2.0) vs 3.8 m (CI95% 0.7-6.7) p 0.59].

Conclusions: AXL expression in tumor and stroma might have a negative prognostic relevance in mCRC, irrespective of RAS status. In RAS WT pts, AXL expression might represent a predictive biomarker of lack of efficacy for both anti-EGFR and anti-angiogenic agents.

A METABOLOMIC RECURRENCE SCORE AS PROGNOSTIC BIOMARKER IN ELDERLY PATIENTS (pts) WITH EARLY COLORECTAL CANCER (eCRC)

Di Donato S.¹, Vignoli A.², Mori E.¹, Malorni L.¹, Tenori L.², McCartney A.¹, Mottino G.³, Becheri D.³, Cantafio S.⁴, Ciarlo A.¹, Del Monte F.¹, Biagioni C.⁵, Di Leo A.¹, Luchinat C.⁶, Biganzoli L.¹

¹Medical Oncology Department, Nuovo Ospedale Santo Stefano, Prato; ²Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino; ³Geriatric Medicine Department, Nuovo Ospedale Santo Stefano, Prato; ⁴Surgery Department, Nuovo Ospedale Santo Stefano, Prato; ⁵Bioinformatics Unit, Medical Oncology Department, Nuovo Ospedale Santo Stefano, Prato; ⁶Magnetic Resonance Center (CERM), University of Florence, Prato

Background: Adjuvant management of eCRC is guided by pathological staging and risk stratification, but a significant proportion of pts who receive chemotherapy derive no benefit, particularly in elderly population. Metabolomics measures multiple cancer-related metabolites which may identify new prognostic and predictive biomarkers, potentially enabling a personalized approach to curative therapy.We have previously shown that serum metabolomics can separate pts with eCRC from pts with metastatic CRC (mCRC). In order to evaluate this potential prognostic role in eCRC, we performed a retrospective evaluation of serum metabolomics in a cohort of elderly pts with CRC.

Methods: Serum samples from a cohort of 103 pts aged = 70(55 with eCRC, 48 with mCRC) were pooled from four clinical trials (follow up: 5 years). Samples were retrospectively analyzed via proton nuclear magnetic resonance (1H NMR), to evaluate each metabolomic fingerprint. A Random Forest (RF) classification model was built using a training set of eCRC pts free from relapse at 5 years (N = 30) and all mCRC pts (N = 48). This model was then applied to a validation set made of the remaining eCRC pts (10 relapse-free; 15 with relapse). A risk-of-recurrence score was built on the basis of the likelihood of a sample being misclassified as metastatic.

Results: In the overall eCRC group, 44% (n = 24) received adjuvant chemotherapy. Over a quarter (27%; n = 15) experienced relapse. In the training set, the RF model split CRC from mCRC with an accuracy of 74.4%.The RF risk of recurrence score correlated with relapse, with an AUC of 0.754 in ROC analysis. By maximizing specificity and sensitivity in the training set, a threshold for the RF score was set at 0.55. In the validation set, using this threshold, an AUC of 0.727 in ROC analysis, and a prediction accuracy of 76% (73.3% sensitivity, 80% specificity) were obtained in predicting relapse.

Conclusions: Metabolomic fingerprinting of post-operative sera from elderly pts with eCRC identifies pts with higher risk of relapse with good accuracy. This may represent a tool to refine risk stratification in this population, to maximize the benefit from adjuvant chemotherapy. Analysis of an additional cohort drawn from a prospective trial of elderly pts is ongoing to confirm this data. Based on these results, a larger prospective, multicenter trial has recently opened to accrual (Liquid BIopsy and METabolomics in CRC- LIBIMET), with a focus on high-risk disease.

COLORECTAL CANCER LUNG-LIMITED METASTASIS: CLINICO-PATHOLOGICAL FEATURES AFFECTING PROGNOSIS, OUTCOME AND TREATMENT STRATEGY

Raffaella V.¹, Zurlo I.V.², Basso M.³, Salvatore L.³, Congedo M.T.⁴, Vita M.L.⁴, Petracca L.⁴, Calegari M.A.³, Di Stefano B.², Bensi M.², Pozzo C.³, Anghelone A.², Nachira D.⁴, Chiappetta M.⁴, Meacci E.⁴, Barone C.³, Cassano A.³, Margaritora S.⁴, Tortora G.³

¹Università Cattolica del Sacro Cuore, Oncologia Medica, Roma; ²Oncologia Medica, Università Cattolica del Sacro Cuore, Roma; ³Oncologia Medica, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Roma; ⁴Chirurgia Toracica, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma

Background: Unlike liver metastases, the role of surgery in colorectal cancer lung-limited metastasis (CCLM) is not yet established and data are still poor. We conducted a retrospective analysis to evaluate the management of CCLM at our Centre, prognostic factors and their impact on survival.

Material and method: We retrospectively analyzed patients (pts) with CCLM treated at our Institution from Jan-2006 to Jan-2019. Aim of the study was to evaluate the impact of clinical and pathological features on survival outcomes (DFS and OS). Differences were compared with the use of log-rank test andstatistically significant (p value <0.5) parameters at univariate analysis were included in the multivariate analysis.

Results: One-hundred and forty-four pts were included in the analysis. 70 pts received a preoperative chemotherapy (pCT), 56 an adjuvant chemotherapy (a)CT, while 18 underwent up-front surgery without CT. Seventy-three patients also received liver surgery, 57 before and 16 after lung surgery. In the whole population median DFS (mDFS) was 24 m (20-34) and median OS (mOS) 54 m (46-82), while mDFS and mOS were 20 m (13-34) and 53 m (33-82) for pts undergoing pCT and 23 m (15-31) and 65 m (42 – 204) for those receiving aCT respectively, without statistically significant differences. Among patients receiving both liver and lung surgery, mDFS and mOS were 21 and 54 months respectively. Age, gender, PS, disease-free interval (DFI) (> or <18 months), primary tumor sidedness, mucinous histology, grading, RAS status, timing of lung metastasis (metachronous vs synchronous), number of lesions (>2), metastasis location (uni vs bilateral) and liver resection were evaluated at univariate and multivariate analysis. At univariate analysis, DFS was correlated with DFI > 18m (p = 0.047), timing (p = 0.03) and number (p<0.0001) whereas OS was associated to number (p = 0.0005) and RAS status (p = 0.05). At multivariate analysis, number of lesions was the only factor correlated to DFS (p<0.0001) and OS (p = 0.0233).

Conclusions: Our study, although retrospective and small-sized, strongly suggests that surgery of lung metastasis prolongs survival, since mOS is much higher when compared to that of patients treated in a metastatic setting in phase III randomized studies. These data strengthen the role of a multidisciplinary management to allow pts with lung-limited metastasis to achieve surgery whenever possible, even regardless of previous liver surgery and RAS status.

AN ITALIAN OBSERVATIONAL, MULTICENTER, RETROSPECTIVE STUDY IN PATIENTS WITH STAGE IV RIGHT-SIDED COLON CANCER

Gelsomino F.¹, Garajovà I.², Spallanzani A.¹, Caputo F.¹, Lodesani M.¹, Santini C.¹, Andrikou K.¹, Salati M.¹, Bardasi C.¹, Cerma K.¹, Casadei Gardini A.¹, Tamberi S.³, Vecchiarelli S.⁴, Tamburini E.⁵, Pagan F.⁶, Frassineti L.⁶, Luppi G.¹, Cascinu S.¹

¹University Hospital of Modena, Division of Oncology, Modena; ²University Hospital of Parma, Parma; ³Degli Infermi Hospital, Oncology Unit, Faenza; ⁴S Maria delle Croci Hospital, Onco-Hematology Department, Ravenna; ⁵Rimini Hospital, Department of Medical Oncology, Rimini; ⁶IRST-IRCCS, Medical Oncology Unit, Meldola

Background: Colorectal cancer is one of the leading cause of cancer death worldwide. Recently, primary tumor location has emerged as one of the factor that may influence prognosis and treatment response in the metastatic setting. Right-sided tumors are less prevalent than left-sided counterpart and seem to be associated with worse survival and resistance to anti-EGFR therapy.

Methods: this retrospective analysis investigated clinical outcomes of a population of patients (pts) with advanced right-sided colon cancer. PFS and OS were compared between 3 groups (group 1 RAS mut/BRAF WT, group 2 RAS WT/BRAF mut, group 3 RAS WT/BRAF WT) by using log-rank test.

Results: 194 pts were included in the analysis. Median age was 66.6 y/o. 104 pts (53.6%) were RAS mut/BRAF WT, 43 (22.2%) were RAS WT/ BRAF mut and 47 (24.2) were RAS WT/BRAF WT. In first-line 93 (47.9%) pts were treated with chemo plus bevacizumab, 43 (22.2%) with chemo plus anti-EGFR and 58 (29.9%) with chemo alone. Globally, 75 (38.7%) pts had an objective response (OR), median PFS and OS were 8.5 and 19.9 months, respectively. No statistical differences were observed in OR rate, median PFS and OS between group 1 and 3, while pts in group 2 had inferior outcomes. 17/32 (53.1%) pts treated with anti-EGFR in first-line (group 3) had an OR. No statistical difference were observed in PFS and OS according to first-line treatment.

Discussion: a relevant proportion of pts were treated in a real-world setting with chemotherapy alone. This can be due both to clinical (performance status, older age) and economic reasons. A significant proportion of patients with metastatic right-sided colon cancer were RAS WT/BRAF WT. These patients seem to benefit from the use of anti-EGFR in term of OR, while the choice of first-line treatment does not have any impact on survival. These data could be of particular interest in patients with potentially resectable disease who need tumor shrinkage.

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Table.

Summary of results.

treatment	OR	Median PFS (months)	Median OS (months)
All patients	75/194 (38.7%)	8.5	19.8
Group 1	37/104 (35.5%)	9.5	22.3
Group 2	12/43 (27.9%)	6.0	13.4
Group 3	23/47 (48.9%)	8.0	19.2

HEMOSTATIC BIOMARKERS PREDICT PROGNOSIS IN PATIENTS WITH METASTATIC GASTROINTESTINAL CANCER: RESULTS FROM THE HYPERCAN STUDY

Marchetti M.¹, Giaccherini C.¹, Masci G.², Verzeroli C.¹, Russo L.¹, Celio L.³, Sarmiento R.⁴, Gamba S.¹, Tartari C.J.¹, Malighetti P.⁵, Spinelli D.⁵, Tondini C.¹, Giuliani F.⁶, Petrelli F.⁷, D’Alessio A.⁸, Gasparini G.⁴, Santoro A.², De Braud F.⁹, Labianca R.¹, Falanga A.¹

¹ASST Papa Giovanni XXIII, Bergamo; ²IRCCS Humanitas Institute, Rozzano; ³IRCCS National Cancer Institute, Milano; ⁴Hospital San Filippo Neri, Rome; ⁵University of Bergamo, Bergamo; ⁶IRCCS Cancer Institute Giovanni Paolo II, Bari; ⁷Hospital Treviglio-Caravaggio, Treviglio; ⁸Policlinico San Marco -Zingonia, Bergamo; ⁹IRCCS National Cancer Institute, Milan

Background: Laboratory evidence of hypercoagulability and high incidence of thromboembolic events are often associated with low response to chemotherapy and disease progression (DP) in patients with gastrointestinal (GI) cancer, particularly in metastatic condition. In a cohort of patients with newly diagnosed metastatic GI cancer participating to the HYPERCAN study (ClinicalTrials.gov ID#NCT02622815), we aimed to prospectically assess whether the pre-chemotherapy levels of thrombotic biomarkers may predict for resistance to first line chemotherapy.

Materials and Methods: The study cohort included 160 consecutive cancer patients (100 colorectal/60 gastric) with a median age of 65 (41-78) years. Clinical data were recorded at enrollment and during scheduled follow-up visits for at least two years. DP was monitored by imaging at each time point. Fibrinogen, D-Dimer, and thrombin generation (TG) were measured at diagnosis, before starting any curative chemotherapy. The study protocol has been approved by the local Ethics Committee. Informed written consent was obtained from all study subjects.

Results: At diagnosis, patients presented with a hypercoagulable state, as shown by significantly (p<0.01) higher plasma levels of fibrinogen, D-Dimer and by increased endogenous TG potential (ETP) as compared to healthy control subjects. In the cohort of patients, cumulative incidence of disease progression after six months of follow-up was 23.7% (CI 95% 17-30.1). Analysis of thrombotic biomarkers according to DP, showed that patients with DP (n = 38) were characterized by significantly (p<0.05) greater pre-chemotherapy levels of ETP compared to patients with no DP [2,050 vs 1,699 nM*min]. Furthermore, by multivariate Cox regression analysis, plasma levels of D-Dimer (HR = 1.08) and TG ETP (HR = 1.01), together with gastric cancer diagnosis (HR = 2.2), were identified as independent risk factors for DP.

Conclusions: Our data show that elevated levels of circulating thrombotic biomarkers and increased TG potential are associated with chemotherapy failure and DP in GI cancer patients. The possible role of these biomarkers for DP prediction is of utmost importance for treatment decision making and a more personalized approach to each patient. Further analysis are warrant to confirm the role of these biomarkers in DP prediction by a clinical risk assessment score model.

This project is funded by “5xMILLE” n. 12237 grant from the “Italian Association for Cancer Research (AIRC)”.

THE POTENTIAL PROGNOSTIC ROLE OF METABOLOMICS IN EARLY COLORECTAL CANCER (eCRC)

Mori E.¹, Vignoli A.², Ciarlo A.¹, Tenori L.², Malorni L.¹, Cantafio S.³, Romoli L.³, Zalla T.³, Biagioni C.⁴, Del Monte F.¹, Vitale S.¹, Biganzoli L.⁵, Di Leo A.¹, Luchinat C.², Di Donato S.¹

¹Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Prato; ²Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino; ³Surgery Department, Nuovo Ospedale-Santo Stefano, Prato; ⁴Bioinformatics Unit, Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Prato; ⁵Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Carmignano (PO)

Background: The prognosis of early colorectal cancer (eCRC) differs according to the stage of disease, informing the choice of adjuvant therapy. A significant proportion of patients (pts) who receive adjuvant chemotherapy derive no benefit from treatment. Therefore, biomarkers to improve risk stratification are urgently needed. Metabolomics allows to concurrently study multiple metabolites in body fluids, including serum. We used metabolomics to explore the potential prognostic role of metabolomic profiles in a prospective cohort of patients with eCRC (METCOLON Study).

Material and Methods: Pts with histologically proven stage I-III CRC, candidate for radical resection were prospectively enrolled in the study. Blood serum samples were taken from each patient before surgery (T0) and after surgery (T1) and these samples were analyzed using 1H-NMR spectroscopy to characterize the metabolomic profile. To investigate the differences of metabolomic profiles before and after surgery mPLS was applied.

Results: A total of 41 pts (11 stage I, 13 stage II, 17 stage III) were enrolled into the study between May 2017 and September 2018. At the time of the analysis pts median follow-up was 15 months. Tumor relapse was observed in 5 pts. Using the mPLS, serum samples were correctly classified between pre-operative (T0) and post-operative (T1), and showed significant differential clustering, with good separation of the two groups with the all 3 spectra CPMG, NOESY and DIFFUSION. Three metabolites were found to differ significantly (p < 0.05) between the pre- and post-operative metabolomic profiles: pyruvic acid was found higher in the T1 samples and the acetone and 3-hydroxybutyric acid in the T0 samples.

Conclusions: Metabolomic analysis correctly classifies pre- and post- operative serum samples of patients with eCRC, suggesting that this methodology can identify tumor-related specific metabolites with a potential role for biomarkers in the adjuvant setting. The limited number of observed relapse events prevents our possibility of inferring prognostic information. With further maturity of the data, we plan to correlate intra-patient differences in metabolomic spectra between T0 and T1 with clinical outcome. A larger prospective clinical trial testing the prognostic role of metabolomics in patients with early and metastatic CRC is currently ongoing (LiBiMet).

SAFETY AND EFFECTIVENESS OF REGORAFENIB (REG) IN ITALIAN PATIENTS WITH METASTATIC COLORECTAL CANCER (mCRC): A SUBGROUP ANALYSIS FROM THE PROSPECTIVE, OBSERVATIONAL CORRELATE STUDY

Bergamo F.¹, Falcone A.², Frassineti G.L.³, Biglietto M.⁴, Romano C.⁵, Montesarchio V.⁶, Bordonaro R.⁷, Morano F.⁸, Del Prete S.⁹, Merlano M.C.¹⁰, Cinieri S.¹¹, Amatu A.¹², Berardi R.¹³, Gebbia V.¹⁴, Sobrero A.¹⁵, Torresi U.¹⁶, Natoli C.¹⁷, Fiala-Buskies S.¹⁸, Ducreux M.¹⁹, Zaniboni A.²⁰

¹Istituto Veneto Oncologico (IOV)-IRCCS, Padova; ²Università di Pisa, Pisa; ³Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola; ⁴Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, Napoli; ⁵Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, Napoli; ⁶A. O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli; ⁷Presidio Ospedaliero Garibaldi, Catania; ⁸Fondazione IRCCS Istituo Nazionale Tumori, Milano; ⁹San Giovanni di Dio Hospital, Via Giovanni XXIII, Frattaminore; ¹⁰AO ‘S Croce e Carle’, Cuneo; ¹¹Ospedale San Antonio Perrino, Brindisi; ¹²Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano; ¹³Università Politecnica Marche, Ospedali Riuniti, Ancona; ¹⁴La Maddalena Cancer Clinic, Palermo; ¹⁵IRCCS Ospedale San Martino IST, Genova; ¹⁶Ospedale Generale Provinciale Macerata, Macerata; ¹⁷University G. d’Annunzio, Chieti; ¹⁸Bayer AG, Wuppertal; ¹⁹Gustave Roussy Cancer Campus Grand Paris, Villejuif; ²⁰Fondazione Poliambulanza, Brescia

Background: REG (160 mg daily, 3 weeks on/1 week off) is approved for the treatment of patients with mCRC refractory to standard therapies.CORRELATE (NCT02042144) evaluated the safety and effectiveness of REG for mCRC treatment in real-world clinical practice. Here we present the final results of the Italian patient subgroup.

Patients and methods: CORRELATE was a prospective, observational study conducted in 13 countries across Europe, Latin America, and Asia, and included patients with mCRC who were previously treated with approved therapies and for whom the decision to use REG was made by the treating physician according to the local health authority approval. The primary aim was to assess safety (treatment-emergent adverse events [TEAEs]; NCI-CTCAE v4.03). Secondary endpoints included overall survival (OS) and progression-free survival (PFS).

Results: Of 1037 patients, 193 (19%) were treated in 32 centers in Italy: 56% were male, the median age was 67 years (range: 30–84), most patientswere ECOG PS 0–1 (86%), and 62% had KRASmutations. Patients had received a median of 3 prior systemic treatments. The median REG treatment duration was 2.7 months (range: 0.03–13.4). The REG starting dose was 160 mg in 68% of patients, 120 mg in 18%, and 80 mg in 13%. Overall, 39% of patients had dose reductions,52% had an interruption/delay, while 33% had no dose modifications. Most dose modifications were due to AEs (69%). TEAEs of any grade and grade ⩾3 occurred in 94% and 59% of patients, respectively; REG related TEAEs of any grade and grade ⩾3 occurred in 78% and 39% of patients, respectively. The most common grade ⩾3 TEAEs were fatigue (15%), hypertension (10%), blood bilirubin increased (9%), and hand–foot skin reaction (8%). Grade 5 TEAEs occurred in 10% of patients, none of which were considered REG related. Median OS was 8.9 months (95% CI 6.5, not reached) and median PFS was 3.4 months (95% CI 3.1, 3.8).

Conclusions: The safety profile in this real-world, observational study was generally consistent with the known safety profile of REG in mCRC. Most patients started at the approved starting dose (160 mg/day). Outcomes were in the range of those previously observed in phase 3 trials.

Clinical trial registration: NCT02042144

EXOSOMES AS NOVEL PROGNOSTIC BIOMARKER IN POTENTIALLY RESECTABLE COLORECTAL CANCER LIVER METASTATIC (CCLM) PATIENTS

Zurlo I.V.¹, Di Salvatore M.², Lucchetti D.³, Colella F.⁴, Ricciardi Tenore C.⁴, Perelli L.⁴, Ferrucci M.⁵, Basso M.⁶, Vellone M.⁵, Calegari M.A.⁶, Salvatore L.⁶, Giuliante F.⁵, Cassano A.⁶, Pozzo C.⁶, Sgambato A.⁴, Tortora G.²

¹Università Cattolica del Sacro Cuore sede di Roma, Oncologia Medica, Roma; ²Oncologia Medica, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS., Roma; ³Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Roma, Italia, Roma; ⁴Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Roma; ⁵Unità di Chirurgia Epatobiliare, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Roma; ⁶Oncologia Medica, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Roma

Background: Target therapies and new surgical strategies deeply modify CCLM history. Several prognostic scoring systems have been developed but no one is able to identify patients (pts) who should be excluded from a potentially useless surgery. The current goal of research is to identify early biomarkers able to discern pts who could benefit from an aggressive approach. Exosomes are arising as promising biomarkers in cancer. The aim of this pivotal study was to analyze the association among exosome levels during CCLM-pts treatment, clinical outcomes and Kras status.

Material and Methods: We enrolled 22 pts with CCLM candidate to preoperative chemotherapy (pCT) and subsequent liver surgery. A blood sample was collected before pCT, after surgery, monthly during follow-up and at progression (PD). Exosomes were isolated by ultracentrifugation and characterized by standard methods. Exosomes concentration was assessed by Bradford assay. We adopted ddPCR™ KRAS G12/G13 Screening Kit to evaluate the status of Kras in exosomal DNA (e-DNA).

Results: 22 CCLM pts received pCT and underwent liver surgery: 5 major hepatectomies and 17 multiple liver resections. Changes in exosomes plasma levels were found to correlate with each treatment step, resulting reduced after pCT and surgery and increased at PD, respectively (p = 0.0026). Pts with higher baseline exosome levels experimented shorter PFS than those with lower levels (p = 0.0033 HR 0.2). No association was found between exosome levels after liver surgery and disease free interval nor overall survival. RAS status on e-DNA was evaluated on 10 pts in baseline, in pCT, after surgery, and in PD samples. In 8 out of 10 pts e-DNA displayed the same mutational status than the one detected on tumor DNA. Changes in e-DNA Kras copies were found statistically significant in pCT vs surgery and pCT vs PD (p = 0.039; p = 0.04).

Conclusion: Our study suggests a prognostic role of exosome levels in CCLM pts. Moreover, we showed that Kras mutational status could be monitored during the post-surgery follow up by analyzing e-DNA. Overall, our data confirm the potential role of exosomes in liquid biopsy tool to monitor molecular changes during the treatment of CCLM pts.

CORRELATION BETWEEN VALUES OF SPECIFIC BIOMARKERS AND OUTCOME IN METASTATIC COLORECTAL CANCER (mCRC) PATIENTS TREATED WITH REGORAFENIB

Ricci V.¹, Falletta A.², Granetto C.¹, Paccagnella M.², Abbona A.², Fea E.¹, Fabozzi T.³, Lo Nigro C.⁴, Merlano M.¹

¹Medical Oncology, Oncology Department, S. Croce & Carle Teaching Hospital Cuneo, Cuneo, Italy, Cuneo; ²Laboratory of Translational Oncology, Arco Cuneo Foundation, Cuneo, Italy, Cuneo; ³Medical Oncology, S.G. Bosco Hospital, Torino, Italy, Torino; ⁴SC Intercompany Analysis Laboratory, S. Croce & Carle Teaching Hospital Cuneo, Cuneo, Italy, Cuneo

Background: Regorafenib is an oral small-molecule multiple kinase inhibitor indicated as third-line treatment for metastatic colorectal cancer (mCRC) patients. Regorafenib has shown significant benefits in Overall Survival (OS) and Progression-Free Survival (PFS) compared to placebo in mCRC patients in two phase III trials. This study aims to evaluate the role of specific biomarkers potentially involved in the clinical activity of regorafenib.

Material and methods: We determined the concentration of 6 proteins of interest in plasma samples collected from 17 mCRC pts before starting regorafenib (baseline).The proteins selected are: VEGF, TNF-a, TGF-ß, CCL2, CCL4, and CCL5. They were analysed with ELISA test.The values obtained were compared with the values of 7 healthy controls, in order to evaluate the differences in the concentration of the cytokines examined. All analysis were performed using GraphPad (Version5). Additional ongoing analysis include other cytokines.

Results: We found that plasma basal level of TNF-α (P = 0.011), TGF-β (P = 0.031) and CCL-5 (P = 0.31) are significantly higher in Non responders compared to Responders (complete response n = 1, partial response n = 1 or Stable Disease SD n = 3). Moreover, plasma basal levels of CCL-4 are lower in NR compared to R patients. NR patients have also shown slightly higher level of VEGF and CCL-2 compared to R. Plasma concentration of VEGF, CCL-2, CCL-4, CCL-5 are higher in R compared to healthy controls. Furthermore, TGF-β negatively correlates with PFS (P = 0.038). According to ROC analysis, there was also improvement in PFS (5.2 vs. 2.57 months, P = 0.005). We observed also significant better OS in the same patterns (16.6 vs. 7.3 months, P = 0.010). These results might discriminate mCRC patients that will respond better to the treatment.

Conclusions: Our data show that in R pts the baseline cytokine signature approaches the values observed in healthy volunteers. On the contrary, pts that do not benefit by the treatment can be identified by a different cytokines profile. However, it must be stressed that our population is small and data should be verified on a larger number of pts. It might also be of interest to extend analysis to other cytokines and cells population not yet determined in our study.

PREDICTIVE AND PROGNOSTIC FACTORS IN LOCALLY ADVANCED RECTAL CANCER PATIENTS: A USEFUL TOOL FOR PERSONALIZED TREATMENT SELECTION?

Fenocchio E.¹, Filippi R.¹, Mazzetti S.¹, Giannini V.¹, Delmastro E.¹, Cauda S.¹, Bertotto I.¹, Lombardi P.¹, Quarà V.¹, Aimar G.¹, Milanesio M.¹, Ferraris R.¹, Rua F.¹, Regge D.¹, Aglietta M.¹, Leone F.²

¹Candiolo Cancer Institute FPO-IRCCS, Candiolo; ²Ospedale degli Infermi, Dipartimento di Oncologia Medica, Biella

Background: Neoadjuvant chemoradiation (CRT) is the standard treatment of locally advanced rectal cancer (LARC). However, although beneficial for most patients, a significant fraction derives no response from CRT. Knowledge of predictive and prognostic factors at the time of diagnosis is scant.

Methods: Data of LARC patients treated at Candiolo Cancer Institute between Oct 2010 and Apr 2017 were retrospectively analysed to assess the correlation of a diverse variables with median overall survival (OS) and with pathologic response to CRT assessed by Mandard tumor regression grade (TRG, considering TRG = 2 a good response and = 3 a poor response).

Clinicopathologic variables embraced age, sex, BMI, distance of the neoplasm from the anal margin (AM), standard pathological report, time interval between CRT and surgery, adjuvant chemotherapy, site of progression and pre- and post-CRT carcinoembryonic antigen (CEA), pre- CRT platelet count and neutrophil/lymphocyte ratio (NLR).

Radiological and nuclear variables - from pre- and post- CRT MRI and pre- CRT PET scan - included tumor circumferential extension, mesorectal fascia (MRF) involvement, metabolic volume (MV), total glycolytic volume (TGV) and median standardized uptake value (mSUV).

Results: Data from 75 clinical histories were retrieved; median follow-up was 36 months.

Age ⩽65 years (P = 0.02), pre-CRT MRI tumor circumferential extent ⩽50% (P = 0.01), pre-CRT CEA ⩽5.0 ng/ml (P = 0.015) and mSUV <4.9 (P = 0.03) independently predicted good response on multivariate analysis. On univariate analysis only, distance from AM>5 cm was a positive predictor, while MV>55 and TGV>215 predicted poor response.

Good responders (n = 28) experienced longer OS than poor responders (n = 47; P = 0.01). OS was 81, 79 and 41 months in TRG⩽2, 3 and 4 groups, respectively.

While the pathological finding of vascular invasion was significant on univariate only, post-CRT MRF involvement (P = 0.039), an elevated (>4) NLR (P = 0.037), grade = 3 tumor (P = 0.001) and positive resection margins (P = 0.01) retained a significant adverse prognostic impact on multivariate analysis.

Conclusions: To our knowledge, this is the first attempt to evaluate diverse classes of features for a prediction study in LARC. A limited number of predictors of response to CRT and a non-overlapping set of prognostic factors were identified. Upon validation on a larger dataset, these factors may help to personalize the therapeutic algorithm in LARC.

CHEMOTHERAPY-INDUCED CARDIOTOXICITY AND RISK FACTOR CORRELATION IN PATIENTS WITH COLORECTAL CANCER RECEIVING FLUOROPYRIMIDINE TREATMENT

Aimar G.¹, Lombardi P.¹, Bonzano A.¹, Depetris I.², Filippi R.¹, Elisabetta F.¹, Quarà V.¹, Milanesio M.¹, Ferraris R.¹, Cagnazzo C.³, Peraldo Neia C.¹, Basiricò M.¹, Cavalloni G.¹, Aglietta M.¹, Leone F.¹

¹Department of Oncology, University of Turin; Department of Medical Oncology, Candiolo Cancer Institute, FPO - IRCCS, Candiolo; ²Unit of Medical Oncology 1, Department of Oncology Veneto Institute of Oncology - IRCCS, Padova; ³Disattiva per: inglese Department of Oncology, University of Turin; S.C. Medical Oncology 1, A.O.U. Città della Salute e della Scienza, Molinette, Torino, Torino

Background: Fluoropyrimidines (FP), 5-fluorouracil (5-FU) and capecitabine, are essential agents in the treatment of colorectal cancer (CRC). Despite being considered well-tolerated drugs, cardiotoxicity represents a rare but potentially fatal adverse event. The reported incidence of cardiovascular (CV) events during 5-FU or capecitabine administration varies greatly among different studies in patients treated with FP. The most frequently reported symptoms are chest pain, palpitations, dyspnea and hypotension. The mere presence of these symptoms is sufficient in most studies to ascribe the case to fluoropyrimidine-induced cardiotoxicity (FIC). Moreover, the correlation between presence of CV risk factors (CV-RF) or cardiac comorbidity and incidence of FIC is not clear.

Primary objective: The aim of this study is to evaluate prospectively the incidence of FIC in cancer patients treated for the first time with FP and to identify predisposing risk factors.

Study design: FP-naïve CRC patients (pts) treated at our Institute were evaluated for CV-RF and preexisting CV comorbidities and treated before starting chemotherapy (CT). Patients were followed during FP treatment with seriated electrocardiograms, questionnaires on the symptoms and analysis of troponine I (TnI) and brain natriuretic peptide (BNP) measurements at day 1 and 3 of the first 3 cycles of CT (observation period).

Result: Data from the first 101 patients enrolled from January 2016 to April 2019 are presented 43.3% had 3 or more CV-RF (among BMI >25, smoker, heavy drinker and sedentary life-style) and 77,5% had at least one CV comorbidity at screening. During the treatment period 19 pts (18.8%) experienced FIC: 1 acute coronary syndrome (ACS), 1 coronary vasospasm, 1 paroxysmal supraventricular tachycardia (PSVT), 1 complete left bundle branch block (LBBB), 2 syncope, 4 typical chest pain, 6 sudden wheezing 3 sudden palpitations. After treatment of the CV events, only 3 pts discontinued FP (ACS, LBBB and PSTV). No further cardiac events occurred in patients who resumed treatment after being diagnosed with FIC. No difference in FIC incidence was observed according to sex or CT type (capecitabine vs 5-FU) (all Fisher’s exact test p>0.05).

Discussion: Preliminary data suggest the lack of excess risk of FIC in patients with CV-RF or cardiac comorbidities and the safety of the reintroduction of FP after a CV event.

LIQUID BIOPSY FOR RAS ASSESSMENT IN METASTATIC COLORECTAL CANCER (MCRC) PATIENTS USING HIGH-AFFINITY PLASMA DNA-BINDING MAGNETIC BEADS AND QUALITATIVE REAL-TIME PCR PRECEDED BY MUTANT ALLELE ENRICHMENT

Lucchetti J.¹, Formica V.¹, Doldo E.¹, Nardecchia A.¹, Morelli C.¹, Renzi N.¹, Iannantuono G.M.¹, Orlandi A.¹, Roselli M.¹

¹Policlinico Tor Vergata, Roma

Background: Plasmatic RAS testing of cancer cell free DNA is increasingly being used to rapidly assess mCRC mutational status and monitor biological evolution of the disease during the course of treatment.

Methods: Broadly available kits of plasma DNA-binding magnetic beads (MagCore® Plasma DNA Extraction Kit) and post-mutant allele enrichment qualitative Real-Time PCR for RAS mutations (EasyPGX® ready KRAS and NRAS Kit) were used to assess at baseline circulating RAS status and compare it to the gold standard (tumor tissue RAS status) in consecutive mCRC patients. Sensitivity, specificity and prognostic value of the liquid biopsy were determined. Either tissue or plasma BRAF mutated patients were excluded from the analysis

Results: Enrolled mCRC patients (n = 21, female 6, male 15) had a median age of 63 years (range 38-83), and were all candidate for first-line standard chemotherapy. According to liquid biopsy, the prevalence of RAS mutation was 33% (7 mutated cases = 3 of KRAS codon 12, 1 of KRAS codon 13, 1 of KRAS codon 61, 2 of NRAS codon 61). As compared to the gold standard of tissue mutations, only two cases of discordant results were observed (1 NRAS codon 61 mutation in the plasma but not in the tissue and 1 KRAS codon 13 mutation in the tissue but not in the plasma). All RAS concordant cases were also concordant for the specific RAS mutation subtype. Sensitivity and specificity of the liquid biopsy were 86% and 93%, respectively. Determined AUC was 0.893. Positive and negative Likelihood Ratios were 12.000 (1.772-81.261) and 0.154 (0.025-0.950), respectively. Positive and negative predictive values were 86% and 93%, respectively. After a median follow-up of surviving patients of 8.7 months, progression free survival (PFS) was shorter in liquid-biopsy defined RAS mutated patients as compared to wild type patients (median PFS 5.6 vs 9.8 months, respectively, Hazard Ratio 1.92, p value non significant because of the small sample size)

Conclusions: Liquid biopsy for RAS mutations using broadly available kits of high-affinity plasma DNA-binding magnetic beads and qualitative Real-Time PCR preceded by mutant allele enrichment was feasible and yielded high sensitivity and specificity testing performance. Liquid biopsy-determined RAS status was confirmed to be of prognostic value even though sample size needs further increase. The value for monitoring disease biological evolution requires further investigation.

TOXICITY SYNDROMES, PATIENT-RELATED CLINICAL INDICATOR OF TOXICITY BURDEN INDUCED BY INTENSIVE TRIPLET CHEMOTHERAPY-BASED REGIMENS IN METASTATIC GASTROINTESTINAL CANCERS

Bruera G.¹, Mastropietro S.², Dari Salisburgo L.², Cosenza P.², Ricevuto E.¹

¹Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy; Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy, L’Aquila; ²Short Hospitalization Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy, L’Aquila

Background: Cancer treatments induce symptoms/signs superimposing on clinical and cancer-related status of individual patient, determining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens developed in fit metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule including fluorouracil and weekly alternating irinotecan/oxaliplatin, to point out clinical relevance of integration of limiting TS (LTS).

Patients and methods: Metastatic colo-rectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making in real life phase II studies: FIr-B/FOx adding bevacizumab (B) in overall, FIr-C/FOx-C adding cetuximab (C) in KRAS/NRAS wild-type mCRC; FIr/FOx in mPDAC; FD/FOx adding docetaxel (D) in mGC. Toxicity, and individual LTS, classified as limiting toxicity alone (LTS-single site, LTS-ss) or associated to other limiting or G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated and compared by chi-square test. More, in FIr-C/FOx-C study, 5-fluorouracil/irinotecan pharmacogenomic biomarkers, specifically 5-fluorouracil degradation rate (5-FUDR), Single Nucleotide Polimorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated and related with LTS occurrence.

Results: FIr-B/FOx and FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, respectively showed activity, efficacy, limiting toxicities similar to reported triplet chemotherapy-based regimens. Reported LTS: in mCRC FIr-B/FOx 44%, LTS-ms 24% and LTS-ss 20%, in young elderly (yE) 46%, LTS-ms significantly increased vs LTS-ss; in KRAS/NRAS wild-type mCRC FIr-C/FOx-C 65.5%, significantly increased LTS-ms vs LTS-ss, in yE 83%; in mPDAC FIr/FOx 27.5%, mostly LTS-ms, in yE 38.4% all LTS-ms; in mGC FD/FOx 30%, all LTS-ms, in yE 25%. Reduced FUDR, SNPs CYP3A4, UGT1A1, >1 positive pharmacogenomic biomarkers were prevalent in patients with gastrointestinal LTS.

Conclusions: LTS met the need of an innovative clinical parameter of patient-related toxicity burden, indicating global and individual toxicity, including differential spectrum/intensities of TS related to cancer treatment, according to clinical status of individual patient. LTS integrated with conventional toxicity can also represent the proper indicator to evaluate predictive relevance of pharmacogenomic biomarkers to properly select patients fit for intensive medical treatments in mGI cancers, at risk of limiting gastrointestinal toxicity.

GENDER-RELATED CUT-OFF DEFINITION AND PROGNOSTIC ROLE OF MONOCYTE-TO-LYMPHOCYTE RATIO (MLR) IN METASTATIC COLORECTAL CANCER

Lisanti C.¹, Basile D.¹, Garattini S.K.¹, Parnofiello A.², Corvaja C.¹, Cortiula F.², Bartoletti M.¹, Cattaneo M.², Andreotti V.J.², Bertoli E.², Bortot L.¹, Ongaro E.³, Di Nardo P.³, Iacono D.⁴, Foltran L.³, Casagrande M.⁴, Cardellino G.G.⁴, Fasola G.⁴, Pella N.⁴, Buonadonna A.³, Puglisi F.³

¹Department of medical oncology and cancer prevention, IRCCS National Cancer Institute, Aviano (IT); Department of Medicine (DAME), University of Udine, Udine (IT), Aviano; ²Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, (IT); Department of Medicine (DAME), University of Udine, Udine, Udine; ³Department of medical oncology and cancer prevention, IRCCS National Cancer Institute, Aviano (IT), Aviano; ⁴Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, (IT), Udine

Background: Gender-related immune system composition influences immune response and, subsequently, efficacy of immunotherapy in cancer patients (pts). The purpose of this study is to investigate the gender-related prognostic role of MLR in metastatic colorectal cancer (mCRC) pts, defining at the same time a gender-specific cut-off value.

Material and methods: This retrospective study analyzed a consecutive cohort of 490 mCRC pts treated in 2004-2017 at the Oncology Departments of Aviano, Pordenone (training set) and Udine (validation set), Italy. Association analysis was explored by Chi-squared or Kruskal-Wallis test, as appropriate. The prognostic impact of MLR on overall survival (OS) was evaluated with uni- and multivariable Cox regression models. The best cut-off value to predict survival was determined through a ROC analysis.

Results: We identified 288 males and 202 females; 324 pts (67%) had a left-sided cancer and 161 (33%) a right-sided one. Sex was significantly associated with MLR (p = 0.004). The obtained cut-off value for MLR in females was 0.27 and in males was 0.49. Univariate analysis of the training set showed a poorer OS for females when MLR was >0.27 (HR 1.95, p = 0.003) and in males when MLR was >0.49 (HR 2.65, p = 0.010); this was confirmed in the validation set for the values of MLR >0.27 in females (HR 2.21, p = 0.010) and MLR >0.49 in males (HR 2.99, p = 0.002). Overall, high MLR was more frequently detected in females than in males (41% vs 9%). At univariate analysis on overall population, MLR >0.27 in females (HR 2.07, p⩽0.001), MLR >0.49 in males (HR 2.87, p ⩽0.001), KRAS (HR 1.37 p = 0.008) and BRAF mutations (HR 1.69 p = 0.009), sidedness (right vs left HR 1.59, p⩽0.001) and peritoneal metastases (HR 2.32, p⩽0.001) were associated with shorter OS. Conversely, primary tumor resection (HR 0.37 p⩽0.001) was associated with prolonged OS. Multivariate analysis confirmed the association of MLR >0.27 in females (HR 2.77, p = 0.002), MLR >0.49 in males (HR 5.39, p⩽0.001), BRAF mutation (HR 3.38, p⩽0.001) and peritoneal metastases (HR 2.50, p = 0.003) with worse OS.

Conclusions: Our findings suggest that the impact of high MLR as unfavorable independent prognostic factor is significant both in males and females. Higher MLR was found more frequently in females. Further prospective studies are needed to confirm these data.

SQUAMOUS CELL CARCINOMA ANTIGEN (SCCAG) AND CARCYNOEMBRIONIC ANTIGEN (CEA) AS PROGNOSTIC BIOMARKERS IN ANAL SQUAMOUS CELL CARCINOMA (ASCC): THE EXPERIENCE OF A SINGLE RESEARCH CANCER CENTER

Rotundo M.S.¹, Ravenda P.S.¹, Dell’Acqua V.¹, Surgo A.¹, Trovato C.¹, Bottiglieri L.¹, Bertani E.¹, Petz W.L.¹, Fazio N.¹, Zampino M.G.¹

¹Istituto Europeo di Oncologia, Milano

Background: Many efforts are ongoing to individuate biological characteristics suitable for targeting new medical approaches for ASCC. Currently different biomarkers emerged, but their ability to predict clinical outcome is still unclear. Among them, SCCAg firstly identified in malignant cervical tissue was also found in anal tumors, with conflicting data about its correlation with survival. Serum CEA level was evaluated also in patients with ASCC undergoing combined chemoradiotherapy, without demonstrating any correlation with outcome.

Patients and methods: We performed a retrospective study on 53 consecutive patients affected by non-metastatic ASCC and treated with cisplatin (CDDP) or mitomycin (MMC) plus 5-fluorouracil (5FU) or capecitabine (C) concomitant to pelvic Intensity-Modulated Radiation Therapy (IMRT) for curative intent, with the aim to evaluate the prognostic role of baseline SCCAg and CEA serum values in this setting.

Results: Patient characteristics are shown in Table 1. At a median follow up of 48 months, among 32 evaluable patients the Complete Response (CR) obtained at the 6-month time-point was 86% (25/29) in the group with normal basal CEA and 0% (0/3) in the group with high CEA (p = 0.007). Hazard ratios (HRs) resulted 0.30 for Disease-free Survival (DFS) (95% CI 0.02-3.41; p = 0.03) and 0.34 for Overall Survival (OS) (95% CI 0.01-8.65; p = 0.27) in favor of normal values, respectively.

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Table 1.

Patient characteristics for stage and biomarkers levels (N = 53).

	Normal CEA	High CEA	Normal SCCAg	High SCCAg	Normal CEA+ SCCAg	Normal CEA, high SCCAg	High CEA, normal SCCAg	High CEA+ SCCAg
stage
I	1 F (MMC-5FU)*	_____	1 F	_____	_____	1 M (C)*	_____	_____
II	1 M, 5 F	_____	6 F	3 F	1 M (C)*	_____	_____	_____
IIIA	1 M, 4 F	2 F	4 F	1 M, 1 F	1 M, 1 F	1 F	_____	_____
IIIB	5 F (1 MMC-C)*	1 F	3 F	2 F	1 F	6 F	_____	_____

*

All patients received CDDP-C except for 4 cases. F: female; M: male.

Among 33 evaluable patients, the CR at the 6-month time-point was 89% (16/18) in the group with normal basal SCCAg and 93% (14/15) in the group with high SCCAg (p = 1.0). HRs resulted 0.38 for DFS (95% CI 0.1-1.45; p = 0.13) and 0.10 for OS (0.006-1.69; p = 0.11) in favor of normal values.

Conclusions: SCCAg and CEA appear interesting biomarkers in ASCC and in our setting CEA levels more markedly seem to correlate with response and survival. Further prospective studies are necessary to confirm these observations.

PROGNOSTIC ROLE OF K-RAS MUTATION RATE IN STAGE II-III CRC PATIENTS

Imperatori M.¹, Marrucci E.¹, Formica V.², De Lisi D.¹, Catania G.¹, Spalato Ceruso M.¹, Dell’Aquila E.¹, Pantano F.¹, D’Onofrio L.¹, Armento G.¹, Stumbo L.¹, Grilli C.¹, La Cesa A.¹, Perrone G.³, Russano M.¹, Santini D.¹, Vincenzi B.¹, Tonini G.¹

¹Oncologia Medica, Università Campus Bio-Medico di Roma, Roma; ²Oncologia Medica, Università Tor Vergata, Roma; ³Anatomia Patologica, Università Campus Bio-Medico di Roma, Roma

Background: No data about the prognostic value of K-Ras mutation rate, defined as the percentage of mutated alleles/tumor sample, are available in stage II-III CRC, while it has been already investigated in metastatic stage. We aimed to retrospectively evaluate the correlation between K-Ras mutation rate and DFS in a cohort of relapsed K-Ras mutant stage II-III CRC pts.

Material and Methods: 80 relapsed stage II-III CRC patients from 2 Italian cancer centers were enrolled but only 66 patients (21 pts affected by radically resected rectal cancer and 45 colon cancer pts) were fully evaluable. K-Ras mutation rate was assessed in each center by pyrosequencing on tumor tissue specimen derived from resection of primary tumor. We investigated prognostic significance of different cut-off values of mutation rate corresponding to the first quartile, median value and 25%. Pts with less than 40% of cancer cells in tumor tissue were excluded.

Results: The median KRas mutation rate in the entire cohort was 36.75% and no significant correlation has been evidenced with DFS and OS at univariate analysis. We explored the prognostic role of K-Ras mutation rate according to different cut-offs. More in details, the univariate analysis revealed that CRC pts with K-Ras mutation rate < 29% (n = 15), corresponding to the first quartile cut off, had worse DFS comparing to pts = 29% (n = 51) (12.9 vs 18.3 months, log-rank p = 0.03); moreover CRC pts with KRas mutation rate < 25% (n = 11) maintained a worse DFS comparing to pts = 25% (n = 55) (12.3 Vs 19 months, log-rank p = 0.002). A subgroup univariate analysis exploring the value different cut-offs of K-Ras mutation rate in colon cancer pts (n = 45), who did not received any preoperative treatment, confirmed that low K-Ras mutation rates (< 29.55% or < 25%) correlate with worse DFS. There was no correlation between OS and the previously examined cut-offs.

Conclusions: Our retrospective study, for the first time in literature, showed that low K-Ras mutation rate could be a negative prognostic factor in K-Ras mutant stage II-III CRC pts. Moreover, low K-Ras mutation rate could represent an indirect estimation of high intratumoral stroma and mutational heterogeneity, which are interesting factors affecting prognosis of stage II and III CRC. These data deserve to be verified in larger studies.

RETROSPECTIVE STUDY ON REAL-WORLD USE OF REGORAFENIB IN COLORECTAL CANCER IN THE EMILIA-ROMAGNA REGION: CORE-GI-01 PRELIMINARY RESULTS

Banzi M.¹, Romagnani A.¹, Berselli A.¹, Tamberi S.², Frassoldati A.³, Luppi G.⁴, Di Battista M.⁵, Frassineti L.⁶, Di Fabio F.⁷, Pucci F.⁸, La Torre L.⁹, Bernardini I.¹⁰, Tassinari D.¹¹, Prati G.¹², Romagnani E.¹³, Cavanna L.¹⁴, Pinto C.¹⁵

¹Azienda USL-IRCCS di Reggio Emilia, S. C. di Oncologia Medica, Reggio Emilia; ²Azienda USL della Romagna, Ospedale di Faenza, U.O. di Oncologia Medica, Faenza; ³AOU di Ferrara, Arcispedale Sant’Anna, Ferrara; ⁴AOU Policlinico di Modena, Modena; ⁵Azienda USL di Bologna, Ospedale Bellaria, Oncologia Medica, Bologna; ⁶Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, U.O.C. Oncologia Medica, Meldola; ⁷AOU di Bologna, Policlinico S.Orsola-Malpighi, Bologna; ⁸AOU di Parma, Oncologia Medica, Parma; ⁹Azienda USL di Imola, Imola; ¹⁰Azienda USL di Modena, Ospedale di Carpi, Carpi; ¹¹Azienda USL di Rimini, U.O. Oncologia, Rimini; ¹²Azienda USL-IRCCS di Reggio Emilia, Ospedale di Guastalla, Guastalla; ¹³Azienda USL di Modena, Ospedale di Sassuolo, Sassuolo; ¹⁴Azienda USL di Piacenza, Ospedale, Piacenza; ¹⁵Azienda USL-IRCCS di Reggio Emilia, S.C. di Onoclogia Medica, Reggio Emilia

Background: Regorafenib is a multitargeted inhibitor that blocks angiogenesis, oncogenesis and stromal protein kinases and is approved for the treatment of colorectal cancer. To date there are limited data on the real-world adherence to treatment.

Methods: This is a multicentric retrospective study on patients (pts) with colorectal cancer previously treated with regorafenib in any setting in Emilia-Romagna Region. The aim of the study was to evaluate adherence to treatment, effectiveness and safety. Descriptive statistics are reported for patient/tumor/treatment characteristics, and observed Adverse Events (AEs) were graded by CTCAE v. 4.03. The Kaplan-Meier analysis was used for duration of treatment (DT) and overall survival (OS).

Results: 144 pts were treated from December 2013 and June 2017. Of these, 81.3% had non-mucinous histology, 45.1% had tumor located in left colon, 29.2% in rectum, 54.2% were KRAS mutated. Median age was 63 years (range 28-85), and 79.9% of pts had Performance Status 0-1. 68% of pts had liver metastasis. The median of previous systemic anticancer therapies was 2.6 (range from 1 to 5), and the trend shows that in 2016-2017 regorafenib was mostly used in third- and fourth-line treatment. Precisely 7% were in second-line, 47.6% third-line, 28.7% fourth-line, 11.9% fifth-line, and 4.9% sixth-line. 69.4% of pts started treatment at full dosage of 160mg/day, while 17.4% started at 120mg/day. There was no need for treatment reduction in 49.3% of pts. Patients reduced treatment due to all grades of toxicities: hand-foot syndrome (6.9%), fatigue (6.9%), diarrhea (6.2%), mucositis/stomatitis (4.2%). Treatment was interrupted due to disease progression (75.7%) and toxicity (8.3%). Median duration of treatment was 3.2 months (CI95% 2.7-3.8 months). Median overall survival was 5.5 months (CI95% 4.3-6.7 months). Grade 3-4 toxicities were experienced in 30.5% of patients. The most frequently observed G3-4 AEs include fatigue (6.9%), hand-foot syndrome (5.5%), and diarrhea (3.5%).

Conclusions: The frequency and severity of AEs were consistent with the known safety profile of regorafenib. OS was similar to reports of phase III trials. Over time, the management of adverse events in daily practice has improved. We learned to better select patients by anticipating the use of the drug in earlier lines. In this way, with the best management of adverse events, it was possible to avoid dose reductions at the beginning as well as in subsequent cycles.

ROLE OF GENETICS POLYMORPISMS OF MTHFR AND DPYD IN PREOPERATIVE CHEMO-RADIOTHERAPY FOR LOCAL ADVANCED RECTAL CANCER

Potì O.¹, Di Paola G.², De Giorgi D.¹, Mancarella S.³, Rizzo A.³

¹ASL Lecce, Copertino; ²ASL Lecce, Lecce; ³ASL Lecce, Galatina

Background: Radiotherapy and 5 FU based chemotherapy is the most common pre-operative regimen used for cT3-T4, N1 rectal cancer (RC). Evaluation of predictive markers of response and toxicity to radio-chemotherapy is a challenging approach to select the best chemotherapy or chemo-radiotherapy tratment for the individual patient (pz) and the best surgical tretment. In the present experience we have analyzed the predictive role of the genetic polymorfisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy.

Materials and methods: We have enrolled twenty- four patients with locally advanced RC treated with pre-operative radiotherapy and 5- fluorouracil based chemotherapy. Genetic polymorphisms of MTHFR C677T, MTHFRA 1298C, DPYD IVS 14+1G>A, DPYDA 2846T, DPYD T 1679 G, TSER 28 bp VNTR were analyzed by PCR and pyrosequensing of genomic DNA extracted from peripheral blood samples. This genetics markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response.

Results: Patients characteristics were: male 21 pts, female 3 pts, median age 66 years, ECOG PS 0-1 all pts. We found DPYD IVS 14+1 G>A G/G homozygous wilde type, DPYD A2846T, T/T homozygous wilde type and DPYD T1679 g, T/T homozygous wilde type in 100% of pts, homozygous wilde type MTHFR C677T in 15% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 70% of pts and homozygous wilde type MTHFR A 1298C in 40% of pts. G3-G4 advers events (diarrhea, neutropenia, asthenia, mucositis, bleeding) were observed in 50% of pts with heterozygous MTHFR A 1298C and in 10% of pts with homozygous mutated MTHFR C 677t. treated with chemo and/or chemo- radiotherapy combination. DPYD homozygous wilde type was not associated with severe toxicity. Rectal surgery with TME/TEM will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 13 clinical complete response and 11 partial clinical response. Adjuvant chemotherapy has been planned especially in patients with partial remission of disease and was well tolerated without G3-G4 adverse events. Ten pts with patological complete respose were treated with Transanal Endoscopic Microsurgery (TEM) and they are currently in close follow-up.

Conclusions: Concomitant assesment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative treatment approach for pts with locally advanced rectal cancer.

SURVEY ON TREATMENT WITH TAS 102 IN PATIENTS WITH METASTATIC COLORECTAL CANCER

Mare M.¹, Garofano N.^1,Adamo V.², Blasi L.³, Butera A.⁴, Chiarenza M.⁵, Colina P.⁶, Cordio S.⁷, Dottore A.⁸, Gebbia V.⁹, Lucenti A.¹⁰, Montalto E.¹¹, Parisi A.¹², Santangelo D.¹³, Scuderi C.¹⁴, Spada M.¹⁵, Tralongo P.¹⁶, Vigneri P.¹⁷, Vitello S.¹⁸, Giuffrida D.¹

¹Istituto Oncologico del Mediterraneo, Catania; ²Azienda ospedaliera Papardo, Messina; ³U. O.C. polo oncologico Ospedale Civico, Palermo; ⁴Ospedale S.Giovanni di Dio, Agrigento; ⁵Humanitas, Catania; ⁶Ospedale San Vincenzo, Taormina; ⁷Ospedale Garibaldi Nesima, Catania; ⁸Policlinico Universitario G.Martino, Messina; ⁹Ospedale La Maddalena, Palermo; ¹⁰Ospedale Sebastiano Ferrera Asp Ragusa, Ragusa; ¹¹Ospedale Caltagirone, Caltagirone; ¹²Ospedale Cannizzaro, Catania; ¹³Ospedale Sciacca, Sciacca; ¹⁴Clinica Morgagni, Catania; ¹⁵Fondazione Istituto G.Giglio, Cefalù; ¹⁶Ospedale Umberto I Siracusa, Siracusa; ¹⁷Policlinico Universitario V.Emanuele Catania, Catania; ¹⁸Ospedale Caltanissetta, Caltanissetta

Introduction: trifluridine/tipiracil (TAS102) is a new drug that has been shown to have a moderate activity and efficacy with an acceptable toxicity profile in the treatment of metastatic colon cancer beyond the second lines. In Sicily TAS102 has been used since July 2018. We conducted a survey in 18 Sicilian oncological centers to evaluate from July 2018 how oncologists employ this drug and which type of toxicity was experienced by patients (pts).

Materials and methods: we asked the oncologists to evaluate six questions: how many pts they have treated or are still on treatment with TAS 102, how many pts were over 75, how many pts received the drug on the third line, which drug they were more likely to use on the third line, which G3/G4 toxicity they have detected and which dose of TAS102 they use.

Results: The survey showed that in 18 centers 223 pts with mCRC received TAS102. 52% were over 75 years old (117), 60% (134) of the pts received the drug as third line. 89% of interviewed Sicilian oncologists prefer to use TAS 102 as third line (11% Regorafenib) and 67% of these start with the standard dose. Detected toxicity =G3 was mostly hematologic with neutropenia 38% and anemia 11%.

Conclusions: Thanks to this survey we have tested the Sicilian oncological network and it has been proved that TAS 102 is adequately and correctly used, although it was introduced later than in other Italian regions. No unexpected toxicity emerged from this real life experience on the use of this drug and it also seems to be well tolerated by elderly pts (over 75) who represent about half of the examined population.

CLINICOPATHOLOGICAL FEATURES IN RELATION TO TUMOR LOCATION IN ELDERLY PATIENTS (⩾ 70 YEARS OLD) WITH METASTATIC COLORECTAL CANCER (mCRC): A RETROSPECTIVE SINGLE-INSTITUTE ANALYSIS

Signorelli C.¹, Chilelli M.G.¹, Amodio P.M.², Macarone Palmieri R.², Ranalli T.V.³, Gomes V.V.³, Rosetto M.E.⁴, Ruggeri E.M.¹

¹Medical Oncology Unit, Belcolle Hospital, Viterbo; ²General Oncological Surgery, Belcolle Hospital, Viterbo; ³Pathology Unit, Belcolle Hospital, Viterbo; ⁴Radiotherapy Unit, Belcolle Hospital, Viterbo

Background: Aging is one of the factors we need to take into account in defining a comprehensive strategy of CRC treatment. Elderly patients (pts) with CRC tend to be under-presented in clinical trials and undertreated in clinical practice.

Materials and methods: We retrospectively reviewed the records of mCRC pts who underwent first-line therapy from 2011 to 2018 at our institute. We also examined the subgroup of pts aged ≥70 years. The aim was to analyse the correlation between the clinicopathological features and tumor location in terms of gender, RAS status, grading, T, N, adjuvant therapy, metastatic pts at diagnosis, chemotherapy regimens and monoclonal antibodies (Abs) use.

Results: Overall, 130 pts were considered eligible: 93 left-sided CRC (LCC) and 37 right-sided CRC (RCC). We analyzed the subgroup of pts aged 70 or over (36 pts) too: 15 RCC and 21 LCC. M/F = 19/17, median age 76 years (y) (70-82). 21 LCC (8 RAS-wt, 11 RAS-mut, 2 not tested) and 15 RCC (6 RAS-wt, 8 RAS-mt, 1 not tested). There were no significant differences in terms of grading and T3-T4 status (33.3% G3, 60.0% T3 and 26.6% T4 vs 38.0% G3, 61.9% T3 and 33.3% T4, respectively). The highest incidence of N+ in RCC pts was confirmed (86.6% vs 76.1%). We noted a higher percentage of LCC in elderly pts (58.3% vs 41.6%), particularly in the males (57.1% vs 46.6%) whereas a higher incidence of RCC was confirmed in the females (53.3% vs 42.8%). The principal tumor site was rectum-sigmoid junction (19.4%). There were no significant differences about metastatic pts at diagnosis (27.7% RCC vs 33.3% LCC) while 13.8% RCC pts vs 25% LCC pts underwent prior adjuvant therapy. Liver only metastases were more observed in RCC pts (40% vs 23.8%), liver + other metastases more in LCC pts (28.5% vs 13.3%); no differences about all the other metastatic sites (27.7% vs 33.3%) had been found. The most used chemotherapy regimens were doublets compared to fluoropyrimidines alone (particularly in LCC pts 85.7% vs 14.2%). Bevacizumab use has prevailed in both sides.

Conclusions: With the limit of the sample size, considering the increased fragility of elderly patients caused by multiple pathophysiological factors and comorbidities, our data confirm that age is not necessarily an absolute contraindication to adjuvant or palliative combination chemotherapy and the use of targeted therapies. Further studies are needed about tumor location in this population in order to develop a standardized treatment of elderly patients with CRC.

DEPARTMENT OF ONCOLOGY (DO) OF AZIENDA USL TOSCANA NORD OVEST (ATNO): TRIFLURIDINE/TIPIRACIL (T/T) (LONSURF ®) EXPERIENCE IN METASTATIC REFRACTORY COLORECTAL CANCER PATIENTS (mr-CRC-P)

Barbara C.¹, Cupini S.¹, Cirigliano G.², Caparello C.³, Del Freo A.⁴, Camerini A.⁵, Fontana E.⁶, Arrighi G.⁷, Biasco E.⁸, Farnesi A.¹, Finale C.¹, Masini L.C.¹, Bertolini I.⁶, Vivaldi F.⁹, Carissimi A.G.⁹, Cavazzana A.¹⁰, Marcucci L.⁷, Dargenio F.³, Mambrini A.⁴, Allegrini G.¹

¹Division of Medical Oncology Livorno Hospital,Department of Oncology ATNO, Livorno; ²Division of Medical Oncology Lucca Hospital,Department of Oncology ATNO, Lucca; ³Division of Medical Oncology Piombino Hospital,Department of Oncology ATNO, Piombino; ⁴Division of Medical Oncology Carrara Hospital,Department of Oncology ATNO, Carrara; ⁵Division of Medical Oncology Versilia Hospital,Department of Oncology ATNO, Versilia, Lido di Camaiore; ⁶Division of Medical Oncology Cecina Hospital,Department of Oncology ATNO, Cecina; ⁷Division of Medical Oncology Pontedera Hospital,Department of Oncology ATNO, Pontedera; ⁸Division of Medical Oncology Porto Ferraio Hospital,Department of Oncology ATNO, Porto Ferraio, Elba; ⁹Department of Drug, Division of Pharmacy, Apuane Hospital, Massa, Italy, ATNO, Massa; ¹⁰Division of Pathological Anatomy Carrara Hospital, Department of Pathological Anatomy ATNO, Carrara

Background: The DO of ATNO with its 5 Divisions of Medical Oncology, covers a catchment area of more than one million and three hundred thousand of people, over a third of the Tuscan population. The possibility of having a large and unique database allows for extensive analysis, crossing the data from the department of the drug and the pathological anatomy with those from clinical setting. In this report, we report our initial experience with T/T in an unselected population of mr-CRC-p.

Patients and methods: We considered the first group of patients treated with T/T. All patients included in this analysis were not candidates for further treatment with available therapies, due to a progressive disease within three months from the end of the last treatment.

Results: A total of 28 mr-CRC-p were included, 18 (64%) males and 10 (36%) females; median age was 67 years (range 30-80); performance status ranged between 0 and 1; median number of cycles was 2 (range 1-6); RAS mutation was in 12 (42%) patients. A stable disease was observed in 11 (39%) patients, a partial response in 3 (11%) and 14 (50%) patients experienced a progression of disease. Of note, the patients with the partial response were previous heavily treated with chemotherapies and refractory to fluoropyrmidines. Median progression-free survival was 2.5 months (range 1-7+); at median follow-up of 8,5 months, median overall survival was 7.5 months (range 2-9+). Treatment was generally well tolerated and T/T was interrupted only for a disease progression. G3 neutropenia was the most frequent adverse event, observed in 14 (50%) patients.

Conclusions: These results seem to confirm those reported in literature when mr-CRC-p are treated with T/T. However, more than 50% of patients interrupt treatment too early. So, more efforts needed to better select patients candidate to T/T. For this reason, taking into account that many other patients are expected to be treated in ATNO in a short time, we have planned a Next Generation Sequencing (NGS) analysis with a 45-gene panel to investigate possible molecular predictive factors to improve response to T/T.

PROGNOSTIC ROLE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO (NLR) AND PATHOLOGICAL RESPONSE (PR) IN LOCALLY ADVANCED RECTAL CANCER (LARC) TREATED WITH NEOADJUVANT CHEMORADIOTHERAPY (CRT)

Marino L.¹, Colarossi C.², Garofano N.², Forte S.³, Giannone G.², Giuffrida D.², Di Mattia P.², Munaò S.², Mare M.²

¹REM radioterapia, Viagrande (CT); ²Istituto oncologico del Mediterraneo, Viagrande (CT); ³Istituto Oncologico del Mediterraneo Ricerca (IOM Ricerca), Viagrande (CT)

Introduction: In Italy Colorectal cancer (CRC) is still one of the most common malignancy with 51.000 new cases observed in 2018. About 30% of these new cases are rectal cancers. Preoperative chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC) before surgery. Few studies have reported data of the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) in patients with rectal cancer. A lot of studies relates the raise of NLR to the poor survival of patients with rectal cancer (RC). Nowadays, the greatest number of scientific publications regards the Asian population. We retrospectively investigated the relationship between NLR and response to neoadjuvant treatment.

Material and methods: From July 2017 to April 2019 we consecutively treated 39 patients (pts) with LARC with capecitabine (825 mg/mq/bid) and concomitant RT. Subsequently patients received radical surgery. Baseline clinical and radiological staging was T4N0 for one patient (pt); T3 N1 for 17 pts, T3N0 for 18pts, T2N1 1 pt and T2N0 for 2 pts. Before starting CRT (baseline), we collect white blood cell count (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). NLR was calculated as ANC/ALC. NLR = 3 was defined high. NLR was related to patological tumor response (sec.AJCC/CAP). We made a comparison between pre-CRT NLR and post-CRT NLR, gathering pts in four subgroups.

Results: At baseline NLR was < 3 in 24/39 (62%) and a NLR = 3 15/39 (38%) respectively. A 0 TRG was recorded for 7 pts with NLR = 3 (46%) and for 13 pts with NLR < 3 (54%). The percentage of lymphocytes in the total WBC population was higher in pts with pCR than that without pCR. One pt with NLR = 6 showed disease progression, in this case percentage of lymphocytes was low (13%).

Conclusions: Our data suggest that baseline low NLR could be an indication of a good pathological response but our cohort is too small to have statistical relevance. Other studies with numerous samples are needed to validate the prognostic meaning of NLR as prognostic marker in pts with LARC who received CRT.

CIRCULATING-FREE DNA ANALYSIS FROM LONG-TERM SURVIVING METASTATIC COLORECTAL CANCER PATIENTS UNDERGOING SURGERY FOR RESECTABLE DISEASE

Ghidini M.¹, Hahne J.C.², Senti C.¹, Lampis A.², Ratti M.¹, Pizzo C.¹, Gobbi A.¹, Tomasello G.³, Passalacqua R.¹, Valeri N.²

¹Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy; ²Institute of Cancer Research, Sutton, Surrey, United Kingdom; ³Oncologia Falck, Niguarda Cancer Center, Milano, Italy

Background: Liquid biopsies (LB) allow monitoring of genetically different and co-occurring cancer cell clones present in primary tumor and all metastatic sites in parallel. In metastatic colorectal cancer (mCRC), circulating-free DNA (cfDNA) can be relevant for monitoring treatment and identification of molecular alterations resulting in disease relapse often earlier than radiological examinations.

Patients and methods: Patients with mCRC at diagnosis and treated with chemotherapy (CT) in combination with antibodies (bevacizumab, cetuximab or panitumumab) before undergoing surgery for resectable disease were included in this study. LB were collected before therapy start, every four weeks during treatment, within ten days of radiological disease evaluation, at radiological relapse and until two months after relapse. Next generation sequencing based on plasma samples was performed (testing for mutations and copy number variations covering 77 genes).

Results: From February 2016 to October 2018, 14 patients having surgery after first line treatment were included herein; median follow-up was 21.5 months. Five of them had RAS wild-type disease and received CT plus anti-EGFR treatment, while nine RAS mutated mCRC patients received bevacizumab. Surgery was radical in 10 cases, with no further treatment. In four cases, surgery was not radical and required further treatment. Disease relapse happened in seven cases, with subsequent death in three cases. In six out of seven cases, gene alterations were already detected in the pre-operative cfDNA. In the seven cases without disease relapse, gene variants were detected even after the surgery in two patients despite receiving radical resection. Median number of gene variants was two. Beside the well-established mutations in TP53 gene, both APC and ROS1 gene mutations were frequent, while further evaluations are required for the other variants detected.

Conclusion(s): Evaluation of cfDNA mutations in LB from mCRC may be a useful tool for monitoring clinical response and predict treatment outcome. Moreover, this molecular analysis can help to subgroup patients with regard to risk of relapse after radical surgery. Indeed, cfDNA mutations present before surgery seem to be an indication for a higher risk of post-surgery disease relapse.

CDX2 PROGNOSTIC VALUE IN STAGE II/III RESECTED COLON CANCER IN ELDERLY PATIENTS

Toma I.¹, Lerda L.², Carandina I.², Daniel F.², Galli G.², Martella L.R.², Lancia F.², Lanza G.², Frassoldati A.²

¹Arcispedale S. Anna, Ferrara; ²Arcispedale S. Anna, Ferrara

Background: Loss of CDX2 expression has been proposed as a prognostic biomarker in patients (pts) with stage II and III colorectal cancer (CRC). The elderly population is poorly represented in large randomized trials, due to specific characteristics of geriatric patients: comorbidities, concomitant therapies, poor adherence to therapy and increased risk of developing toxicity. The aim of his study is the assessment of the impact of CDX2 on the prognosis of elderly pts with stage II and III CRC and the assessment of the impact of the loss of CDX2 expression on the efficacy of adjuvant therapy.

Patients and methods: We retrospectively reviewed clinical data on pts with stage II-III CRC treated with adjuvant chemotherapy or with exclusive follow up in Clinical Oncology Unit of the University Hospital of Ferrara. The immunohistochemical analysis of CDX2 expression was performed using a specific monoclonal antibody. Cases classified as CDX2 + had an intense nuclear signal in all or almost all the tumor cells, while the negative cases had complete absence or a weak signal which was present in few cells. We performed survival analysis with a univariate analysis according to the Kaplan-Meier method. In addition, a multivariate analysis was performed to confirm the independent prognostic value of the statistically significant data.

Results: We conducted an analysis on 98pts aged 65 or older with stage II-III CRC. 77 pts were treated with adjuvant chemotherapy between January 2010 and December 2014.

A group of 8 of 98 tumor samples (8,2%) lacked CDX2 expression. Thecorrelation with Loss of CDX2 expression in the univariate analysis is associated with DFS (p <0.0001) and OS (p <0.034); the multivariate analysis confirmed CDX2 as an independent prognostic factor for survival ( p<0.05). Subpopulation analysis of stage III CRC pts treated with adjuvant chemotherapy, showed a significant worsening in DFS (p <0.0001) and OS (p <0.039) in patients CDX2- negative.

Conclusions: Lack of CDX2 expression can be considered an adverse prognostic factor in the elderly pts with stage II-III CRC. CDX2 would also appear to be a bad prognostic factor in OS in stage III patients undergoing chemotherapy. It indicates a cohort in which innovative treatments must be developed, or where the utility of adjuvant treatment may be questioned. The latter hypothesis must also be supported by an analysis of the prognostic value of CDX2 by randomized studies.

HIGH-DOSE CONFORMAL RADIATION THERAPY IN REFRACTORY METASTATIC COLORECTAL CANCER

Santoro M.¹, Molinaro M.², Scalzo C.², Prantera T.³

¹Operative Unity of Medical Oncology, Hospital N. Giannettasio, ROSSANO; ² Operative Unity of Radiation Oncology, AOPC, CATANZARO; ³ Operative Unity of Medical Oncology, Hospital S. Giovanni di Dio, CROTONE

Background:, In this study we have retrospectively analyzed the survival and relapse free-survival after high-dose radiation in patients with unresectable intrahepatic metastatis in refractory metastatic colorectal cancer.

Material and Methods: Between May 2016 and December 2018, 12 patients with unresectable chemotherapy-refractory metastatic colorectal cancer have been treated at the Department of Hemato-Oncology, AOPC, Catanzaro and at Operative Unity of Medical Oncology, Hospital N.Giannettasio, Rossano ASP Cosenza, Three-dimensional conformal high-dose radiation therapy was delivered in 12 patients, The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15% Figg 1,2).

Results: The median radiation dose delivered was 5000 cGy (1.25-Gy fractions bid). At a median follow-up time of 11 months (22 months in patients who were alive) the median survival was 11.8 months (95% CI, 10.3 to 15.3 months). The actuarial 2-year survival was 11%. The total dose was the only significant predictor of survival. Overall toxicity was acceptable, with 3 patients (21%) and 1 patients (8%) developing grade 3 and 4 toxicity, respectively.

Conclusions: The results suggest that high-dose focal liver irradiation prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer. This provides a rationale for intensification of local therapy for integration of this regimen with newer systemic therapy for patients with metastatic/refractory colorectal cancer.

REAL LIFE EXPERIENCE ABOUT THE USE OF TAS-102 AND REGORAFENIB IN THE DAILY CLINICAL PRACTICE FOR PATIENTS WITH REFRACTORY METASTATIC COLORECTAL CANCER

Bustreo S.¹, Fanchini L.², Ritorto G.², Spadi R.³, Racca P.²

¹Oncologia Medica 1, Colorectal Cancer Unit, A. O.U. Città della Salute e della Scienza, Torino; ²Colorectal Cancer Unit, A.O.U. Città della Salute e della Scienza, Torino, Torino; ³Oncologia Medica 1, Colorectal Cancer Unit, A.O.U. Città della Salute e della Scienza, Torino, Torino

Background: TAS 102 and Regorafenib showed to be superior to placebo plus best supportive care in refractory metastatic colorectal cancer (mCRC) and these drugs appeared to have similar efficacy but a different toxicity profile. No studies have directly compared both drugs. Giving the lack of standard options, we performed a retrospective analysis of our clinical experience in the use of TAS 102 and Regorafenib in the treatment of patients with refractory mCRC. Here we report the efficacy and safety of these two drugs in a series of refractory mCRC patients treated at our Colorectal Cancer Unit.

Patients and methods: Patient’s data and data about response rate and toxicities were collected from December 2016 to January 2019. A retrospective analysis was conducted on 38 consecutive mCRC patients. 25 (66%) were treated with TAS 102 and 13 (34%) were treated with Regorafenib. Median age was 60 yrs. Male/Female 23 (60%)/ 15 (40%). PS ECOG 0 70%, PS ECOG 1 30%. 28 (74%) patients received active 3L and 10 (26%) patients 4L treatment prior TAS-102 or Regorafenib.

Results: Globally since 2016, 38 patients received TAS 102 or Regorafenib at our Colorectal Cancer Unit for refractory mCRC. A median of three cycles per patient were administered.

We observed in term of hematological toxicity neutropenia grade 3-4 in 10 (26%) patients. The most frequent non hematological toxicities were: decreased appetite G3/4 in 4 (10%) patients, fatigue G3/4 in 5 (13%) patients and HFSy G3/4 in 3 (8%). Any treatment related deaths have been observed. There were 1 patient (3%) that achieved partial response, while 4 (10%) patients showed stable disease and 33 (87%) had progressive disease. Median time to progression was 2,8 months.

Conclusions: Our results suggest that TAS-102 or Regorafenib represent a possible option of palliative treatment in daily clinical practice for fit “trials ineligible” patients with refractory pretreated mCRC. The use of these drugs in this advanced setting can bring a clinical benefit and the choice among them must take into account their different toxicity profile.

RANDOMIZED PHASE 3 STUDY OF ADJUVANT CHEMOTHERAPY WITH FOLFOXIRI COMPARED TO GEMCITABINE IN RESECTED PANCREATIC CANCER: THE “GRUPPO ITALIANO PANCREAS” GIP-2 STUDY

Vasile E.¹, Vivaldi C.¹, Bianco R.², Lonardi S.³, Di Donato S.⁴, Brugnatelli S.⁵, Latiano T.⁶, Mosconi S.⁷, De Vita F.⁸, Cinieri S.⁹, Berardi R.¹⁰, Silvestris N.¹¹, Ricci V.¹², Tonini G.¹³, Andreotti V.J.¹⁴, Boni L.¹⁵, Labianca R.¹⁶, Di Costanzo F.¹⁷, Maiello E.¹⁸, Falcone A.¹⁹

¹Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Pisa; ²Dipartimento di Medicina Clinica e Chirurgia, UOC Oncologia Medica, Università Federico II, Napoli; ³SC Oncologia Medica 1, Dip. Oncologia Clinica e Sperimentale, Istituto Oncologico Veneto IRCCS, Padova; ⁴SOC Oncologia Medica, Nuovo Ospedale di Prato, Azienda USL Centro Toscana, Prato; ⁵SC Oncologia, Fondazione IRCCS Policlinico San Matteo, Pavia; ⁶SC Oncologia Medica, Casa Sollievo della Sofferenza, San Giovanni Rotondo; ⁷Oncologia Medica, ASST Papa Giovanni XXIII, Bergamo; ⁸Oncologia Medica, Università Luigi Vanvitelli, Napoli; ⁹Oncologia Medica, Ospedale Senatore Antonio Perrino, Brindisi; ¹⁰Oncologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona; ¹¹Oncologia Medica, Istituto IRCCS Giovanni Paolo II, Bari; ¹²SC Oncologia Medica, AO S. Croce e Carle, Cuneo; ¹³Oncologia Medica, Università Campus Bio-Medico, Roma; ¹⁴Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata, Udine; ¹⁵Clinical Trial Center, Azienda Ospedaliero-Universitaria Careggi, Firenze; ¹⁶Oncologia Medica, ASST Papa Giovanni XXIII and GISCAD, Bergamo; ¹⁷FICOG (Federation of Italian Cooperative Oncology Groups) and GOIRC, Firenze; ¹⁸SC Oncologia Medica, Casa Sollievo della Sofferenza and GOIM, San Giovanni Rotondo; ¹⁹Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana and GONO, Pisa

Background: Even at early stage, 80-90% of resected pancreatic cancer patients show recurrence. Adjuvant gemcitabine increases the probability of cure of about 10-15%. FOLFIRINOX prolonged survival compared to gemcitabine in metastatic pancreatic cancer patients and, recently, also in adjuvant setting. FOLFOXIRI demonstrated activity also in this setting. The phase 3 multicenter randomized national GIP-2 trial (NCT02355119) aimed therefore to evaluate FOLFOXIRI as adjuvant treatment in resected pancreatic cancer.

Methods: Patients aged 18-75 years, with ECOG PS 0-1, radically resected pancreatic adenocarcinoma and Ca19.9 = 2.5 x ULN were randomized 1:1 within 12 weeks after surgery to receive adjuvant FOLFOXIRI (irinotecan 165 mg/ m²; oxaliplatin 85 mg/ m²; folinate 200 mg/ m²; 5-Fluorouracil 3200 mg/ m²in 48 hours, every 14 days) for 12 cycles or gemcitabine (1000 mg/m²days 1, 8 and 15 every 28 days) for 6 cycles. Primary endpoint was DFS; OS and toxicity were secondary endpoints. Expecting a median DFS with gemcitabine of 13.4 months, 253 events were required to detect a HR of 0.70 in favour of FOLFOXIRI with overall 2-sided-a and ß errors of 0.05 and 0.20, respectively. On June 2018, considering the results of PRODIGE24 trial, the accrual was early stopped.

Results: From 1/2015 to 5/2018 a total of 77 patients were randomized in 18 centres. Median age was 61 years (range 39-73), 91% of patients had PS0 and 83% had tumour on pancreatic head; pathological stage was II or III in 94% of cases, 77% had positive nodes, 95% had grade (G) 2 or 3. Adjuvant chemotherapy was initiated after a median of 8 weeks after surgery (range 3-12). FOLFOXIRI increased the risk of G 3-4 neutropenia (53 vs 23%; p = 0.007) even if no neutropenic fever occurred. No major differences have been observed among other G 3-4 toxicities. After a median follow up of 26 months, 56% of patients had progressive disease and 31% died. Median DFS was 11.4 months with gemcitabine and 30.4 months with FOLFOXIRI, p = 0.038; HR 0.53 (95%CI:0.28-0.97). Median OS resulted 19.3 months in control arm while was not reached with FOLFOXIRI with survival proportions at 2 and 3 years of 83% and 69%, respectively, compared to 44% and 33% with gemcitabine.

Conclusions: Even if GIP-2 study was early stopped, adjuvant FOLFOXIRI seems to prolong DFS and OS in resected pancreatic cancer patients. GIP-2 results are in line with those from PRODIGE24 trial and support the use of this triple-drug regimen in this setting.

THE OUTCOME OF METASTATIC (M) OR LOCALLY ADVANCED (LA) GASTRIC CANCER (GC) IS NOT IMPROVED BY A NEW DOCETAXEL (DOC)-BASED TRIPLET REGIMEN AS COMPARED WITH AN EPIRUBICIN (EPI) STANDARD TRIPLET REGIMEN: A GISCAD TRIAL

Labianca R.¹, Rosati G.², Fazio N.³, Cavanna L.⁴, Ferrari D.⁵, Di Bartolomeo M.⁶, Mosconi S.¹, Giordano M.⁷, Silvestris N.⁸, Artioli F.⁹, Iaffaioli V.¹⁰, Veltri E.¹¹, Amoroso D.¹², Ciarlo A.¹³, Barni S.¹⁴, Cascinu S.¹⁵, Davite C.¹⁶, Di Sanzo A.¹⁶, Casolaro A.¹⁶

¹Asst Papa Giovanni XXIII, Bergamo; ²A. O. SanCarlo, Potenza; ³Istituto Europeo di Oncologia, Milano; ⁴A.O. di Piacenza, Piacenza; ⁵A.O. S.Paolo, Milano; ⁶Istituto Nazionale Tumori- Fondazione IRCCS, Milano; ⁷A.O. S.Anna, Como; ⁸A.O. Istituto Tumori Giovanni Paolo II, Bari; ⁹Ospedale Ramazzini, Carpi (MO); ¹⁰INT-IRCCS Fondazione G.Pascale, Napoli; ¹¹Ospedale Santa Maria Goretti, Latina; ¹²Ospedale Versilia USL12, Lido di Camaiore (LU); ¹³USL4 Ospedale di Prato, Prato (PO); ¹⁴A.O. Treviglio-Caravaggio, Treviglio (BG); ¹⁵Policlinico di Modena A.O.Universitaria, Modena; ¹⁶Nerviano Medical Sciences, Nerviano (MI)

Background: in advanced gastric cancer EOX (EPI + oxaliplatin-OHP + capecitabine-CAPE) is one of the standard regimens, but the role of EPI is under discussion and DOC substituted it in many centers. An innovative DOC-based regimen was developed, aiming at increasing the outcome vs EOX without the important side-effects of the conventional DOC combination.

Methods: from 1/2013 to 11/2018, 169 chemo-naive patients (pts) with M (87,6%) or LA GC were randomized by 23 institutions between low-TOX (arm A) and EOX (arm B): Arm A: DOC: 35 mg/m2 iv, d 1 and 8 + OHP: 80 mg/m2 iv, d 1 + CAPE: 750 mg/ m2 x2 daily p.o. for 2 weeks; Arm B: EPI: 50 mg/m2 iv, d 1 +OHP: 130 mg/m2 iv, d 1 +CAPE: 625 mg/m2 x2 daily p.o. for 3 weeks. Both regimens recycled q 21 days.

If no PD or heavy toxicity, pts were programmed on therapy for a maximum of 5 (if CR) or 6 courses (if PR or SD). The primary endpoint was PFS, the secondary OS, ORR, DCR and tolerability. The study was designed to detect a 35% (80% power at a two side 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events (75% of expected).

Results: At the cut-off date of interim analysis, 164 pts (median age 62 y; 63,9% male; ECOG PS: 0 in 75,7%) have available data for primary efficacy analysis. The median PFS was 5.8 months (m) (95% CI: 5.0 – 7.8) in arm A vs 6.5 m (95% CI: 5.0 – 8.9) in arm B, without statistical difference (NS). Also OS was comparable: 12.2 (95% CI: 8.6 -16.0) vs 12.8 m (95% CI: 9.1-21.0). ORR were 22% and 35.4% and DCR 59.8% and 65.9%, again NS.

The median number of courses per pt was 6 and treatment modification was higher in arm A (90,2% vs 78%) with a weakly higher number of CTC ⩾ 3 AE in arm A (54 vs 41).

Conclusions: On the basis of these results, it is unlikely that low-TOX regimen can reach the target of improvement vs EOX, both in efficacy/activity and in tolerability. Therefore, if clinicians decide for a triplet (i.e. in aggressive or very symptomatic disease), EOX could remain a standard option.

THE PROGNOSTIC NUTRITIONAL INDEX (PNI) IS AN INDEPENDENT PREDICTOR OF SURVIVAL IN ADVANCED BILIARY CANCERS (ABC) RECEIVING FIRST-LINE CHEMOTHERAPY (1L)

Cerma K.¹, Caputo F.², Salati M.², Spallanzani A.², Andrikou K.², Gelsomino F.², Rimini M.², Pipitone S.², Molinaro E.², Orsi G.², Rovesti G.², Cortesi G.², Schipilliti F.², Bardasi C.², Riggi L.², Canino F.², Santini C.², Cascinu S.², Casadei Gardini A.²

¹Policlinico Universitario Modena, Modena; ²Policlinico Universitario di Modena, Modena

Background: ABC portend a dismal prognosis despite standard chemotherapy treatment. A proper risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment. The PNI is an immune-inflammatory and nutritional indicator showing to be prognostic across a number of malignancies. We aimed at investigating the impact on survival of the PNI in ABC patients (pts) treated with 1L.

Methods: Electronic medical records of pts diagnosed with ABC and treated with 1L between 2002 and 2018 at the Modena Cancer Centre were retrospectively reviewed. Clinical, pathological and biochemical variables of potential interest were collected. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm2) and dichotomized using the ROC analysis with 36.7 as the cut-off value. Univariate and multivariate analysis were performed to assess the impact of covariates on overall survival (OS). Kaplan-Meier survival curves were generated and log-rank testing was used to make comparisons.

Results: Overall, 114 pts fulfilled the inclusion criteria and were included in the analysis. 51% (n = 58) were female and 49% (n = 56) had an ECOG PS of 0. 35% (n = 40) of pts received a platinum/gemcitabine doublet, while 65% (n = 74) were treated with other regimens. The median OS in the cohort was 8.1 months. At the univariate analysis the following covariates were associated with OS: PNI (P<0.0001), CA19.9 (P = 0.0063), CEA (P = 0.0004), LDH (P = 0.0360), alkaline phosphatase (P = 0.0308), monocyte count (P = 0.0124), neutrophil count (P = 0.0013), ECOG PS (P<0.0001), neutrophil/lymphocyte ratio (NLR) (P<0.0001). Interestingly, the PNI retained a statistical significance (P = 0.0011) also at the multivariate analysis, together with NLR (P = 0.0046) and ECOG PS (<0.0001). The median OS in pts with a PNI > 36.7 and < 36.7 was 12.1 months and 5.4 months, respectively.

Conclusions: We demonstrated an independent prognostic role for the PNI in a cohort of ABC treated with 1L. Since it is based on easy-to-collect and inexpensive parameters it should be implemented in the clinical practice to improve the accuracy of current available tools.

MULTICENTRIC PROSPECTIVE STUDY OF VALIDATION OF ANGIOGENESIS-RELATED GENE POLYMORPHISMS IN HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH SORAFENIB(S): FINAL RESULTS OF INNOVATE STUDY

Casadei Gardini A.¹, Marisi G.², Dadduzio V.³, Faloppi L.⁴, Ierlasi L.⁵, Vivaldi C.⁶, Rizzato M.D.⁷, Fornaro L.⁶, Lonardi S.⁷, Gramantieri L.⁸, Pecora I.⁷, Silvestrs N.⁹, Fornari F.⁸, Orsi G.⁸, Rovesti G.⁸, Santini D.¹⁰, Zagonel V.⁷, Cascinu S.¹, Scartozzi M.¹¹

¹UNIMORE, Modena; ²IRST-IRCCS, Meldola; ³IOV Veneto, Padoba; ⁴University of Cagliari, Cagliari; ⁵University of Bologna, Bologna; ⁶University of Pisa, Pisa; ⁷IOV Veneto, Padova; ⁸UNIBO, Bologna; ⁹IRCCS oncologico Bari, Bari; ¹⁰Campus BIOMEDICO, Roma; ¹¹University of Cagliari, Cagliari

Background: In two retrospective studies we analyzed endothelial-derived nitric oxide synthase (eNOS) and angiopoietin-2 (ANGPT2) polymorphismsand patients with eNOS-786CC+TCgenotype and ANGPT2rs55633437 GG genotypes had significantly higher median PFS and OS compared to those with other genotypes. On the basis of these preliminary results, our aim is to validate in a prospective study these data in patients with HCC treated with sorafenib (NCT02786342).

Methods: The primary outcomes were PFS. 160 total sample size were planned with the aim to confirm a HR of 0.58. Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test.

Results: 165 patients in 9 Italian hospital were enrolled in the study between 03/2015 and 06/2018.

Median OS was 13.1 months (95% CI 10.4-15.7) and median PFS was 4.2 months (95% CI 3.2-5.3).

At univariate analysis, we confirmed that eNOS-786 CC+CT genotype was significantly associated with a higher median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p = 0.0007) and OS (15.7 vs 8.6 months, HR 0.38, 95% CI 0.24-0.60 p<0.0001) than the other genotypes. At univariate analysis, we not confirmed that ANGPT2rs55633437 GG genotypes were significantly associated with a lower median OS (p = 0.55) and PFS (p = 0.13).

No differences were found between eNOS-786 TTand eNOS-786 CT/CCgenotypes in term of disease control rate and best response. No correlation were found between eNOS polymorphisms and toxicity.

Following adjustment for clinical covariates positive in univariate, multivariate analysis confirmed eNOSas only independent prognostic factor predicting OS (p = 0.0072).

After progression to S in all population we highlight that patients with eNOS-786 CC+CT genotype was significantly associated with a lower median OS (HR 0.56, p = 0.0343) and a trend was found for patients treated with Regorafenib (HR 0.13 p = 0.0573).

Conclusions: Our Italian multicenter, prospective study meet the primary end point and we confirmed thateNOS-786 TT genotype may be capable of identifying a subset of HCC patients who have a lower median OS and PFS. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study.

AEROBIC GLYCOLYSIS ENZYMES GENE EXPRESSION ANALYSIS IN GASTRIC CANCER (GC) AND SELECTIVE METABOLIC ADVANTAGE IN THE CLINICAL PROGRESSION OF PATIENTS WITH METASTATIC DISEASE TREATED WITH TAXOL-RAMUCIRUMAB

Graziano F.¹, Bagaloni I.², Di Bartolomeo M.³, Brignola S.⁴, Vincenzi B.⁵, Fornaro L.⁶, De Vita F.⁷, Ongaro E.⁸, Aprile G.⁹, Perrone G.⁵, Catalano V.¹⁰, Gobbi A.¹¹, Tomasello G.¹¹, Alberti G.¹², Prisciandaro M.¹³, Laterza M.M.¹⁴, Vivaldi C.¹⁵, Manai C.¹⁶, Sarti D.¹⁰, Magnani M.¹⁷, Ruzzo A.²

¹Azienda Ospedali Riuniti Marche Nord - Unità di oncologia Medica, Fano; ²Università Degli Studi di Urbino - Dipartimento di Scienze Biomolecolari, Fano; ³Oncologia Medica GI Fondazione IRCCS istituto Tumori Milano, Milano; ⁴Istituto Oncologico Veneto - IRCCS, Padova; ⁵Università Campus Bio-Medico, Roma; ⁶Azienda Ospedaliero-Universitaria Pisana, Pisa; ⁷Oncologia Medica Universita’ della Campania Luigi Vanvitelli, Napoli; ⁸Dipartimento di Oncologia, ASUI S. Maria della Misericordia, Udine; ⁹Ospedale San Bortolo Azienda ULSS8 Berica - Distretto Est, Vicenza; ¹⁰Azienda Ospedali Riuniti Marche Nord - Unità di oncologia Medica, pesaro; ¹¹S. C. Oncologia ASST Ospedale di Cremona, Cremona; ¹²Dep of Oncology, Unit of Oncology 1, Veneto Institute of Oncology IOV – IRCCS and Dep of Surgery, Oncology and Gastroenterology, University of Padua, Padova; ¹³ Oncologia Medica GI Fondazione IRCCS istituto Tumori Milano, Milano; ¹⁴Universita’ della Campania Luigi Vanvitelli, Napoli; ¹⁵U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa; ¹⁶Department of Clinical and Experimental Oncology, Medical Oncology 1 Unit, IOV - Istituto Oncologico Veneto - IRCCS, Padova; ¹⁷Università Degli Studi di Urbino - Dipartimento di Scienze Biomolecolari, Urbino

Background: Invasive cancer cells mostly produce lactate even in the presence of sufficient levels of oxygen (AG). This metabolic shift promotes a survival advantage in proliferating cells and it makes them insensitive to transient or permanent hypoxia. This phenomenon may cause secondary resistance to anti-angiogenic compound and identify new targets in cancer metabolism. We analyzed mRNA expression of AG key-enzymes in primary tumor (PT) of GC pts who underwent second-line therapy with paclitaxel/ramucirumab. This setting was chosen for verifying the possible clinical impact of adaptive hypoxia with AG against a prevalent anti-angiogenic regimen.

Methods: Tissues of pts were retrospectively studied by RT-qPCR for mRNA expression of the following AG-related genes: HK1, HK2, PKM2, LDH-A, GLUT-1, VDAC1. The relative mRNA expression of each candidate gene was expressed as the DCt =Ct(target gene) – Ct(reference gene). By comparing DCt values between the tumor sample and the normal counterpart the differential expression was estimated. A doubled mRNA expression (DCt⩾1) in all AG “core” enzymes (HK1/HK2 PKM2 LDH-A) identified high glycolytic score (HGS) samples, otherwise as having low glucolytic sore (LGS). Data of HGS and LGS were associated with clinical outcomes.

Results: A retrospective series of 50 pts from the RAMoss study (Di Bartolomeo et al, Target Oncol, 2018), treated with second-line Paclitaxel/Ramucirumab was analyzed. The median age was 60 years (range 38-60) with prevalence of ECOG performance status 0 (55%), multiple sites of metastatic disease (65%), male gender (65%), peritoneal involvement (40%) and time-to progression on first-line treatment > 6 months (66%). At the time of writing of this paper, results are available for 30 pts with 9 having HGS. Median PFS were 2.3 and 5 months in pts with HGS and LGS, respectively (p<.001). Median OS were 4.4 and 9.6 months in pts with HGS and LGS, respectively (p<.01). Multivariate analysis will be performed in the final dataset.

Conclusions: GC displaying an aerobic glycolysis metabolic profile may tolerate the unfavorable microenvironment determined by anti-angiogenic therapies. This feature may explain secondary resistance to anti-angiogenic therapies in subset of patients and it deserves further investigations for potential innovative treatment strategies. Final data will be presented at the meeting and results in the whole sample size would allow additional analyses in combination with GLUT-1 and VDAC1.

NAB-PACLITAXEL (NAB) PLUS GEMCITABINE (G) IS MORE EFFECTIVE THAN G ALONE IN LOCALLY ADVANCED, UNRESECTABLE PANCREATIC CANCER (LAUPC): THE GAP TRIAL, A GISCAD PHASE II COMPARATIVE RANDOMIZED TRIAL

Piccirillo M. C.¹, Berardi R.², Bianco R.³, Bilancia D.⁴, Zaniboni A.⁵, Ferrari D.⁶, Mosconi S.⁷, Spallanzani A.⁸, Cavanna L.⁹, Leo S.¹⁰, Negri F.¹¹, Beretta G.¹², Sobrero A.¹³, Banzi M.¹⁴, Morabito A.¹⁵, Bittoni A.², Marciano R.³, Ferrara D.⁴, Noventa S.⁵, Labianca R.⁷, Cascinu S.⁸

¹Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli; ²AOU Ospedali Riuniti Ancona, Torrette Di Ancona; ³Dipartimento di Medicina Clinica e Chirurgica, Università Federico II, Napoli; ⁴AO San Carlo, Potenza; ⁵Casa di Cura Poliambulanza, Brescia; ⁶AO San Paolo, Milano; ⁷AO Papa Giovanni XXIII, Bergamo; ⁸AOU Policlinico di Modena, Modena; ⁹USL di Piacenza - Ospedale Guglielmo da Saliceto, Piacenza; ¹⁰AO Vito Fazzi, Lecce; ¹¹AOU di Parma, Parma; ¹²Humanitas Gavazzeni, Bergamo; ¹³IRCCS AOU San Martino, Istituto Nazionale per la Ricerca sul Cancro, Genova; ¹⁴AO Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia; ¹⁵ULSS6 EUGANEA, PO Cittadella-Camposampiero, Camposampiero

Background: The role of a combination therapy is defined in metastatic pancreatic cancer but not in LAUPC. Lacking dedicated randomized trials, evidence mostly comes from retrospective or phase II studies. G alone remains the standard option following a subgroup LAUPC analysis of a GERCOR/GISCAD trial (J Clin Oncol 2005).

Methods: GAP is a multicentre, open-label, randomized, comparative phase II trial testing the efficacy of NabG vs G. Patients ⩽75 years, PS 0-1, were randomized 1:1 to Nab/G (Nab 125 mg/mq plus G 1000 mg/mq on days 1, 8 and 15 every 28 days for 3 cycles) or G (same schedule and doses). Patients not progressing after 3 cycles had to receive capecitabine plus radiotherapy for 5 weeks. Disease progression rate (DPR) according to RECIST 1.1 after 3 cycles of chemotherapy is the primary endpoint. With 80% power in detecting a reduction of DPR from 40% to 20%, one-tailed alpha = 0.05, 124 patients were required. Progression-free survival (PFS) is a secondary endpoint; with 109 events the study has 80% power, with one-tailed alpha = 0.05, to detect a 0.62 hazard ratio of PFS.

Results: 124 patients were enrolled in this trial (4 withdrew consent after randomization in the G arm). Most of the patients were PS 0 (65.8%), and women (56.7%). The study met its primary endpoint DPR, with a reduction from 45.6% with G to 25.4% with Nab/G.

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Arm	Patients	DPR	One-tail chi square	Median PFS(102 events)	HR of PFS	Progression at distant site	Median OS(82 events)	HR of OS
G	57	26 (45.6%)	P = 0.01	5.1 mos	0.71 (90% CI 0.51-0.99)	18/26	10.7 mos	0.65 (90% CI 0.44-0.94)
NabG	63	16 (25.4%)		7.6 mos		6/16	13.1 mos

There was no unexpected toxicity. One patient died during treatment with G due to a stroke.

Conclusion: NabG reduces the rate of LAUPC patients who progress after 3 cycles of chemotherapy compared with G, especially in terms of distant relapses, positively affecting PFS and overall survival. Nowadays it should be the therapeutic option in this setting.

ClinicalTrials.gov Identifier NCT02043730. The study was supported by Celgene.

ADJUVANT CHEMOTHERAPY IN RESECTED BILE DUCT CANCER: A METANALYSIS OF RANDOMIZED TRIALS

Messina C.¹, Merz V.¹, Michela F.¹, Trentin C.¹, Grego E.¹, Salati M.², Veccia A.³, Messina M.³, Carnaghi C.³, Caffo O.³

¹Ospedale S. Chiara, Trento; ²Department of Medical Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy., Trento; ³ospedale S.Chiara, Trento

Background: Despite improvements in surgical resection techniques and multidisciplinary management, patients suffering from bile tract cancers (BTC) have a poor prognosis. About 50% of them will develop disease recurrence after curative surgery, and the 5-year survival rate accounts for 10-40%. The role of adjuvant chemotherapy (ACT) is still unclear and no specific adjuvant treatment is recommended by international guidelines given conflicting results from the available clinical trials. We performed a meta-analysis of randomized clinical trials (RCTs) to better define the clinical benefits and the risk of ACT or observation in resected BTC.

Method: A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to April 2019. Phase II/III prospective randomized controlled trials comparing ACT or observation in BTC patients were eligible for the metanalysis. Overall survival (OS) and recurrence free survival (RFS) were co-primary end-points. Hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and RFS, as well as Risk Ratio (RRs) for ⩾ G3-G4 adverse events (AEs) were calculated for each trial. A pooled analysis was carried out using the random effects model. A pre-specified subgroup analysis was performed to assess OS in patients with node positive or positive surgical margins (R1). Results: Three RCTs including 866 BTC patients (435 ACT arm vs 431 observation arm) were eligible for the metanalysis. A trend toward better OS (HR: 0.91, 95% CI 0.75-1.09) and a statistically significant difference in RFS (HR: 0.83, 95% CI 0.69-0.99) was reported among patients who underwent ACT. Similarly, a trend toward better OS in ACT arm was reported in node positive subgroup (HR: 0.84, 95% CI 0.65-1.08), whereas there was no difference in R1 subgroup (HR: 0.95 95% CI 0.69-1.31). The use of ACT was characterised by a significant increase of ⩾G3-G4 AEs (RR: 3.03, 95% CI 2.22-4.15).

Conclusions: This metanalysis showed for the first time that ACT meaningfully improved RFS in resected BTC patients’ and led to longer OS than observation alone in overall population and node positive subgroup, although the difference was not statistically significant. As expected, ACT caused treatment-related toxicities which offsets benefits.

THE MANAGEMENT OF BILIARY TRACT CANCER: A NEW PROGNOSTIC SCORE SYSTEM

Ziranu P.¹, Casadei Gardini A.², Pretta A.¹, Andrikou K.², Lai E.¹, Faloppi L.³, Astara G.¹, Leone F.⁴, Mariani S.¹, Fornaro L.⁵, Liscia N.¹, Vivaldi C.⁵, Soro P.¹, Sperti E.⁶, Filippi R.⁷, Pusceddu V.¹, Demurtas L.¹, Puzzoni M.¹, Cascinu S.², Scartozzi M.¹

¹Medical Oncology Unit, University of Cagliari, Cagliari; ²Medical Oncology Unit, Modena Cancer Center, University Hospital of Modena, Modena; ³Oncology Unit, Macerata Hospital, Macerata; ⁴Medical Oncology, ASL BI, Ospedale degli Infermi Biella, Biella; ⁵Department of Medical Oncology, Pisa University Hospital, Pisa; ⁶Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Turin; ⁷Department of Oncology, University of Turin, Turin

Background: Biliary tract cancers (BTCs) are heterogeneous tumours with poor prognosis and limited therapeutic options.Innovative predictive and prognostic factors are urgently needed in order to improve the global management of BTC patients (pts).

Methods: From August 2001 to March 2019, clinical and demographic data of advanced BTCs pts attending the Medical Oncology Department of Cagliari, Modena, Meldola and Macerata University Hospitals, were retrospectively collected.All pts underwent at least one line of chemotherapy.The aim of our research was to investigate the correlation between clinical data and outcomes in order to identify a prognostic index, clustering pts in low and high-risk subgroups.The score was validated by a confirmation-cohorts (Medical Oncology Department of Pisa, Torino, Candiolo and Alba). Survival analysis were performed using the Kaplan-Meyer method and log-rank test, ROC curves were applied to define cut off values for Ca19.9

Results: Exploratory cohort and validation cohort considered data of 256 and 294 advanced BTCs pts respectively.In exploratory cohort median overall survival (mOS) was 9,23 months. Clinical parameters correlating with OS were primary tumour site, age, ECOG PS, biliary stenting and baseline Ca19.9 values.The intrahepatic cancer mOS was 11,6 months, 9,16 months in extrahepatic subgroup and 8,1 in gallbladder tumours(p = 0,04). Age = 70 years and the presence of biliary stent were associated to a lower OS [(12,3 vs 7,8 months; p = 0,0006) and (12,3 vs 7,9 months; p = 0,0342) respectively]; ECOG-PS0-1 was associated with longer survival than ECOG-PS>1 (12,3 vs 3,23 months;p<0,0001); pts with Ca19.9 levels = 305 U/ml had a mOS of 12,6 months, while those with higher levels showed a mOS of 7,63 months (p<0,0001). A unitary value was assigned to each significative prognostic factor, in order to stratify pts in 2 prognostic groups. We found a statistical significative difference between pts located in the 0-2 score group and pts in the 3 score group in terms of OS (12,3 vs 7,6 months respectively, p<0,0001).Confirmatory results were obtained by the same analysis in the validation cohort with a mOS of 14,43 and 11,16 months in pts with low (n = 127) and high-risk group (n = 167) respectively (p = 0.0001).

Conclusions: Prognostic score including primary tumour site, ECOG PS, age, presence of biliary stent, baseline Ca19.9 values, was significantly correlated with survival in BTCs.Further studies with larger sample size are needed to confirm our results.

TARGETING DNA REPAIR IN BILIARY TRACT CANCER (BTC): ARE IDH AND MGMT NEW THERAPEUTIC TARGETS?

Niger M.¹, Morano F.¹, Manglaviti S.¹, Nichetti F.¹, Tamborini E.¹, Perrone F.¹, Marcuzzo M.¹, Corallo S.¹, Brambilla M.¹, Pagani F.¹, Torchio M.¹, Colombo E.¹, Antista M.¹, Pietrantonio F.¹, Pusceddu S.¹, Pruneri G.¹, De Braud F.¹, Di Bartolomeo M.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano

Background: Biliary Tract Cancers (BTC) are molecularly heterogeneous malignancies with significant molecular differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gall bladder (GB) cancer. DNA Damage Repair (DDR) is relevant to BTC proliferation and apoptosis and DDR deficiency can lead to sensitivity to novel therapies, such as Poly(ADP-ribose) polymerases inhibitors (PARPi), due to synthetic lethality. Among DDR genes, IDH1/2 mutations (~15% of CC) convert a-ketoglutarate (aKG) into 2-hydroxyglutarate (2HG) and drive a homolougus repair (HR) defect, and consequently sensitivity to PARPi in preclinical models. Another DDR gene, MGMT, is responsible of alkyl groups’ elimination from the O6-position of guanine. Reductions in MGMT expression and MGMT promoter methylation result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as Temozolomide (TMZ). Here we present data on these DDR alterations tested in BTC pts at our center.

Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®”). MGMT promoter methylation was studied via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), while protein expression was assessed via immunohistochemistry (IHC).

Results: Archived FFPE tissue sections from 100 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, from October 2017 to February 2019, were analyzed. Amongst the 89 samples with adequate tissue, 73% were ICC, 16% were ECC and 8% were GC. We found IDH1/2 mutations in 15% (all ICC). 34 pts (38%) had MGMT promoter methylation, while low/negative MGMT protein expression was found in 45 pts (50%). Of note, MGMT methylation was identified in each soubgroup of pts, with 38% of ICC, 26% of ECC and 62% of GC. Amongst MGMT methylated pts, 4 (11%) had concomitant IDH1/2 mutations, which are reported to be associated with CpG Island Methylator Phenotype.

Conclusions: Evidence supporting the role of IDH1/2 mutations and MGMT methylation in leading to sensitivity to PARPi and TMZ is increasing. In our single-center experience, IDH1/2 mutations and MGMT promoter methylation were found in 15% and 38%, respectively, of patients with BTC. More data are needed, but there is definitely a definitely an interest in exploring the prognostic role of IDH1/2 mutations and MGMT methylation in BTC and novel therapies targeting these DDR genes.

RETROSPECTIVE SURVIVAL ANALYSIS IN METASTATIC PANCREATIC CANCER PATIENTS AFFECTED BY TYPE 2 DIABETE MELLITUS

Pretta A.¹, Ziranu P.², Lai E.², Casadei Gardini A.³, Puzzoni M.², Orsi G.³, Mariani S.², Molinaro E.³, Liscia N.¹, Riggi L.³, Pusceddu V.², Rovesti G.³, Impera V.¹, Camera S.¹, Musio F.², Soro P.², Demurtas L.², Astara G.², Andrikou K.³, Cascinu S.³, Scartozzi M.²

¹Medical Oncology, Sapienza-University of Rome, Italy; Medical Oncology Unit, University Hospital and University of Cagliari, Italy, Monserrato; ²Medical Oncology Unit, University Hospital and University of Cagliari, Italy, Monserrato; ³Medical Oncology Unit, University Hospital and University of Modena, Italy, Modena

Background: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated, some studies had described diabetes mellitus 2 as a risk factor for the development of PCAD or as its epiphenomenon. The objective of the present study was to investigate the correlation between overall survival (OS) and DM2-PDAC versus not DM2 PDAC.

Methods: We retrospectively analyzed an exploratory cohort from Medical Oncology of Cagliari University Hospital and a validation cohort from Medical Oncology of Modena University Hospital. All patients had stage IV disease and received at least 1 line of chemotherapy treatment for metastatic disease. Statistical analysis was performed with MedCalc package. Our aim is to evaluate the correlation between DM2 and overall survival (OS), and subsequently investigate the differences between insulin and metformin therapy in relation to OS. Survival distribution was assessed by the Kaplan-Meyer method.

Results: 86 pts of Cagliari University Hospital and 45 pts of Modena University Hospital were included in our analysis. 63/86 (73.3%) and 31/45 (68,9%) pts were not affected by DM2, instead 23/86 (26.7%) and 14/45 (31,1%) pts were affected by DM2. Median OS (mOS) was significantly improved in DM2 pts versus (vs) not DM2 pts (24 months, 95% CI 0.19-0.59 vs 8 months, 95% CI; p<0,0005); in validation cohort mOS was improved in DM2 pts vs not DM2 pts (11 months, 95% CI 0.21-0.72 vs 6 months, 95% CI; p<0,001).

Within the DM2 group of exploratory cohort 16/23 (69.6%) pts were insulin treated and 7/23 (30.4%) with metformin; mOS was significantly improved in the metformine subgroup (30 months, vs 24; p <0,005). In the DM2 group of validation cohort 9/14 (64,3%) pts were insulin treated and 5/14 (35,7%) pts were metformin treated; mOS was significantly improved in metformin subgroup (11 months vs 10.5 months; p<0,01).

Conclusions: PDAC patients with DM2 have shown better OS than non-DM, as demonstrated by the validation cohort. Furthermore, the role of metformin in improving OS was confirmed in PDAC patients of both cohorts. However, if the molecular mechanism of metformin in improving OS has been investigated and partially explained, the mechanism by which the DM2 not metformin treated can improve the OS should be investigated.

MGMT METHYLATION IN PANCREATIC CANCER (PAC): A NEW TARGET?

Manglaviti S.¹, Niger M.¹, Morano F.¹, Nichetti F.¹, Perrone F.¹, Tamborini E.¹, Marcuzzo M.¹, Raimondi A.¹, Peverelli G.¹, Brambilla M.¹, Pagani F.¹, Torchio M.¹, Prisciandaro M.¹, Antista M.¹, Pietrantonio F.¹, Pusceddu S.¹, Pruneri G.¹, Di Bartolomeo M.¹, De Braud F.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano

Background: Pancreatic adenocarcinoma (PAC) is a devastating disease with few therapeutic options. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene and MGMT alterations are described in various gastrointestinal cancers, including colorectal cancer. Reports regarding the frequence and the role of MGMT methylation and/or low protein expression by immunohistochemistry (IHC) in PAC are conflicting. It is established that low MGMT expression and MGMT promoter methylation are related to reduced DNA-repair of O6-alkylguanine adducts. In fact, there is increasing evidence of the activity of alkylating agents, such as temozolomide (TMZ), in these patients (pts). This report presents data on MGMT testing PAC pts admitted at our center.

Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), to assess MGMT promoter methylation, and IHC, to assess protein expression. Furthermore,

Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI) were performed.

Results: Archived FFPE tissue sections obtained from 90 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to April 2019 were analyzed. By May 2019, 60 samples (66%) had adequate tissue for MGMT status analyses. We identified MGMT promoter methylation in 21 pts (35%), of which 13 (61%) had low/negative MGMT protein expression. Of note, amongst MGMT methylated pts, there were 5 (23%) BRCA1/2 somatic mutant and 2 (9%) MSI, which may suggest possible genomic instability in this subset of pts. It is worth considering BRCA1/2 somatic mutations (VUS or pathogenic) and microsatellite instability (MSI) were identified in 9 (15%) and 2 (3%) pts, respectively.

Conclusions: In our single center experience, MGMT methylation was found in 35% of patients with PAC. This data warrant further confirmation; nevertheless, considering the role of MGMT alterations in glioblastoma and other gastrointestinal cancers, there is definitely a rationale in investigating MGMT methylation as a predictive and prognostic biomarker in PAC.

ANALYSIS OF ACCRUAL IN GIP-2 STUDY, AN ITALIAN MULTICENTER PHASE III RANDOMIZED TRIAL COMPARING FOLFOXIRI VERSUS GEMCITABINE AS ADJUVANT TREATMENT FOR RESECTED PANCREATIC CANCER

Vivaldi C.¹, Bianco R.², Pellino A.³, Mori E.⁴, Latiano T.⁵, Delfanti S.⁶, Merelli B.⁷, De Vita F.⁸, Cinieri S.⁹, Berardi R.¹⁰, Silvestris N.¹¹, Ricci V.¹², Tonini G.¹³, Pella N.¹⁴, Passalacqua R.¹⁵, Bengala C.¹⁶, Cavanna L.¹⁷, Martignetti A.¹⁸, Marciano R.¹⁹, Bergamo F.³, Vasile E.²⁰

¹Università di Pisa, Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa; ²Dipartimento di Medicina Clinica e Chirurgia, UOC Oncologia Medica, Università Federico II, Napoli; ³SC Oncologia Medica 1, Dip. Oncologia Clinica e Sperimentale, Istituto Oncologico Veneto IRCCS, Padova; ⁴SOC Oncologia Medica, Nuovo Ospedale di Prato, Azienda USL Centro Toscana, Prato; ⁵SC Oncologia, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo; ⁶SC Oncologia, Fondazione IRCCS Policlinico San Matteo, Pavia; ⁷Oncologia Medica, ASST Papa Giovanni XXIII, Bergamo; ⁸Oncologia Medica, Università Luigi Vanvitelli, Napoli; ⁹Oncologia Medica, Ospedale Senatore Antonio Perrino, ASL Brindisi, Brindisi; ¹⁰Oncologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona; ¹¹Oncologia Medica, Istituto IRCCS Giovanni Paolo II, Bari; ¹²SC Oncologia Medica, AO S. Croce e Carle, Cuneo; ¹³Oncologia Medica, Università Campus Bio-Medico, Roma; ¹⁴Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata, Udine; ¹⁵Oncologia, Azienda Ospedaliera “Istituti Ospitalieri”, Cremona; ¹⁶Oncologia Medica, Azienda USL Sud-Est Toscana, Grosseto; ¹⁷Oncologia, Azienda USL, Ospedale di Piacenza, Piacenza; ¹⁸Oncologia Medica Area Senese, Osp. Alta Val D’Elsa-Campostaggia, Poggibonsi; ¹⁹Dipartimento di Medicina Clinica e Chirurgia, UOC Oncologia Medica, Università Federico II, Roma; ²⁰Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Pisa

Background: Adjuvant chemotherapy with gemcitabine increases survival over surgery alone in resected pancreatic cancer. Modified FOLFIRINOX demonstrated higher survival compared to gemcitabine in this setting. However, this triple-drug combination may be more aggressive and not all patients could be eligible to this treatment. No data regarding screening failure were presented in PRODIGE 24 trial. The GIP-2 trial recently investigated FOLFOXIRI versus gemcitabine in the same setting. We decided to analyze the number of screened patients and reasons for ineligibility.

Methods: A retrospective analysis of clinical data of patients with resected pancreatic cancer evaluated at the centers enrolling patients in GIP-2 trial during the time the study was conducted in order to evaluate the population of patients not included in the trial and the reasons for ineligibility. To avoid risks of overweighting screening failure rate, we decided to include only patients evaluated in active centers who enrolled at least one patient in the trial.

Results: A total of 77 patients were enrolled in GIP-2 study in 18 centers from 1/2015 to 5/2018, with an accrual rate of 1.25 patients/center/year that was similar to those of other adjuvant trials in pancreatic cancer (PRODIGE 24: 1.42; ESPAC-4: 1.33). In the same period, a total of 461 resected pancreatic cancer were evaluated in the 18 centers; the 77 enrolled patients represent about 17% of all the assessed patients.

Main reasons of ineligibility to the study were:

Conclusions: Patients enrolled in phase III trials of adjuvant chemotherapy for resected pancreatic cancer are selected for good performance status, age, with no evidence of metastatic disease after surgery, having a good recovery after surgery. These results are crucial for design of possible future clinical trials investigating chemotherapy in different settings (preoperative versus postoperatitve) for resectable pancreatic cancer.

USER-FRIENDLY SCORING SYSTEM AND NOMOGRAM TO PREDICT RELAPSE-FREE SURVIVAL (RFS) IN WESTERN PATIENTS (pts) WITH RESECTED GASTRIC CANCER (GC)

Rimini M.¹, Salati M.², Pipitone S.², Gelsomino F.², Casadei Gardini A.², Andrikou K.², Schipilliti F.², Cortesi G.², Cassanelli L.², Caffari E.², Serra F.², Ricciardolo A.², De Ruvo N.², Gelmini R.², Cascinu S.², Spallanzani A.²

¹Univeristà di Modena e Reggio Emilia, Modena; ²Università di Modena e Reggio Emilia, Modena

Background: Despite multimodality treatment, in the Western world >50% of GC pts relapse following curative-intent surgery. The absolute survival benefit of perioperative or adjuvant chemotherapy ranges from 6 to 15% at 5 years and must be balanced against treatment-related toxicities. Reliable tools to risk-stratify patients are lacking. The aim of this study was to build a practical tool to guide daily decision-making and clinical trial design.

Methods: Data of pts undergoing curative-intent surgery for T2-4 and N-positive GC between 2008 and 2018 at the Modena Cancer Centre were retrieved. Clinico-pathologic and biochemical parameters deemed of potential interest were collected. The cut-off value for continuos variables was assessed at 75° percentile. Univariate and multivariate Cox proportional-hazard models were used to assess the prognostic value of covariates. Based on the multivariate model, a nomogram to predict 2- and 3-year RFS was developed with a corresponding number of points assigned to a given magnitude of the variable.

Results: A total of 157 pts were eligible for the analysis. 51% (n = 80) were female and 88% (n = 139) had an ECOG PS of 0-1. Only 6% of cases were gastroesophageal cancers. 13% (n = 20), 25% (n = 40), 62% (n = 97) presented at diagnosis with stage I, II and III, respectively. Adjuvant chemotherapy was administered to 49% of patients. Out of 15 covariates tested, the following were independent predictors of outcome in the multivariate analysis and therefore included in the nomogram: ECOG PS (HR 2.51; p = 0.006), nodal status (HR 3.04; p = 0.078), angioinvasion (HR 2.62; p = 0.005) and logNeutrophil/Lymphocyte ratio (HR 3.50; p<0.001). Moreover, by assigning to each of them weight equal to 1, a scoring system was devised that differentiates 3 prognostic groups: low- (0-1 factors), intermediate- (2 factors) and high-risk (3-4 factors) group with a mOS of 35, 22 and 8 months (p<0.001), respectively.

Conclusions: We built an easy-to-use prognostic score and a nomogram to estimate 2- and 3-year individual RFS probability in resected GC. Interestingly, these tools incorporate variables reflecting patients characteristics (ECOG PS), tumour aggressiveness (nodal status and angioinvasion) and immune-inflammation status (NLR). Both the scoring system and the nomogram could assist clinicians in discussing with patients prognosis and risk-to-benefit ratio of systemic treatment as well as the design of future trials.

EFFICACY, SAFETY, AND CANCER-RELATED SYMPTOMS IN PATIENTS WITH HEPATOCELLULAR CARCINOMA WITH ALPHA-FETOPROTEIN GREATER THAN OR EQUAL TO 400NG/ML: A POOLED ANALYSIS FROM REACH AND REACH-2 STUDIES

Borbath I.¹, Kudo M.², Finn R.³, Galle P.⁴, Llovet J.⁵, Blanc J.⁶, Okusaka T.⁷, Chau I.⁸, Cella D.⁹, Peck-Radosavljevic M.¹⁰, Girvan A.¹¹, Gable J.¹¹, Bowman L.¹¹, Abada P.¹¹, Hsu Y.H.¹¹, Zhu A.¹², Dadduzio V.P.¹³

¹HepatoGastroenterology and Digestive Oncology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Bruxelles, Belgium, Bruxelles; ²Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan, Osaka; ³Los Angeles Medical Center, University of California, Los Angeles, CA, USA, Los Angeles; ⁴First Department of Internal Medicine, Universitätsmedizin Mainz, Mainz, Germany, Mainz; ⁵Mount Sinai School of Medicine, New York, NY, USA, New York; ⁶Department of Hepato-gastroenterology and Medical Oncology, CHU Bordeaux Hopital St. André, Bordeaux, France, Bordeaux; ⁷Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan, Tokyo; ⁸Department of Medicine, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, Sutton, UK, Sutton; ⁹Northwestern University, Evanston, IL, USA, Evanston; ¹⁰Department of Internal Medicine & Gastroenterology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria, Klagenfurt; ¹¹Eli Lilly and Company, Indianapolis, IN, USA, Indianapolis; ¹²Department of Hematology/Oncology, Massachusetts General Hospital, Boston, USA, Boston; ¹³Istituto Oncologico Veneto IRCCS, Padua, Italy, Padua

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Advanced stage is associated with symptoms and poor quality-of-life. Ramucirumab (RAM) shows survival benefits in patients with alpha-fetoprotein (AFP) ⩾400 ng/ml who failed prior sorafenib treatment. We present efficacy, safety, and cancer-related symptoms in HCC patients with AFP ⩾400 ng/ml.

Material and methods: This meta-analysis included individual patient-level data from REACH and REACH-2. Both studies had the same eligibility criteria (except AFP⩾400 ng/ml in REACH-2): prior sorafenib treatment, advanced HCC (BCLC-C), Child-Pugh score <7, ECOG PS 0-1. Patients received RAM (8 mg/kg) or placebo (PBO) on day 1 every 14 days. Functional Assessment of Cancer Therapy (FACT) Hepatobiliary System Index (FHSI)-8 assessed cancer-related symptoms. Time-to-deterioration (TTD) was time from date of randomization to date of first FHSI-8 deterioration (3+ point worsening). Efficacy assessment included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety.

Results: 542 patients with AFP ⩾400 ng/ml pooled from REACH (n = 250) and REACH-2 (n = 292) were treated with RAM (n = 316) and PBO (n = 226). Patients treated with RAM had improved OS (RAM = 8.1 months; PBO = 5.0 months; HR = 0.694; 95% CI = 0.571-0.842; p<.0002), PFS (RAM = 2.8 months; PBO = 1.5 months; HR = 0.572, 95% CI = 0.472-0.694; p<.0001), and ORR (RAM = 5.4%; PBO = 0.9% [p<.004]). TTD of FHSI-8 total score was delayed in patients treated with RAM (3.3 months) vs PBO (1.9 months; HR = 0.725, 95% CI = 0.559-0.941). Overall, 9.5% (RAM) and 3.6% (PBO) of patients discontinued due to adverse events (AEs). Hypertension (RAM = 12.0%; PBO = 3.6%) and hyponatremia (RAM = 5.1%; PBO = 2.2%) were the grade ⩾3 treatment-emergent AEs occurring in ⩾5% in RAM.

Conclusions: RAM significantly improved OS, PFS, ORR, and delayed deterioration of cancer-related symptoms in HCC patients with AFP>400ng/ml, with an acceptable safety profile.

A CLINICAL SCORE IDENTIFIES PROGNOSTIC CLASSES IN CHOLANGIOCARCINOMA (CCA) TREATED WITH FIRST-LINE CHEMOTHERAPY

Salati M.¹, Caputo F.¹, Spallanzani A.¹, Ratti M.², Pizzo C.², Passalacqua R.², Cascinu S.¹, Ghidini M.³

¹Azienda Ospedaliero-Universitaria di Modena, Modena; ² ASST Ospedale di Cremona, Cremona; ³ASST Ospedale di Cremona, Cremona

Background: The first-line treatment of CCA relies on palliative-intent chemotherapy with median overall survival (mOS) hardly exceeding 12 months. Hence, the trade-off between efficacy, toxicity and quality of life must be carefully evaluated. However, it exists an unmet need for factors aiding risk-stratify CCA in both the clinic and trials. We aimed at evaluating the impact on OS of clinical, pathologic and biochemical factors to develop a prognostic tool assisting in treatment decision.

Methods: Medical records of patients affected by unresectable locally advanced and metastatic intrahepatic, perihilar and distal CCA who received first-line chemotherapy from 2006 to 2018 at the Modena Cancer Centre and Cremona Cancer Centre were retrospectively reviewed. Variables of potential interest were collected. Kaplan-Meier survival curves were generated and differences between covariates were addressed with the log-rank test. Univariate and multivariate Cox proportional-hazard models were used to assess the prognostic value of covariates.

Results: Amongst 122 CCA included in the analysis, 53% were female and 55% had an ECOG PS of 0. 87% of patients presented with stage IV disease. Tumour site was iCCA, pCCA and dCCA in 60%, 22% and 18% of cases. The mOS in the overall population was 11.5 months and 1-year OS was 52%. Globally, 24 variables deemed of potential interest were evaluated in the univariate analysis. ECOG PS > 0 (p<0.001), age > 75 years (p = 0.009), NLR > 3.0 (p<0.001), CEA > 9.5 (p<0.001) and stage IV (p = 0.001) remained independently associated with worse survival in the multivariate analysis. By assigning to each of these five variable weight equal to 1 and grouping together the patients based on their presence, we identified a low- (0-1 factors), intermediate (2 factors) and high-risk (3-5 factors) group, respectively. The mOS differed significantly in the three groups being 19 months in the low-risk group (p<0.001), 11 months in the intermediate-risk group (p<0.001) and 3 months in the high-risk group (p<0.001).

Conclusions: We developed a clinical score based on readily-available and inexpensive parameters that risk-stratifies CCA treated with first-line chemotherapy in three significantly different prognostic classes. Although an external validation is required, this score could be a valuable tool to guide clinical decision-making and patient stratification.

EPSTEIN-BARR VIRUS (EBV) ASSOCIATED METASTATIC GASTRIC CANCER (GC) AND ITS CORRELATION TO CLINICAL OUTCOMES

Morano F.¹, Corallo S.¹, Guarini V.¹, Lobefaro R.¹, Antista M.¹, Cubeddu A.¹, Gloghini A.¹, Volpi C.¹, Monica M.¹, Prisciandaro M.¹, Brambilla M.¹, Palermo F.¹, De Braud F.G.¹, Pietrantonio F.¹, Di Bartolomeo M.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milano

Background: EBV-associated gastric cancer (EBVaGC) has been recently categorised as a specific subgroup of gastric cancer (GC), harbouring a remarkable sensitivity to immune-checkpoint inhibitors. As today, few evidences are available on the prognosis of this subgroup and its sensitivity to chemotherapy in the metastatic setting, especially in the non asian population. This study aims to investigate the prevalence, the clinical-pathological characteristics and the prognosis of metastatic EBVaGCs in a single centre population.

Methods: Formalin-fixed, paraffin-embedded tumour samples from 170 stage IV GC treated at Istituto Nazionale dei Tumori of Milan from April 2009 to April 2019 were examined. Ventana Benchmark in situ hybridization (ISH) system was used for EBV-encoded RNA (EBER) ISH. Patients were considered EBV positive when the presence of EBV in tumour cells was detected in EBER-ISH analysis. Medical records were reviewed to obtain data on clinical characteristics and survival outcomes.

Results: One-hundred-seventy stage IV GC patients were analyzed: EBV infection was found in 3 cases (1.8%). After a median follow up of 23.4 months, median overall survival (mOS) was 15.83 months in the EBV negative population, while it was not reached in EBVaGC cases. At the univariate analysis, EBV infection was significantly associated with high grade tumours (66.7% vs 50%, p<0.001) and the presence of distant nodal metastases at diagnosis, without liver and /or peritoneal lesions (100%, p<0.001).

Conclusions: Our single institution retrospective analysis shows that the prevalence of EBVaGC metastatic patients is small, lower than expected based on data derived from asiatic population series. Indeed, our results suggest that this patients subgroup is characterized by extraordinary long survival, even in the pre-immunotherapy era. Further investigations are warranted in larger patient series.

PLASMATIC CXCL8 IS A MARKER FOR TGFß-ACTIVATED KINASE 1 (TAK1) ACTIVATION WHICH MAY PREDICT RESISTANCE TO NANOLIPOSOMAL IRINOTECAN (nal-IRI) IN GEMCITABINE-REFRACTORY PANCREATIC CANCER (PC) PATIENTS

Zecchetto C.¹, Merz V.¹, Santoro R.¹, Simionato F.¹, Piro G.¹, Cavaliere A.¹, Casalino S.¹, Auriemma A.¹

¹Università di Verona, Verona

Background: PC remains one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We recently identified TAK1 as a central hub integrating the most relevant signals sustaining PC chemoresistance. nal-IRI is a novel standard of care for metastatic PC patients who had been previously treated with a gemcitabine-based therapy.We endeavoured to identify circulating markers for TAK1 activation predicting chemoresistance in this clinical setting.

Methods: In vivo activity of nal-IRI was validated in an orthotopic nude mouse model of PC cells expressing TAK1- specific shRNA or a scramble sequence as control. Using multiplex xMAP/Luminex technology, the samples from 77 metastatic PC patients progressing after gemcitabine and prospectively enrolled to receive nal-IRI + 5FU/LV were analysed for the plasma concentration of 20 different TH1and TH2cytokines. The optimal cut-off thresholds able to significantly predict patient outcome were obtained based on the maximization of the Youden index.

Results: A significant tumor volume reduction in mice bearing shTAK1 PC treated with nal-IRIwas detected, whereas controls were resistant to this agent. Differential gene expression profiling revealed CXCL8 as the most significantly downregulated gene coding for secreted proteins in shTAK1 PC cell lines. After a 27 month median follow-up, in the overall population the median progression-free survival (PFS) was 3.3 months (95% CI = 3.039-3.561) and the median overall survival (OS) was 7.3 months (95% CI = 5.487-9.113). Cox proportional hazard regression multivariate analysis confirmed CXCL8 as the circulating factor most significantly correlated with survival outcomes. Patients with CXCL8 higher than 16.68 pg/mL cut-off value had a PFS of 2.8 vs 3.4 months (HR = 2.61, 95% CI = 1.42-4.79, p = 0.0014), and an OS of 5.3 vs 8.9 months (HR = 3.7, 95% CI = 1.93-7.11, p = 2.6e-05), respectively.

Conclusions: We identified CXCL8 as the most significant circulating marker of TAK1 activation. Our study candidates CXCL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine- refractory PC patients.

RELATIONSHIP BETWEEN CHANGE IN A-FETOPROTEIN (AFP) AND PATIENT (pt) SURVIVAL IN HEPATOCELLULAR CARCINOMA (HCC): A REAL-WORLD ELECTRONIC MEDICAL RECORDS (EMR) DATABASE STUDY

Hess L.¹, Cui Z.L.¹, Sugihara T.², Fang Y.², Girvan A.¹, Abada P.B.¹, Brandi G.P.³

¹Eli Lilly and Company, Indianapolis, IN, USA, Indianapolis; ²Syneos Health, Indianapolis, IN, USA, Indianapolis; ³Department of Experimental, Diagnostic and Speciality Medicine, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna, Italy, Bologna

Background: Serum AFP levels are used as diagnostic and prognostic markers for pts with HCC. Assessment of clinical relevance of changes in AFP over time outside of clinical trials is lacking. This study explored the relationship between changes in AFP levels and overall survival (OS) in a real-world setting.

Material and methods: This retrospective analysis used the IMS Oncology EMR database (US patients 12/01/2007-12/31/2014). Eligible pts were diagnosed with HCC, 18+ years old, had ⩾1 AFP test recorded 60 days prior to 180 days after diagnosis and received anticancer therapy ⩽180 days after diagnosis. Survival analyses were by Kaplan-Meier method. The gamma-frailty model was used to correlate AFP change utilizing previously reported definitions of AFP change (above/below 400 ng/mL, ⩾20 ng/mL, ⩾7 ng/mL/month, ±20%, ±50%) and OS.

Results: 907 pts met eligibility criteria (77.3% male, median 65 years). Of 697 pts with AFP prior to start of first-line therapy (1L), 453 (65%) with baseline AFP <400 ng/mL had an OS of 4.2 months and 244 (35%) with ⩾400 ng/mL an OS of 2.9 months. An increase in AFP was associated with a decrease in OS in 278 patients with baseline and 1L AFP (Table). Of the 101 pts with an AFP test before start of second-line therapy, 32.7% had AFP ⩾400 ng/mL.

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Relationship between change in AFP and OS
Observed AFP change during 1L	N	Median OS (95% CI), months	Cross-ratio	Kendall’s Tau
Decrease (≥) to <400 from ⩾400 ng/mL	20	14.3 (4.8–30.9)	1	0
↓ ⩾20 ng/mL	85	7.4 (5.7–11.9)	1	0
↓ ⩾7 ng/mL/month	68	6.8 (5.0–12.7)	1	0
↓ ⩾20%	98	11.1 (7.3–13.2)	1	0
↓ ⩾50%	51	12.2 (7.3–18.2)	1	0
Increase (≥) to ⩾400 from <400 ng/mL	18	5.9 (3.6–7.4)	1.506	0.202
↑ ⩾20 ng/mL	140	4.8 (3.7–5.5)	1.902	0.311
↑ ⩾7 ng/mL/month	124	4.5 (3.1–5.2)	2.006	0.335
↑ ⩾20%	141	5.2 (4.1–6.5)	1.841	0.296
↑ ⩾50%	109	5.4 (4.5–6.9)	1.755	0.274

Conclusions: Increases and decreases in AFP during 1L, regardless of AFP change definition, were generally associated with shorter and longer OS, respectively. Conclusions are limited by the risk of immortal time and selection bias, as not all patients had multiple AFP measures recorded.

Disclosure: This was an unfunded research project. Eli Lilly and Company provided employee time and database access.

PREOPERATIVE NUTRITIONAL STATUS AS A PREDICTIVE FACTOR OF SURVIVAL FOLLOWING RESECTION FOR PANCREATIC DUCTAL ADENOCARCINOMA

Trestini I.¹, Paiella S.², Sperduti I.³, Sandini M.⁴, Elio G.², Melisi D.¹, Auriemma A.¹, Soldà C.¹, Tregnago D.¹, Avancini A.⁵, Secchettin E.², Bonamini D.², Malleo G.², Gianotti L.⁴, Pilotto S.¹, Bassi C.², Milella M.¹

¹Department of Oncology, Pancreas Institute, University of Verona Hospital Trust, Verona; ²General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona; ³Biostatistical Unit - Clinical Trials Center, Bio-Statistics Unit, Regina Elena National Cancer Institute, Rome; ⁴Department of Surgery, School of Medicine and Surgery, San Gerardo Hospital, University of Milano-Bicocca, Monza; ⁵Biomedical Sciences, Department of Medicine, University of Verona Hospital Trust, Verona

Background: Nutritional derangements and loss of skeletal muscle mass are common hallmarks of pancreatic ductal adenocarcinoma (PDAC). Their early detection and management are usually overlooked in routine practice, so their impact on outcome is poorly described. Therefore, this study aimed to investigate the prognostic value of nutritional status in patients (pts) undergoing surgery for PDAC.

Patients and methods: Clinical data of non-consecutive pts submitted to surgery for PDAC from November 2015 to January 2018 at General and Pancreatic Surgery Unit, Pancreas Institute, University Hospital of Verona, were prospectively collected. Nutritional screening was performed according to the standard of Nutritional Risk Screening (NRS)-2002. Body composition was evaluated using Bioelectrical Impedance Vector Analysis (BIVA) the day before the scheduled surgery. Clinical, pathological and nutritional data were correlated to disease-free/overall survival (DFS/OS) using a Cox and logistic regression model. Kaplan-Meier curves were compared with Log-Rank.

Results: Overall data from 73 patients (41 males [56.2%], 32 females [43.8%]) were gathered. The median age was 65 years [range 37-81] and the median follow-up was 11 months [range 1-40]). The majority (80.8%) were at risk of malnutrition (NRS-2002⩾3), despite median BMI was 23.9 kg/m². At multivariate analysis, stage (HR 4.30, 95% CI 1.03-17.92, p = 0.045), NRS-2002 (HR 6.51, 95% CI 1.39-30.38, p = 0.017), fat-free mass (FFM) (HR 1.08, 95% CI 1.02-1.14, p = 0.013) were significant independent predictors for OS. Particularly, patients with preoperative NRS-2002 ⩽3 had significantly longer 2-year OS than those with NRS-2002>3 (94% vs 75%, p = 0.02). Conversely, BMI did not affect OS. Twenty-four patients (32.9%) were treated with neoadjuvant therapy. NRS-2002 was significantly higher in this subset of patients (p = 0.026), with a significant difference according to chemotherapy regimens (Folfirinox vs. Gemcitabine/Nab-paclitaxel) (p = 0.035). In pts treated with adjuvant chemotherapy (n = 33, 45.2%) FFM correlated with worse DSF and OS (p = 0.039 and p = 0.039, respectively).

Conclusions: Our analysis suggests that preoperative malnutrition and FFM have a detrimental impact on OS in PDAC. Therefore, preoperative nutritional screening and, possibly, targeted nutritional intervention may improve outcomes in resectable PDAC pts, particularly in those who are candidate to neoadjuvant therapy.

RAMUCIRUMAB (RAM) AS SECOND-LINE TREATMENT IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA (HCC) AND ELEVATED BASELINE A-FETOPROTEIN (AFP): AN ANALYSIS OF AFP KINETICS IN THE PHASE 3 REACH-2 STUDY

Finn R.¹, Kudo M.², Kang Y.³, Yen C.⁴, Galle P.⁵, Llovet J.⁶, Assenat E.⁷, Brandi G.⁸, Lim H.Y.⁹, Pracht M.¹⁰, Rau K.¹¹, Merle P.¹², Motomura K.¹³, Ohno I.¹⁴, Daniele B.¹⁵, Shin D.¹⁶, Gerken G.¹⁷, Abada P.¹⁸, Hsu Y.¹⁹, Zhu A.²⁰

¹University of California Los Angeles, Los Angeles, CA, USA, Los Angeles; ²Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka, Japan, Osaka; ³Department of Oncology, Asan Medical Center, Seoul, Korea, Seoul; ⁴National Cheng Kung University Hospital, Tainan, Taiwan, Tainan; ⁵Universitätsmedizin, Mainz, Germany, Mainz; ⁶Icahn School of Medicine at Mount Sinai, New York, NY, USA, New York; ⁷CHU de Montpellier, Montpellier, France, Montpellier; ⁸Policlinico Sant’Orsola-Malpighi, Bologna, Italy, Bologna; ⁹Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Seoul; ¹⁰Centre Eugène Marquis, Rennes, France, Rennes; ¹¹Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung, Taiwan, Kaohsiung; ¹²Hôpital de la Croix-Rousse, Lyon, France, Lyon; ¹³Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan, Fukuoka,; ¹⁴Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan, Chiba; ¹⁵G. Rummo Hospital, Benevento, Italy, Benevento; ¹⁶Gachon University Gil Medical Center, Incheon, Korea, Incheon; ¹⁷Universitätsklinikum Essen AöR, Essen, Germany, Essen; ¹⁸Eli Lilly and Company, Indianapolis, IN, USA, Indianapolis; ¹⁹Eli Lilly and Company, New York, NY, USA, New York; ²⁰Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA, Boston

Background: REACH-2 demonstrated a significant survival benefit with RAM vs placebo in the second-line treatment of patients with advanced HCC and AFP ⩾400 ng/mL. This analysis investigated changes in AFP during treatment, as well as potential relationships with survival or progression.

Material and methods: Patients were randomized (2:1) to RAM 8 mg/kg IV or placebo Q2W plus best supportive care until disease progression or unacceptable toxicity. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed at each time point up to Cycle 12 with descriptive statistics and Wilcoxon rank sum test between treatment arms. AFP response was defined as ⩾20% decrease from baseline. The association between AFP progression and radiographic progression in each time interval was assessed by odds ratio (OR) and Fisher’s exact test. Time to AFP progression and time to radiographic progression (TTP) were evaluated by the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test. AFP progression was defined as ⩾20% increase from baseline. Hazard ratio (HR) was generated using a stratified Cox regression model.

Results: AFP response was significantly higher with RAM compared with placebo (42.1% vs 10.5%, p<0.0001). Overall survival (OS) was longer in patients with AFP response (13.5 months) than in patients without (6.7 months), irrespective of treatment (HR 0.470, p<0.0001). The median percent increase in AFP level from baseline was smaller in the patient population treated with RAM (0.4%, 6.1%, 15.4%, 10.8%) than with placebo (45.7%, 98.5%, 122.2%, 91.3%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.422, p<0.0001) and TTP (HR 0.427, p<0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 2.44, p<0.0084) and at 12 weeks (OR 1.89, p = 0.0430).

Conclusions: Changes in AFP levels were associated with TTP and OS. RAM prolonged both time to AFP progression and radiographic TTP, and appeared to slow the rate of AFP increase during treatment.

© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 American Society of Clinical Oncology - Gastrointestinal Cancers Symposium. All rights reserved.

INTERIM ANALYSIS OF BI-CAUSE STUDY (BILIARY CANCER IN ITALY: A STUDY ON CHOLANGIOCARCINOMA CAUSES AND RISK FACTORS)

Milanesio M.C.¹, Filippi R.², Aprile G.³, Casagrande M.⁴, Basile D.⁵, Depetris I.⁶, Murgioni S.⁶, Ricci V.⁷, Delcuratolo S.⁸, Sperti E.⁹, Fenocchio E.¹⁰, Cagnazzo C.¹¹, Aglietta M.², Leone F.¹²

¹Department of Oncology, University of Turin; Department of Medical Oncology, Candiolo Cancer Institute, FPO - IRCCS, Candiolo; ²Department of Oncology, University of Turin; Department of Medical Oncology, Candiolo Cancer Insititute, FPO - IRCCS, Candiolo; ³Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine; Department of Oncology, San Bortolo General Hospital, ULSS8 Berica, East District, Vicenza; ⁴Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Udine; ⁵Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Azienda Sanitaria Universitaria Integrata of Udine, 33100 Udine, Italy, Udine; ⁶Unit of Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology - IRCCS, Padova; ⁷Medical Oncology, A. O. S. Croce and Carle Teaching Hospital, Cuneo; ⁸Clinical Trial Center - IRCCS Istituto Tumori “Giovanni Paolo II”, Bari; ⁹Division of Medical Oncology, Ordine Mauriziano Hospital, Torino; ¹⁰Department of Medical Oncology, Candiolo Cancer Insititute, FPO - IRCCS, Candiolo; ¹¹Unità di Ricerca e Sviluppo Clinico S.C. Oncoematologia Pediatrica, AOU Città della Salute e della Scienza di Torino, Presidio Ospedaliero Infantile Regina Margherita, Torino; ¹²S.C. Oncology, Ospedale degli Infermi (Ponderano), Azienda Sanitaria Locale di Biella, Biella

Background: Cholangiocarcinoma (CC), partitioned in intrahepatic (ICC) or extrahepatic (ECC) subsites, is a rare cancer in Italy, whose etiology is still largely unexplained. The majority of the existing etiologic studies is based on Eastern populations and is inherently biased by patient selection, retrospective nature, small sample size or inappropriate grouping with other cancers, such as gallbladder and ampullary cancer.

Patients and Methods: The BI-CAUSE trial is an ongoing multi-centre, observational, prospective study aimed to depict the etiologic landscape of CC in Italy. Per protocol, CC patients admitted to oncologic care are administered an interview on life-style and concomitant conditions and undergo additional laboratory testing at the beginning of chemotherapy; moreover, clinical and pathology informations are collected.

Results: We hereby present results from the first 90 enrolled patients (pts) (male 60.0%; caucasian 98.9%; median age 65 years). ICC were 58.5% of the sample, ECC 41.5% (peri-hilar 12.2%, distal 29.3%). M:F ratio was numerically higher in ECC than in ICC (2.1:1 vs 1.1:1, p = 0.15), whereas median age of onset was identical. The main histology was adenocarcinoma (88.7%), further defined as papillary, mucinous or desmoplastic in 2 cases (2.5%) each; combined hepatocholangiocarcinoma was 3.8% (7.1% of ICC cases).

Active or former smokers were 59.5% of the sample, and most (46.2%) had cumulated a moderate or high exposure (⩾10 pack-years); 33.7% were at least moderate drinkers (⩾2 alcohol unit/day). Only 29.1% did not meet any of the lab criteria of dyslipidemia; 17.0% had type-2 diabetes mellitus; 41.4% had a BMI ⩾25 Kg/m², including 13.1% with BMI ⩾30 Kg/m². One pt had a history of ulcerative rectocolitis, while none of Crohn’s disease, primary biliary cholangitis (PBC) or primary sclerosing cholangitis; however, 7.5% were positive for anti-mithocondrial antibodies (AMA). HBcAb+ pts were 19.9% [ICC 27% vs ECC 7%, p = 0.058], of whom 2.7% were HBsAg+ (1 with detectable HBV-DNA) and 2.7% co-infected with HCV.

Conclusions: In this interim analysis, a high incidence of alcohol consumption, smoke, and features of dismetabolic state (diabetes mellitus, dyslipidemia, excess weight), was observed. The etiologic role in CC of viral hepatitis B -already demonstrated in Countries with high incidence of both entitites- appears confirmed, particularly for ICC. The novel finding of serum AMA in the absence of clinical PBC deserves further investigation.

OXALIPLATIN-BASED THERAPY AND ECOG PERFORMANCE STATUS (PS) ARE PREDICTIVE OF SURVIVAL IN SECOND-LINE ADVANCED PANCREATIC CANCER (PC) AFTER GEMCITABINE PLUS NAB-PACLITAXEL TREATMENT

Merz V.¹, Zecchetto C.¹, Cavaliere A.¹, Casalino S.¹, Simionato F.¹, Milella M.¹, Melisi D.¹, Caffo O.²

¹Università di Verona, Verona; ²Ospedale Santa Chiara, Trento

Background: The most effective chemotherapeutic regimen in patients (pts) affected by PC in the second-line setting has not been defined yet. In two phase 3 randomized trials, doublet chemotherapy provided a survival benefit compared to monotherapy, showing the superiority of OFF (oxaliplatin + fluorouracil) regimen and nal-irinotecan (nal-IRI) + fluorouracil/leucovorin (FU/LV) over FU/LV. Clinical decision is mainly based on persistent toxicities by first-line treatment, and patients preference.

The aim of this analysis is to evaluate different second-line regimens in a real-world population of pts progressing under gemcitabine plus nab-paclitaxel first-line treatment.

Material and methods: Clinical data of pts affected by advanced PC receiving a doublet chemotherapy regimen in the second-line setting between January 2015 and December 2018 were retrospectively reviewed. All pts received at least 3 cycles of gemcitabine and nab-P as first-line therapy.

Median progression free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier method with 95% CI (confidence interval). Cox-regression model was applied to the data with univariate approach.

Results: 136 pts were included in our analysis. The median age was 65 (35-79). 55.9% had head primary tumor location. The majority of pts had an ECOG PS = 0 (65.1% PS 0, 28.7% PS 1, 6.3% PS 2) at the beginning of second line. About one third of pts (33%) previously underwent surgery. Half of pts (48.6%) received a third or further lines of treatment.

Second-line PFS and OS were 3.25 (95%CI 3.01-3.49) and 9.14 (95%CI 7.82-10.47) months, respectively. We measured a significant longer OS in pts receiving an oxaliplatin-based therapy (FOLFOX/XELOX) compared that in pts receiving irinotecan-based chemotherapy (FOLFIRI/nal-IRI+5-FU) (13.75 vs. 8.04 months, p = 0.014). Pts with ECOG PS = 0 had a better OS compared to ECOG PS 1 pts (10.5 vs. 7.79 months respectively, p = 0.044). No difference was detected in PFS.

Conclusions: Pts receiving an oxaliplatin-based chemotherapy and with PS ECOG = 0 had a longer OS in the second-line setting. However, no differences have been shown considering PFS and no analyses have been performed regarding different regimens (e.g. irinotecan versus nal-IRI) because of the limited number of pts included. Further possible predictive factors could be investigated by expanding the population analyzed.

TUMOR MICROENVIRONMENT (TME) IN RESECTED PANCREATIC CANCER (PC): EVALUATION OF FIBROSIS, TUMOR-INFILTRATING LYMPHOCYTES (TILS), AND ANGIOGENESIS

Cortiula F.¹, De Pellegrin A.², Iacono D.³, Basile D.⁴, Bertoli E.¹, Garattini S.K.⁴, Parnofiello A.¹, Cattaneo M.¹, Palmero L.¹, Andreotti V.J.¹, Cardellino G.G.³, Casagrande M.³, Bonotto M.³, Karim R.³, Ermacora P.³, De Maglio G.², Pizzolitto S.², Pella N.³, Puglisi F.⁴, Fasola G.³

¹Department of Medicine (DAME), University of Udine; Department of Oncology, University Hospital of Udine, Udine; ²Department of Pathology, University Hospital of Udine, Udine; ³Department of Oncology, University Hospital of Udine, Udine; ⁴Department of Medicine (DAME), University of Udine; Department of medical oncology and cancer prevention, IRCCS CRO National Cancer Institute, Aviano

Background: Inflammation may promote cancer development and, in turn, an immune suppressive TME with abundant fibrosis may favor tumor progression. Aim of the study was to evaluate the association of fibrosis, TILS (CD4+ and CD8+), blood and lymphatic vessels, within the PC TME, with other PC pathological features, and their impact on disease-free survival (DFS).

Material and methods: The study included 37 consecutive patients (pts) who underwent surgery for PC from January 2012 to December 2017 at the University Hospital of Udine, Italy. Immunohistochemical analyses for CD4, CD8, ERG (blood vessels), D2-40 (lymphatic vessels) and Masson’s Trichrome stain were performed. CD4+ and CD8+ lymphocytes were evaluated as the mean value derived from five counts in hot spot High-Power Field; ERG and D2-40 as the average in 3 fields at 10x magnification; fibrosis as proportion to the total neoplastic mass, clustering every ten percentiles. The prognostic impact on DFS was analyzed through Cox regression model. Associations were explored by Wilcoxon rank-sum test or Kruskal-Wallis test, as appropriate.

Results: Median age was 67.5 years; 19 (51%) pts were male. R0 resection was observed in 28 (76%) pts whereas 9 (24%) pts achieved R1 resection. The median percentile of fibrosis was 30-40%; median number of blood vessels was 13; median number of lymphatic vessels was 5; median CD4+ and CD8+ lymphocytes were 43 and 33, respectively. A higher number of CD4+ was associated (p = 0.016) with pathological nodal involvement (pN1). Higher CD8+ lymphocytes count was associated (p = 0.056) with higher tumor grade (G3 vs G2/G1). No association was shown with pts age, tumor size, vascular or neural invasion, PC site (head vs body vs tail), and site of further disease progression. No association was observed between fibrosis and TILS. No prognostic value was shown for neither fibrosis nor angiogenesis nor TILS.

Conclusions: In resected PC, intriguing association was observed between TILS and nodal involvement. Further investigations and validation on larger case-series are needed to better explore the prognostic impact of TME in pts with resected PC.

NIVOLUMAB IN METASTATIC GASTRIC CANCER PATIENTS PROGRESSED AFTER TWO OR MORE CHEMOTHERAPY LINES: DATA FROM A WESTERN POPULATION

Petrillo A.¹, Sabetta R.², Tirino G.², Panarese I.², Pompella L.², Zito Marino F.², Pappalardo A.², Caterino M.², Ventriglia A.², Laterza M.M.², Morgillo F.², Orditura M.², Ciardello F.², Franco R.², De Vita F.²

¹Università degli Studi della Campania “L. Vanvitelli”, Napoli; ²Università degli Studi della Campania, Napoli

Background: The phase III ATTRACTION-2 trial showed that Nivolumab is a new treatment option for unselected Asian patients (pts) with advanced gastric (GC) and gastro-oesophageal (GEJ) cancer progressed after two or more previous chemotherapy regimens. However, still today there is a lack of evidence about its efficacy in non-Asian pts. The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life western population.

Materials and methods: Pts progressed after two or more chemotherapeutic regimens for advanced disease with performance status of 0 or 1 according to ECOG and without ongoing or previous autoimmune disease were eligible for treatment. Pts were unselected for PD-L1 tumor expression or microsatellite status. All pts received Nivolumab 3mg/Kg every 14 days until progression or unacceptable toxicities. Statistical analysis was performed by SPSS 21.0 software.

Results: 15 pts were treated with Nivolumab as off-label treatment from September 2017 to April 2019. Pts received Nivolumab as third (80%) or fourth line of treatment (20%). The safety profile was in line with the literature and only 6.6% of pts showed unacceptable toxicities, requiring the discontinuation (prolonged anemia and thrombocytopenia G3). Best overall responses were complete response in 2 pts, partial response in one pts and stable disease in 2 pts. Median duration of response was 2 months (range: 2-15 months). Eleven pts discontinued Nivolumab due to PD, worsening of conditions or death, whereas treatment is ongoing in 4 pts. With a median follow-up of 17 months (95% CI: 6.2-27.7), median OS was 6 months (95% CI: 0.5-11.5) and median PFS was 3 months (95% CI: 0.47-5.5). Median OS was 6,18 and 19 months in responders pts. Median treatment duration was 4 months (range:1-19 months). Data for PD-L1 and microsatellite status were retrospectively collected for 10 pts as following: MSS/MSI: 7/3; PD-L1 positive (⩾1%)/negative: 3/7. Although no statistically significant difference in OS or PFS was reported according to PD-L1 expression, neutrophil/lymphocyte ratio or microsatellite status, however all responders had PD-L1 positive or MSI status.

Conclusions: Our results showed that Nivolumab is feasible and effective in real-life unselected western pts affected by advanced GC and GEJ. Moreover, these results might suggest that PD-L1 expression and microsatellite status could be predictive factors for nivolumab efficacy after confirmation in a larger sample.

FOLFIRINOX VERSUS GEMCITABINE-NABPACLITAXEL AS NEOADJUVANT STRATEGIES IN LOCALLY ADVANCED PANCREATIC CANCER: A RETROSPECTIVE MONOCENTRIC STUDY

Napolitano F.¹, Foschini F.¹, Servetto A.¹, Marciano R.¹, Mozzillo E.¹, Carratù A.C.², Santaniello A.¹, De Placido P.¹, Cascetta P.¹, Formisano L.¹, De Placido S.¹, Bianco R.¹

¹Università degli Studi di Napoli “Federico II”, Napoli; ²Università degli Studi di Napoli, Napoli

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive disease, being the 4th leading cause of cancer mortality, expected to achieve second place by 2030. Around one third of cases are diagnosed as locally advanced (LA-PDAC), for which the therapeutic strategy is still unclear.

Methods: Retrospective analysis of patients with LA-PDAC, at least 18 years of age, treated between October 2014 and April 2019, with either FOLFIRINOX or Gemcitabine-NabPaclitaxel as neoadjuvant treatments. The information collected at baseline included the patients’ age, gender, performance status assessed following ECOG scale (PS ECOG), CA19.9, pancreatic lesion site (head vs body/tail), staging (TNM). At the end of treatment, all of the above variables were assessed again.

Results: A total of 73 patients were diagnosed with LA-PDAC during the observation time: 18 patients were offered best supportive care or monotherapy treatment, 35 patients FOLFIRINOX (FFN) and 20 patients Gemcitabine Nab-Paclitaxel (GemNab). At the time of analysis, 2 patients in the GemNab arm were still on treatment. The population characteristics were similar in the two treatment groups. Eighteen patients of the 55 evaluated underwent surgery (32.7%), 13 in the FFN group (37.14%), 5 in the GemNab group (25%). Resection margins were positive in 4/13 and 1/5 patients, in the FFN and in the GemNab groups respectively. The median Disease Free Survival (mDFS) was 70.4 weeks in the resected population; 70.4 weeks in the FFN group and 85.9 weeks in the Gem Nab group (p = 0.96). The median Overall Survival (mOS) for unresected patients was 57 weeks, 73.6 weeks for the FFN group and 57 weeks for the GemNab group (p = 0.26).

Conclusions: The results from our study showed that LA-PDAC patients can be addressed to neoadjuvant strategies with the objective of R0 resections: 18 of the 55 patients evaluated underwent surgery and in more than 70% of cases the margins were negative. A survival benefit can be observed: mDFS of resected patients (70.4 weeks) is even longer than mOS of the unresected population (57 weeks). The OS substantial difference will be appreciated with a longer follow up.

IMMUNE CHECKPOINTS INHIBITORS IN PRE-TREATED GASTRIC CANCER PATIENTS: RESULTS FROM A LITERATURE-BASED META-ANALYSIS

Roviello G.¹, Rosellini P.², Corona S.P.³, D’Angelo A.⁴, Paderi A.¹, Dreoni L.¹, Derio S.¹, Rossi V.¹, Mini E.¹

¹Università di Firenze, Firenze; ²Univerità di Siena, Siena; ³Univerità di Trieste, Trieste; ⁴Univerità di Bath, Bath

Background: Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomized controlled trials to assess the efficacy of the novel immune check-point inhibitors (ICIs) in metastatic gastric cancer.

Materials and methods: The primary outcome was overall survival. We planned a subgroup analysis for OS according to PD-L1 status, age (65 years was the cut-off), tumour location (gastric versus gastro-oesophageal junction), sex and ECOG performance status (1 versus 0).

Results: Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved OS in the experimental arm, in the absence of statistical significance (HR = 0.87, 95%CI: 0.64-1.18; P = 0.37). The subgroup of patients with PD-L1 positive tumours (HR = 0.82 vs 1.04) and gastroesophageal junction cancer (HR = 0.82 vs 1.04) showed a statistically significant advantage.

Conclusions: This study doesn’t support the efficacy of immune check-point inhibitors in unselected patients with metastatic gastric cancer. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICIs’ efficacy.

ROLE OF CHEMORADIATION (CRT) IN THE ADJUVANT TREATMENT OF RADICALLY RESECTED PANCREATIC CANCER (PC) PATIENTS (pts): A MONO-INSTITUTIONAL RETROSPECTIVE ANALYSIS

Bensi M.¹, Salvatore L.², Mattiucci G.C.³, Di Stefano B.¹, Cellini F.⁴, Bagalà C.², Zurlo V.¹, Maratta M.G.¹, Chiaravalli M.¹, Masiello V.⁴, Sara R.¹, De Franco P.¹, Valentini V.³, Tortora G.⁵

¹Università Cattolica del Sacro Cuore, Roma, Italy, Roma; ²U. O.C. Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario “A. Gemelli” - IRCCS, Roma, Italy, Roma; ³U.O.C. Radioterapia, Fondazione Policlinico Universitario “A.Gemelli” - IRCCS, Roma, Italy; Università Cattolica del Sacro Cuore, Roma, Italy., Roma; ⁴U.O.C. Radioterapia, Fondazione Policlinico Universitario “A. Gemelli” - IRCCS, Roma, Italy, Roma; ⁵U.O.C. Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario “A. Gemelli” - IRCCS, Roma, Italy; Università Cattolica del Sacro Cuore, Roma, Italy, Roma

Background: To date, the standard of care for resectable PC pts is upfront radical surgery followed by adjuvant chemotherapy (CT). The role of CRT in this setting remains controversial and often it is reserved for PC pts with a high risk of local relapse, due to positive margins and/or positive lymph-nodes.

Method: Radically resected PC pts receiving adjuvant CT and CRT at our Institution were retrospectively collected. The objective of the analysis was to evaluate the role of postoperative CRT in terms both of disease-free survival (DFS) and overall survival (OS). The association with rate of local recurrence, DFS and OS was evaluated for both margin (R0 vs R1/R2) and nodal status (pN0 vs pN1/2) and also for the combination of these two variables (R0 and pN0 vs R1/2 and/or pN1/2).

Results: From January 2000 to April 2018, a total of 106 radically resected PC, treated with postoperative CT and CRT, were identified. Pts median age was 62 years (range 41-83); 45% of pts were females. Tumor characteristics were the following: head tumor location 81%; stage I, II and III was 6%, 58% and 14%, respectively, not applicable (NA) in 22% of cases; margin status was R0 in 68%, R1 in 21%, R2 in 3% and NA in 8% of pts; 95% of pts had ductal adenocarcinoma; pN0 and pN1/pN2 was 43% and 56%, respectively (NA 1%); grading G1 was 2%, G2 54% and G3 30%; pT1 2%, pT2 17%, pT3 69%, pT4 12%. Adjuvant gemcitabine was administered to 75% of pts; RT technique was intensity modulated RT and 3D RT in 22% and 75% of cases, respectively. Disease progression (PD) was observed in 66% of pts: local and distant recurrence occured in 35% and 47% of cases, respectively. Median DFS was 19.2 months, median OS was 36.7 months. No significant association of margin and nodal status with local recurrence, DFS and OS was observed.

Conclusions: Our analysis, although limited by the small sample size, its retrospective nature and the lack of pts treated with a more efficacious adjuvant CT such as FOLFIRINOX, might suggest a possible role of postoperative CRT in maximizing adjuvant treatment of radically resected PC pts, in particular of those with poor prognostic factors such as positive margins and/or positive lymph-nodes.

FOLFIRINOX AFTER FIRST LINE GEMCITABINE BASED CHEMOTHERAPY IN METASTATIC PANCREATIC CANCER: A MONO-INSTITUTIONAL EXPERIENCE

Foschini F.¹, Napolitano F.¹, Servetto A.¹, Marciano R.¹, Mozzillo E.¹, Carratù A.C.¹, Santaniello A.¹, De Placido P.¹, Cascetta P.¹, Formisano L.¹, De Placido S.¹, Bianco R.¹

¹AOU Federico II, Napoli

Background: Pancreatic adenocarcinoma represents the fourth cause of death among both males and females. For many years the standard of care for the locally advanced or metastatic setting was Gemcitabine-based chemotherapy. There are only few data on the safety and efficacy of FOLFIRINOX or fluoropyrimidine (5FU)-based chemotherapy after Gemcitabine-based first line’s failure.

Methods: From February 2013 to August 2018, a total of 102 locally advanced or metastatic pancreatic patients, who progressed from Gemcitabine-based first line chemotherapy, were candidate to receive a second line chemotherapeutic treatment based on 5-FU. The goal of this study was to evaluate the progression free survival (PFS); overall survival (OS), and safety were also analyzed.

Results: At the time of the analysis, out of 102 patients with metastatic pancreatic adenocarcinoma that underwent first-line chemotherapy with gemcitabine-based schedules (92.5% of these patients were treated with Gemcitabine-NabPaclitaxel), only 37 of them succeeded to receive a second line 5FU-based treatment and only 26 of them succeeded to receive 4 cycles of chemotherapy, at least. The schedules used were FOLFIRINOX (11 patients), FOLFOX (7 patients), FOLFIRI (8 patients). Median PFS was longer in the FOLFIRINOX group compared to FOLFOX (32.1vs23 weeks, p = 0.03) and FOLFIRI (32.1vs15.8 weeks, p = 0.004), while there was no difference between the FOLFOX and FOLFIRI groups (23vs15.8 weeks, p = 0.34). As well as the PFS, the median OS, calculated as the overall survival from the start of second-line treatment, was significantly higher in the FOLFIRINOX group compared with FOLFOX (11.6vs6.9 months, p = 0.01) and FOLFIRI (11.6vs6.4 months, p = 0.001). Main grade 3/4 adverse events were anemia and neutropenia, and they were higher in the FOLFIRINOX and FOLFOX group. Moreover, there was no difference among the three groups of treatment for age, sex, stage of disease, adjuvant treatment performed, and the presence of biliary stent. However, patients enrolled in the FOLFIRINOX group had better performance status (ECOG0 = 80%) compared with FOLFOX and FOLFIRI (ECOG1 = 80%).

Conclusions: FOLFIRINOX is efficacy and a well tolerated chemotherapeutic schedule as second-line treatment in patients with advanced pancreatic cancer after gemcitabine-based first line. Patients should be selected according to performance status, comorbidities and previous toxicities reported during first line.

FLOT REGIMEN AS PERIOPERATIVE TREATMENT IN RESECTABLE GASTRIC CANCER: SAFETY UPDATE AND PROGNOSTIC FACTORS ANALYSIS FROM A MONO-INSTITUTIONAL EXPERIENCE

Tirino G.¹, Petrillo A.¹, Pompella L.¹, Pappalardo A.¹, Caterino M.¹, Ventriglia A.¹, Laterza M.M.¹, Orditura M.¹, Ciardiello F.¹, De Vita F.¹

¹Università degli studi della Campania “L. Vanvitelli”, Naples

Background: FLOT-4 is a new standard of care for resectable gastric (GC) and gastroesophageal (GEJ) cancer. Our retrospective analysis aims to evaluate safety and efficacy of FLOT in a real-life population and to identify potential prognostic factors.

Methods: from January 2015 to April 2019, 45 patients (pts) received FLOT (docetaxel 50 mg/mq d1, oxaliplatin 85 mg/mq d1, leucovorin 200 mg/mq d1, and 5FU 2600 mg/mq as 24h infusion all q14) as perioperative treatment. All pts received PEG-G-CSF. Based on our previous data on Neutrophil to lymphocyte ratio (NLR) in GC (Petrillo A, Future Oncology 2018), we evaluated this factor from pretreatment blood count.

Results: median age was 62 years (range 36-78), male/female: 31/14, PS ECOG 0: 97.8%, 1: 2.2%; tumor location: Siewert I: 15.5%; Siewert II/III: 33.3%, stomach: 51.2%; adenocarcinoma with signet ring cells (SRC): 37.8%; Lauren’s type: intestinal 24.4%, diffuse 28.9%, unknown 46.7%; stage: IB: 4.5%, II: 55.5%, III: 40%. Most frequent adverse events (AE) were fatigue G1 (60%), nausea G1 (70%) and neurotoxicity G1 (22%); most common grade 3 AE was neutropenia (2.2%). No grade 4-5 toxicity has been described. Perioperative treatment is ongoing in 8.9%, while 80% underwent surgery. R0 and R1 resection were achieved in 84.4% and 15.6% respectively. Among evaluable pts, 11% reported TRG1, 14% TRG 3, 25% TRG 4, 11% TRG5 and TRG was not reported in 39% of cases. The majority of TRG 4/5 were diffuse with SRC component (54%). With a median FUP of 14 months (mo) [95% CI: 11.5-16.6], mOS and mPFS were not reached. OS was higher in pts with no SRC tumors [NR vs 14 mo, p = 0.35] and in pts with intestinal type [NR vs 18 mo, p = 0.5]. 32% of the 28 pts who received adjuvant treatment did not complete the 4 postoperative cycles due to poor tolerability; these pts had a worse PFS and OS trend when compared to pts who completed treatment: 16 mo vs NR [p = 0.056] and 18 mo vs NR [p = 0.291]. Pretreatment NLR (median value 2.6) did not show a significant correlation with OS and PFS.

Conclusions: Our results showed that FLOT is well tolerated in GC perioperative treatment. Diffuse histology and the presence of SRC component are associated with a worse outcome and TRG. NLR does not correlate with outcome, while a suboptimal adjuvant treatment could be associated with worse prognosis.

ANALYSIS OF NEW POTENTIAL PROGNOSTIC FACTORS IN ADVANCED PANCREATIC ADENOCARCINOMA PROGRESSING TO FIRST-LINE CHEMOTHERAPY: THE EXPERIENCE OF NATIONAL CANCER INSTITUTE OF MILAN

Franza A.¹, Niger M.², Mazzeo L.², Lobefaro R.², Bottiglieri A.², Rametta A.², Torchio M.², Zimatore M.², Zambelli L.¹, Porcu L.³, Prelaj A.⁴, De Braud F.G.M.⁴, Platania M.⁴

¹Faculty of Medicine, University of Milan, Milano; ²Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano; ³Istituto di Ricerche Farmacologiche IRCCS Mario Negri, Milano; ⁴ Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano

Background: Metastatic pancreatic adenocarcinoma (mPAC) is one of the most poor-prognosis cancers, with limited therapeutic options. In the second-line (2L) setting, except for ECOG performance status (PS) and CA 19.9, there is no clear evidence on factors that could predict patients (pts)’ survival. The aim of this monocentre, retrospective study was to investigate the association between other candidate clinical prognostic variables, as neutrophil-to-lymphocyte ratio, modified Glasgow Prognostic Score, BMI, Khorana score, and overall survival (OS).

Methods: Data records of pts affected by mPAC progressing to 1L chemotherapy and treated between 1/08/2008 and 31/08/2018 were reviewed. We considered pts who received at least one administration of 2L therapy (group A) and pts who did not receive any oncologic active treatment by clinical judgement (group B). The statistical analysis was performed separately for each subgroup. OS was defined as the time elapsed between the start of 2L therapy and death (A), or between disease progression and death (B). Cox regression model was used in univariate and multivariate analysis. P-values for interaction are reported in the results section.

Results: Groups were homogeneous for characteristics: 57 out of 63 (90%) pts and 65 out of 67 (97%) pts were respectively dead in group A and group B at the end of follow-up period. Median OS time was 6.2 months in group A and 0.4 months in group B. ECOG PS> = 2 [A: HR = 7.23 (95%CI 2.66-19.60); B: HR = 2.54 (95%CI 1.32-4.88); p: 0.09], mGPS = 2 [A: HR = 4.00 (95%CI 1.88-8.51); B: HR = 2.57 (95%CI 1.39-4.76); p: 0.37], NLR > = 3.5 [A: HR = 2.56 (95%CI 1.44-4.58); B: HR = 1.44 (95%CI 0.82-2.54); p: 0.16], Khorana > 2 [A: HR = 2.32 (95%CI 1.26-4.29); B: HR = 1.91 (95%CI 1.13-3.25); p: 0.646], were significantly related with worse prognosis. Conversely, CA19.9 and BMI did not appear to increase death risk [A: HR = 1.00; B: HR = 1.00; A: HR = 1.12 (95%CI 0.95-1.32); B: HR = 1.12 (95%CI 0.95-1.32); p: 0.13]. In the multivariate analysis point estimates were confirmed, although statistical association was weaker.

Conclusions: In a setting of mPAC progressing to 1L therapy, our analyses confirm several clinical variables as related to a worse outcome and add NLR and Khorana as possible factors conditioning the possibility to receive a 2L therapy. For this instance, we emphatize the importance to conduct prospective studies in order to develop and validate reliable and feasible prognostic nomograms.

IMPACT OF BASELINE CA19.9 LEVELS ON OUTCOMES OF PATIENTS WITH BORDERLINE RESECTABLE AND LOCALLY ADVANCED PANCREATIC CANCER: A RETROSPECTIVE ANALYSIS

Grassi E.¹, Ricci C.², Peterle C.¹, Ingaldi C.², Carloni R.¹, Palloni A.¹, Casadei R.², Brandi G.¹, Di Marco M.¹

¹Dipartimento di Medicina Specialistica Diagnostica e Sperimentale (DIMES), Università di bologna, Policlinico Sant’Orsola-Malpighi, Bologna; ²Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di bologna, Policlinico Sant’Orsola-Malpighi, Bologna

Background: Almost 40% of pancreatic cancer have inoperable, loco-regional tumor at diagnosis with extension to surrounding vasculature or structures. Management of locally advanced tumor (LAPC) and borderline resectable tumor (BRPC) is often heterogeneous and no prognostic or predictive markers are achievable in clinical practice.

Patients and methods: This retrospective analysis included 52 not operable LAPC and BRPC treated at Sant’Orsola-Malpighi Hospital between 2012 and 2017. After data collection we performed an univariate analysis of clinic-pathological and anthropometrics parameters using log-rank test. Survival outcomes were estimated with Kaplan-Meier curves.

Results: Forty patients were included in final analysis. Median age was 65.8 year and 95% had ECOG PS > = 1. At baseline the median tumor marker carbohydrate antigen 19-9 (CA 19-9) levels were 1274.25 U/ml (range 0.8-10000). About 47.5% of patients received FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) schedule as first line of therapy, while in 37.5% of cases was given a combination gemcitabine-based chemotherapies and 15% received gemcitabine monotherapy. In 47.5% of cases were given a second-line, whereas in 27.5% received third- or more line therapies. Eighteen patients (45%) were treated with subsequent radiotherapy. The median progression free survival (PFS) and median overall survival were 8.7 months and 11.5 months respectively.

In univariate analysis the factors that significantly influenced PFS were ECOG-PS (p = 0.001), baseline CA19.9 levels (p = 0.034) and radiotherapy treatment (p = 0.033), while only baseline CA19.9 levels (p = 0.033) were significantly associated with OS.

Conclusions: Baseline CA 19-9 levels are significantly correlated with overall survival of patients affected by LPAC and BRPC, suggesting that this evaluation could improve their clinical management and the decision making. Further investigations and multivariate analysis are needed to confirm these data.

HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY FOR ADVANCED BILIARY TRACT CANCERS

Bursi S.¹, Lucchesi M.¹, Pacetti P.¹, Auci A.², Ceccherini C.², Della Seta R.³, Allegrini G.⁴, Valsuani C.¹, Federici F.¹, Ginocchi L.¹, Del Freo A.¹, Biasco E.⁵, Musettini G.⁶, Cupini S.⁴, Fiorentini G.⁷, Liguigli W.⁸, Mambrini A.¹

¹Oncologia Medica Massa Carrara - Azienda USL Toscana Nord Ovest, Massa; ²Radiologia Massa Carrara - Azienda USL Toscana Nord Ovest, Massa; ³Oncologia Massa Carrara - Azienda USL Toscana Nord Ovest, Massa; ⁴Oncologia Livorno - Azienda USL Toscana Nord Ovest, Livorno; ⁵Oncologia Medica Portoferraio - Azienda USL Toscana Nord Ovest, Portoferraio - LI; ⁶Oncologia Medica Pontedera - Azienda USL Toscana Nord Ovest, Pontedera - PI; ⁷Oncologia Pesaro - Azienda Ospedaliera Marche Nord, Pesaro; ⁸Oncologia Mantova - Azienda Ospedaliera Carlo Poma, Mantova

Background: Treatment outcomes and survival for patients with biliary tract cancers (BTCs) have improved little over the past three decades. Approximately half of untreated patients die within 3–4 months of presentation from the indirect effects of local tumor progression, bile duct obstruction, liver failure or sepsis from cholangitis and abscesses. Hepatic arterial infusion of chemotherapy (HAI) gets better pharmacokinetics outcome with some compounds that have a very high vascular extraction ratio on first pass removal.

Patients and methods: This is an observational, single-center, retrospective analysis of HAI associated to systemic fluoropyrimidines-based chemotherapy (sCT) for patients with locally advanced or metastatic BTCs. HAI provided the loco-regional infusion of epirubicin and cisplatin.

Results: From 2000 to 2015, 142 patients were treated with HAI associated to sCT (43% female, 57% male). The median age was 62. Primary tumor were intrahepatic, extra-hepatic, or gallbladder in 102 (72%), 18, (13%) and 22 (15%) cases, respectively. HAI was administered as first-line or second-line in 116 (82%) and 26 (18%) patients, respectively. Extra-hepatic metastases were present in 58 (40%) patients. In 37 (25.5%) cases a curative surgery was performed before the recurrence. There were no difference in median progression-free survival (mPFS) and overall survival (OS) according to primary tumor site. With HAI as first-line the overall response rate (mORR) was 16% with a disease control rate (DCR) of 65% with 5.5 and 13 months of mPFS and mOS. As second-line, the ORR was 19% with DCR of 50% with 3.8 and 20.1 months of mPFS and mOS. Nine (6%) patients have been converted to surgery after HAI, with mOS of 50.3 months. After HAI, liver progression was documented in 81% of patients.

Overall, pre and post treatment median performance status and median CA19.9 level were 1 and 0 – 151.5 and 95.5. Patients that underwent to curative surgery had better survival (p: < 0.0001) – mOS were 50.3, 28.9, and 11.5 months in converted to surgery after HAI group, previous curative surgery group, and no surgery group, respectively.

Conclusions: In our series most of patients were treated with HAI as first-line treatment before the evidence of efficacy of cisplatin and gemcitabine doublet. However, this analysis has demonstrated an interesting activity of HAI associated with sCT despite the line of treatment, and confirms the fundamental role of surgery for a good outcome in BTCs.

MODIFIED FOLFIRINOX FOR UNRESECTABLE LOCALLY ADVANCED/METASTATIC PANCREATIC CANCER. A REAL-WORLD COMPARISON OF AN ATTENUATED WITH A FULL DOSE IN A SINGLE CENTRE EXPERIENCE

Cavanna L.¹, Stroppa E.M.¹, Citterio C.¹, Mordenti P.¹, Di Nunzio C.¹, Peveri S.², Orlandi E.³, Vecchia S.⁴

¹oncologia medica AUSL Piacenza, Piacenza; ²allergologia AUSL Piacenza, Piacenza; ³oncologia medica AUSL Piacenza, Piacenza; ⁴Unità Farmaci Antiblastici AUSL Piacenza, Piacenza

Metastatic pancreatic adenocarcinoma has a very poor prognosis. Although irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) significantly increases survival in advanced pancreatic cancer, compared to employing only gemcitabine (GEM), toxicities have tempered enthusiasm for its use. This study analyses in a retrospective study the real-world clinical practice with full and attenuated doses of FOLFIRINOX in unselected patients with locally advanced unresectable or metastatic pancreatic cancer, treated at an Italian general hospital. Efficacy, tolerability and toxicity were evaluated, and Overall Survival (OS) and Progression-Free Survival (PFS) were estimated by Kaplan-Meier method. Fifty consecutive patients with advanced (13 patients)/metastatic (37 patients) pancreatic adenocarcinoma were treated with FOLFIRINOX at the Medical Oncology Unit, Piacenza General Hospital, North Italy. The first enrolled consecutive eighteen patients (36%) of this series started the treatment with a full dose of the regimen, while the subsequent thirty-two (64%) consecutive patients received dose attenuation (-20% bolus fluorouracil and -25% irinotecan). In the entire group, the response rate (RR), median OS and median PFS were 30%, 10.1 months, and 5.6 months respectively, with no differences in objective response in the 32 patients that received an attenuated dose compared with the 18 patients receiving a full dose of chemotherapy. However neutropenia, anemia, fatigue and vomiting were statistically increased in the 18 patients receiving a full dose compared with the 32 patients receiving an attenuated dose of FOLFIRINOX (p<0,05). This study demonstrates the efficacy and tolerability of modified FOLFIRINOX in advanced/metastatic pancreatic cancer.

COMPARISON BETWEEN FOLFIRINOX AND GEMCITABINE-NABPACLITAXEL FOR METASTATIC PANCREATIC CANCER: A MONOCENTRIC RETROSPECTIVE COHORT STUDY

Santaniello A.¹, Napolitano F.¹, Foschini F.¹, Cascetta P.¹, Mozzillo E.¹, Carratù A.C.¹, De Placido P.¹, Servetto A.¹, De Placido S.¹, Formisano L.¹, Bianco R.¹, Marciano R.¹

¹Università degli Studi di Napoli Federico II, Napoli

Background: Metastatic pancreatic cancer (PC) has a dismal prognosis, with a median overall survival (mOS) of about 6 months without systemic therapy. FOLFIRINOX (FFN) and Gemcitabine plus nab-paclitaxel (GnP) are actually used as first-line treatments in metastatic pancreatic cancer, but there are no head-to-head randomized trials available supporting the optimal choice between these two regimens. The aim of our study is to evaluate the efficacy and the toxicity profile in patients treated with these therapies in a real word setting.

Methods: We retrospectively evaluated 89 chemotherapy-naïve metastatic PC patients treated with FFN or GnP, at the Oncology Department of Federico Ii University of Naples, between September 2011 and March 2018. We compared the patients’ clinical characteristics, and efficacy and tolerability of FFN and GnP.

Results: In our study, 31 patients were treated with FFN and 58 patients with GnP as first line therapy. Baseline characteristics (FFN/GnP) were as follows: median age 56/61.6 years, ECOG performance status (0-1): 100%/96%, gender (female): 31%/44%, median number of cycles: 9.22/6.48 respectively. Objective response rate (41% vs. 43%) and disease control rate (64% vs. 82%) were similar in both groups. Median PFS was 34.86 weeks (95% CI: 0.43-1.12) in FFN and 24.43 (95% CI: 0.89-2.28) in GnP [p = 0.02]. Median OS was 48.6 weeks (95% CI: 0.58-1.50) in the FFN group and 51.9 weeks (95% CI: 0.66 – 1.71) with GnP [p = 0.31]. The frequency of grade 3 or higher adverse events were reported as follow: neutropenia (44% vs. 39%), anaemia (0% vs 18%), thrombocytopenia (6% vs 10%), thrombocytosis (0% vs 50%), elevated transaminases (13% vs 8%), diarrhoea (0% vs. 6%), asthenia (0% vs. 3%), lower extremities oedema (0% vs 58%) and peripheral neuropathy (44% vs. 39%), respectively in FFN and GnP groups.

Conclusions: Patients treated with FFN achieve statistically longer PFS compared to GnP, however OS was similar and response rates were comparable between the two groups of treatment. Only one patient treated with GnP reached a complete response. Incidence of major adverse events (G3 or more) appears similar in both the FFN and GnP groups, excluding anaemia, lower extremities oedema and thrombocytosis which are more frequent or even exclusive in the GnP group.

PHASE 3 (COSMIC-312) STUDY OF CABOZANTINIB IN COMBINATION WITH ATEZOLIZUMAB VERSUS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA (aHCC) WHO HAVE NOT RECEIVED PREVIOUS SYSTEMIC ANTICANCER THERAPY

Rimassa L.¹, Cheng A.², Braiteh F.³, Chaudhry A.⁴, Benzaghou F.⁵, Thuluvath P.⁶, Hazra S.⁷, Borgman A.⁷, Tan B.⁸, Kubala E.⁹, Sinha R.¹⁰, Kayali Z.K.¹¹, Zhu A.X.¹², Kelley R.K.¹³

¹Humanitas Research Hospital - IRCCS, Rozzano (Milano); ²National Taiwan University College of Medicine, Taipei; ³Comprehensive Cancer Centers of Nevada, Las Vegas; ⁴Summit Cancer Centers, Spokane; ⁵Ipsen Innovation, Les Ulis; ⁶Mercy Medical Center, Baltimore; ⁷Exelixis, Alameda; ⁸Siteman Cancer Center, St Louis; ⁹Thomayerova Nemocnice, Prague; ¹⁰Piedmont Cancer Institute, Atlanta; ¹¹Riverside Community Hospital, Rialto; ¹²Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; ¹³UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco

Background: Cabozantinib inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). Cabozantinib is approved in the United States and Europe for treatment of aHCC after prior sorafenib based on improved overall survival (OS) and progression-free survival (PFS) versus placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). Cabozantinib may promote an immune-permissive tumor environment, which could enhance response to immune checkpoint inhibitors. Cabozantinib in combination with the anti-PD-L1 antibody atezolizumab is being evaluated in multiple tumor types including HCC in a phase 1 study; recommended dose, preliminary clinical activity, and safety of the combination have been demonstrated in aRCC (Agarwal Ann Oncol 2018). Atezolizumab in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of cabozantinib + atezolizumab versus sorafenib in patients with aHCC who have not received prior systemic therapy.

Patients and methods: This global, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of cabozantinib + atezolizumab versus sorafenib as first-line treatment for aHCC. Eligibility criteria include age ⩾18 years, BCLC stage B or C, Child-Pugh A, ECOG PS ⩽1, and measurable disease per RECIST 1.1. Patients are randomized 2:1:1 to an experimental arm of cabozantinib (40 mg qd) + atezolizumab (1200 mg infusion q3w), a control arm of sorafenib (400 mg bid), and a cabozantinib monotherapy arm (60 mg qd). 740 patients are planned to be enrolled at ~250 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). PFS and OS for cabozantinib + atezolizumab versus sorafenib are primary endpoints, and PFS for cabozantinib versus sorafenib is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. The first patient was enrolled in December 2018, and enrollment is ongoing.

SECOND-LINE CHEMOTHERAPY WITH GEMCITABIN+VINORELBINE (GEMVIN) IN ADVANCED ESOPHAGEAL CANCER (AEC)

Belloni P.¹, Pelliccione M.², Candido P.¹, Di Bella S.¹, Cozzi C.¹, Bollina R.¹

¹ASST-Rhodense, Rho; ²ASST-Rhodense, Garbagnate Milanese

Background: Esophageal cancer is a very aggressive tumor, most patients are often not fit enough to receive second line chemotherapy, and even in this case results are dismall with poor response and short survival.

A retrospective analysis of all consecutive patients with AEC followed at the our Medical Oncology Unit between from February 2017 and January 2019 was performed.

Methods: a total number of 14 AEC patients treated with one chemotherapy line were eligible for the analysis. Histological type was Squamous cell carcinoma 8SCC) in all patients.

Results: patients characteristics were: male/female 10/4, median age 67 (55-75). ECOG performance status was 0/1/2 in 2/9/3 cases. Mestastatic site of disease were: lung/liver/peritoneum/bone/nodes/brain in 9/5/4/1/14/2 cases. First line chemotherapy regimen were platinum/5FU based. The schedule of treatment was as follows: Gemcitabin 1000 mg/ mg i.v. on days 1 and 8, Vinorelbine 25 mg/ m2 on days 1 and 8 both of them every 3 weeeks. We observed 5 stable disease, 4 progressive disease and 5 objective response. Median time to progression was 5.1 months. All patients was evaluable for survival (median overall survival 8.3 months). No life threatening event occurred. Teatment was well tolerated from the great part of patients and the main toxicities were low-grade (G1-G2). Few patients reported severe (G3-G4) adverse events such as fatigue (2 pts), thrombocytopenia (1 pts), peripheral neuropathy (2 pts).

Conclusions: the study suggest that GEMVIN schedule in effective and well tolerated, and may prolog survival with a relatively good quality of life in patients with AEC previously exposed to one chemotherapy line.

THE REAL-LIFE EXPERIENCE WITH PERIOPERATIVE CHEMOTHERAPY (FLOT) IN THE TREATMENT OF LOCALLY ADVANCED GASTRIC AND GASTRO-OESOPHAGEAL CANCER (GEC)

Giuffrida D.¹, Mare M.¹, Garofano N.¹, Vitale M.P.¹, Failla A.¹, Colarossi C.¹, Giannone G.¹, Caltavuturo C.¹, Castorina L.¹, Sciacca D.¹

¹Istituto Oncologico del Mediterraneo, Viagrande (CT)

Introduction: GEC is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Until not long ago, surgery was considered the only curative treatment for GEC. However, the results are still unsatisfactory, due to the high rate of metastasis and relapse. Chemotherapy together with surgery has shown promising results. Randomized studies proved that perioperative chemotherapy provides a survival benefit over surgery alone and should be considered the standard of care in potentially operable GEC. However, 5-year survival rates are still in the range of just 35-45%.

Materials and methods: From March 2017 to January 2019, 20 fit patients(pts) with operable GEC were treated in our centre with 4 pre- and 4 postoperative cycles of infusional 5-FU 2600 mg mq 24/h, Folinic Acid, Oxaliplatin 85mg/mq and Docetaxel 50 mg/mq every 2 weeks.

Results: treated pts included 10 female and 10 males with median age 64 years (range 36-74) and PS ECOG 0. 8/20 tumors were gastroesophageal junction, 11 were intestinal, 5 diffuse and 4 mixed histotype. All tumors were cT3 and/or N+.19/20 pts have completed the 4 pre-operative cycles while 17/20 have also completed the 4 postoperative. TRG (tumour regression grade sec.AJCC/CAP) was: 10% TRG0,21% TRG1,31% TRG2,36%TRG3. 2/7 non responder (TRG3) were MMRD to IHC (confirmed results by Idylla Biocartis assay). The treatment was well tolerated with only grade 3 neutropenia in 20% and thrombocytopenia in 10% of pts.

Conclusions:Our real-life experience shows that the perioperative FLOT appears to be effective and safe. It would be useful to evaluate prospectively the microsatellite instability as predictive factor to treatment response.

RISE-HEP PROJECT PART 1: TREATMENT SEQUENCES EVALUATION IN HEPATOCELLULAR CARCINOMA CELL LINES

Faloppi L.¹, Nabissi M.², Santoni M.¹, Maggi F.³, Galizia E.¹, Miccini F.¹, Bianconi M.⁴, Puzzoni M.⁵, Astara G.⁵, Battelli N.¹, Santoni G.², Scartozzi M.⁵

¹Medical Oncology Unit, Macerata General Hospital, ASUR Marche AV3, Macerata; ²School of Pharmacy, University of Camerino, Camerino; ³Dept. of Experimental Medicine, University of Rome La Sapienza, Roma; ⁴Medical Oncology Unit, Ospedale “Madonna del Soccorso”, ASUR Marche AV5, San Benedetto del Tronto; ⁵Medical Oncology Department, University Hospital, University of Cagliari, Cagliari

Background: For over ten years the most stimulating results in systemic therapy for advanced HCC derived from the use of sorafenib (S). But in the last two years several drugs, in particular other multikinase inhibitors like lenvatinib (L), regorafenib (R), cabozantinib (C), proved to be effective both as an alternative or a sequential therapy to sorafenib. In this widened and rapidly increased scenario, without any head-to-head trial, clinicians struggle to define the best drug and the best treatment sequence. Aim of the first part of this project is to evaluate the activity of different treatment sequences in HCC cell lines to pave the way to a future clinical trial investigating their efficacy.

Methods: Compounds of S, R, L and C were dissolved in DMSO and aliquoted. HepG2 cell line, obtained from ECACC (Salisbury, UK), was seeded at the density of 3 x 104 cells/ml. After 24 h of incubation, compounds or vehicle (DMSO) were added. Treatments were performed in single administration and six replicates were carried out for each dose. At 48h post-treatment, cells were fixed and stained with acid solution. The absorbance was measured at 520 nm using an ELISA reader (BioTek Instruments, USA). The assay was also performed with the sequences of: S-R, S-C, L-R, L-C (first line treatments for 48h followed by the second compound for 48h). Higher doses than the minimum inhibiting one were tested.

Results: S showed superior activity than L as first line compound. In the sequence assay S-C and S-R seems to have the best results in terms of cell viability. After L the best compound appears to be R. See table.

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Sequences (ng/ml)	% viability
S 2000 + R 2000	14.5
S 4000 + R 2000	11.2
S 2000 + C 1000	16.8
S 4000 + C 1000	10.1
L 250 + R 2000	34.2
L 500 + R 2000	31.0
L 250 + C 1000	53.3
L 500 + C 1000	47.9

Conclusions: Our results showed relevant variations in cell viability with different drug sequences. Already planned analyses in the RISE-HEP project in vivo and in humans are mandatory to confirm which sequence would have the highest efficacy.

REAL-LIFE DATA ON THE PERIOPERATIVE FLOT REGIMEN IN LOCALLY ADVANCED RESECTABLE GASTRIC/GEJ ADENOCARCINOMA

Camera S.¹, Musio F.², Impera V.¹, Pretta A.¹, Mariani S.², Liscia N.¹, Soro P.², Tolu S.¹, Persano M.², Balconi F.², Donisi C.², Pireddu A.¹, Lai E.², Puzzoni M.², Astara G.², Ziranu P.², Scartozzi M.²

¹Medical Oncology Unit, University Hospital and University of Cagliari - Sapien-za University of Rome, Cagliari; ²Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari

Background: Gastric cancer is one of the most frequent neoplasias with an aggressive behavior. Long-term outcome after surgery alone is poor, therefore a combined treatment approach is the standard of care. Perioperative FLOT showed to improve OS in locally advanced, resectable gastric/GEJ adenocarcinoma. Here, we report the results of efficacy and safety of FLOT regimen in our real-life experience. We also evaluated neutrophil-lymphocite ratio (NLR), marker of inflammation associated with worse OS in solid tumours.

Patients and methods: We analysed 18 patients (pts) with locally advanced, resectable gastric/GEJ adenocarcinoma (stage I-III) treated between March 2017 and April 2019 with perioperative FLOT at the Oncology Unit of University Hospital of Cagliari. Pts had the following charactheristics: ECOG PS 0-1. Median age 64 years (range 49-79). 6 were ⩾70 years old. 38,9% had GEJ adenocarcinoma and 61,1% had stomach adenocarcinoma. 5,6% had a clinical stage cT1-2, 72,2% cT3-4 and 22,2% had missing cT. 61,1% had cN+. 22,2% had signet ring cells (SRC). 11,1% had diffuse type. The median duration of treatment was 4 cycles. The cut-off of NLR was evaluated with ROC curves and survival analysis with Kaplan-Meier estimate.

Results: Median OS (mOS) in our whole population is not reached. We observed a significantly higher mOS in pts with cT1-2 (17.83 m) vs cT3-4 (8.53 m) (p = 0.01) and in pts without SRC (not reached) vs pts with SRC (8.53 m) (p = 0.02). We observed a trend toward a higher mOS in pts with cN- vs cN+ and in pts with low NLR (<2,375) vs high NLR (⩾2,375), but these were not statistical significantly (respectively p = 0.47 and p = 0.08). We obtained a similar result in pts <70 years vs ⩾70 years (p = 0.21). DCR was significantly higher in pts without SRC (100%) vs pts with SRC (50%) (p = 0.04). We observed only G1-2 adverse events (AE): fatigue in 38,9% of pts, nausea in 27,8%, neuropathy in 16,7%, diarrhea in 11,1%, thrombocytopenia in 11,1%. No case of neutropenia was registered. All pts received peg-G-CSF. No patient interrupted chemotherapy due to toxicity. Were not differences in terms of AE between young and elderly pts. Surgery was performed in 66.7% of pts. Preoperative FLOT is ongoing for 2 pts.

Conclusions: Despite the limited sample size, our real-life experience confirm that perioperative FLOT is an effective and well tolerated regimen with a significant benefit in survival outcome and a good safety profile, in line with the results of FLOT trial.

NLR (NEUTROPHIL/LYMPHOCYTE RATIO) AND SECOND LINE CHEMOTHERAPY WITH FOLFIRI FOR PATIENTS WITH METASTATIC PANCREATIC CANCER: OUR EXPERIENCE

Munaò S.¹, Mare M.¹, Germanà S.¹, Sciacca D.¹, Foresta G.¹, Vitale M.P.¹, Gagliano A.¹, Giuffrida D.¹

¹Istituto Oncologico del Mediterraneo, Viagrande (CT)

Introduction: Pancreatic cancer (PC) is the fifth most lethal cancer.Metastatic PC still has an estimated 5-year survival rate of 7%, even considering new strategies on treatment. Identifying prognostic factors is important to layer individual risk. Several studies have analyzed FOLFIRI regimen in 2nd line treatment The progression free survival (PFS) varies from 2 to 5 months. The overall survival (OS) varies from 4,2 to 13,2 moths. Neutropenia and diarrhea are the most frequent toxicities. Several evidences suggest that a high NLR is related to an adverse outcome.

Materials and Methods: from December 2015 to March 2019 we evaluated pts with metastatic PC treated with Nab-paclitaxel-Gemcitabine as first line and with standard FOLFIRI regimen as 2nd line. Our endpoints were: the prognostic role of NLR at baseline, safety, PFS and response rate (RR) in second line. FOLFIRI consists of irinotecan 180 mg/m2 on day 1 and leucovorin 400 mg/m2 followed by 5-fluorouracil (5-FU) 400 mg/m2 bolus, then 5-FU 2400 mg/m2 as a 46-h infusion, biweekly.

Results: At time of data analysis among 57 pts with PC treated with Nab-paclitaxel-gemcitabine, 18 pts (31,5%) received 2nd line FOLFIRI chemotherapy (CT). All 18 pts had a NLR<5. Baseline characteristics of 18 pts receiving 2nd line CT were: median age 67,5 (range 45-76), M/F: 7/11. They received a median of 6,5 (range 1-24) drug administrations. mPFS was 3 months (range 1-14) mOS was 11 months (range 2-30). Among the 18 pts, 2 pts (11%) had a partial response (PR) and 7 (38%) a stable disease (SD),with a disease control rate (DCR) of 49%. Detected toxicity G3-4 was neutropenia and diarrhea in 3 and 1 patients, respectively.

Conclusions: Our experience shows that Nab Paclitaxel-Gemcitabine in the first line is an active and well tolerated regimen, allowing about a third of the patients to receive a second-line treatment. FOLFIRI regimen in 2nd line showed a modest activity and discrete tolerance in this setting.NLR <5, in our experience, is correlated to a better prognosis. We are expecting new prognostic factors could be a guidance to choice the treatment.

EFFICACY OF DOSE-DENSE (DD) ADJUVANT CHEMOTHERAPY (CT) IN HORMONE RECEPTOR POSITIVE/HER2-NEGATIVE EARLY BREAST CANCER (BC) PATIENTS (pts) ACCORDING TO IMMUNOHISTOCHEMICALLY (IHC) DEFINED LUMINAL SUBTYPES: AN EXPLORATORY ANALYSIS OF THE GIM2 TRIAL

Conte B.¹, Bruzzone M.², Lambertini M.³, Poggio F.¹, Blondeaux E.¹, De Laurentiis M.⁴, Valle E.⁵, Congnetti F.⁶, Nisticò C.⁷, De Placido S.⁸, Garrone O.⁹, Gamucci T.¹⁰, Montemurro F.¹¹, Marcello C.², Del Mastro L.¹²

¹Oncologia Medica 2, Ospedale Policlinico San Martino, Genova; ²Epidemiologia Clinica, Ospedale Policlinico San Martino, Genova; ³Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università di Genova; Clinica di Oncologia Medica, Ospedale Policlinico San Martino, Genova; ⁴Istituto Nazionale Tumori-Fondazione G. Pascale, Napoli; ⁵Medical Oncology, Ospedale Businco, Cagliari; ⁶Dipartimento di Medicina, Università La Sapienza, Roma; ⁷Oncologia Medica 1, Istituto Nazionale Tumori “Regina Elena”, Roma; ⁸Dipartimento di Medicina Clinica e Chirurgia Università di Napoli Federico II, Napoli; ⁹Dipartimento di Oncologia, Ospedale S. Croce & Carle, Cuneo; ¹⁰Oncologia Medica, Azienda Sanitaria Locale (ASL) Frosinone, Frosinone; ¹¹Istituto di Candiolo - Fondazio-ne del Piemonte per l’Oncologia - IRCCS, Torino; ¹²Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università di Genova; Oncologia Medica 2, Ospedale Policlinico San Martino, Genova

Background: DD adjuvant CT improves disease free survival (DFS) and overall survival (OS) in high-risk, hormone receptor positive BC. Luminal A and luminal B subtypes have different sensitivity to (neo)adjuvant chemotherapy; however, their role in predicting DD efficacy in clinically high-risk setting is uncertain. This exploratory analysis of the GIM2 trial (Del Mastro et al, Lancet 2015) evaluated DD efficacy according to IHC defined luminal subtypes.

Methods: In the GIM2 trial, pts with node-positive early BC were randomized to receive 4 cycles of (fluorouracil) epirubicin/cyclophosphamide every 2 (DD) or every 3 (standard interval [SI]) weeks followed by 4 cycles of DD or SI paclitaxel. Luminal A-like and luminal B-like BC were identified according to 13h St Gallen definition as having a Ki67<20% and a PgR>/ = 20% (luminal A-like), and a Ki67>/ = 20% and/or a PgR<20% (luminal B-like). Pts with HER2-positive BC were excluded. The efficacy of DD CT in terms of DFS and OS was compared between the two subtypes.

Results: Out of 2,003 pts enrolled in the GIM2 trial, 401 had luminal A-like and 657 luminal B-like BC. After a median follow-up of 8 years, DFS was 81.1% (95% Confidence Intervals [CI] 76.6-84.7) and 70.6% (66.6-74.1) in luminal A-like and luminal B-like BC, respectively, and OS was 91.6% (88.1-94.1) and 85% (81.7-87.7), respectively. There was no significant interaction between treatment and luminal subtypes (p_interaction = 0.416 for DFS and p_interaction = 0.313 for OS); however, the effect of DD CT appeared to be greater in luminal-B like BC (see table below).

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	% 8-year DFS SI	% 8-year DFS DD	HR (95% CI)
Luminal A-like	81.6	80.6	0.86 (0.56–1.30)
Luminal B-like	66.8	74.7	0.74 (0.55–0.98)
	% 8-year OS SI	% 8-year OS DD
Luminal A-like	92.9	90.6	0.88 (0.47-1.67)
Luminal B-like	80.8	89.4	0.61(0.40-0.93)

Conclusions: These long-term results confirm the prognostic value of IHC-defined luminal subtypes, with luminal B-like bearing a worse prognosis. In clinically high-risk, hormone receptor positive BC, luminal B-like subtype benefits more from DD CT both in terms of DFS and OS.

NON-ADHERENCE TO TAMOXIFEN ADJUVANT THERAPY THROUGH PLASMA LEVEL ASSESSMENT AMONG EARLY BREAST CANCER PATIENTS IN NORTHERN ITALY

Gusella M.¹, Pellegrinelli E.², Fraccon A.³, Falci C.⁴, Barile C.⁵, Da Corte D.⁶, Pasini F.³, Cretella E.⁷, Segati R.⁸, Brunello A.⁴, Merlin F.⁹, Pegoraro M.C.¹⁰, Nicolardi L.¹¹, Mion M.¹², Perfetti E.¹³, Modonesi C.¹⁴, Modena Y.¹⁵, Rizzi A.¹⁶, Zaninelli M.¹⁷, Toso S.¹⁸, Oliani C.¹⁹

¹Ospedale Rovigo AULSS5 polesana, rovigo; ²AULSS5 polesana, rovigo; ³casa di Cura Pederzoli, Peschiera del Garda; ⁴IOV, Padova; ⁵UOC Oncologia, AULSS5 Polesana, Rovigo; ⁶UOC Oncologia, Belluno; ⁷UOC Oncologia, Bolzano; ⁸UOC Oncologia, Feltra; ⁹UOC Oncologia, San Bonifacio; ¹⁰UOC Oncologia, Montecchio Maggiore; ¹¹UOC Oncologia, Santorso; ¹²UOC Oncologia, Camposanpiero; ¹³UOC Oncologia, Biella; ¹⁴UOC Oncologia, Schiavonia; ¹⁵UOC Oncologia, Rovigo; ¹⁶UOC Oncologia, Brescia; ¹⁷UOC Oncologia, Bussolengo; ¹⁸Oncologia, Adria; ¹⁹Oncologia, Rovigo

Background: Non-adherence to Tamoxifen (TAM) was shown to considerably impact on the risk of recurrence and mortality of women with breast cancer and efforts should be made to ensure therapeutic adherence during clinical follow-up.

Patients and Methods: (pts) age has been suggested as an important factor in adherence to TAM. The TAM study is an Italian multicenter prospective longitudinal study that enrolled around 1000 patients affected by early breast cancer and treated with adjuvant tamoxifen for at least 3 years after surgery. Two blood samples, at least 3 months apart, were obtained by each patient after reaching the steady state and TAM plasma levels were measured by an HPLC system. According to standard definitions, non-adherence to TAM has been defined if TAM plasma levels < 60 ng/mL (<150 nM).

Results: We present here the results of TAM plasma assessment in 580 patients in steady state.Overall, 224 (18.2%) pts appeared not adequately adherent to TAM: 162 (13.2%) non-adherent and 62 (5.0%) poorly-adherent. Matching with pts’ self-declaration and clinical determinants of non-adherence will be presented.

Conclusions: At steady state, around 5% had low TAM plasma measurements, indicative of not adequate adherence to this treatment. Poorly-adherent pts could benefit from metabolic and pharmacogenetic investigations. Identification of pts at risk of non-adherence allows early targeted interventions to promote adherence in this unique population.

TUMOR INFILTRATING LYMPHOCYTES (TILS) IN ER+/HER2- BREAST CANCER

Criscitiello C.¹, Vingiani A.¹, Maisonneuve P.¹, Viale G.¹, Viale G.¹, Curigliano G.¹

¹Istituto Europeo di Oncologia, Milano

Background: The prognostic role of TILs in ER+/HER2- breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with DDFS in a large series of patients with ER+/HER2- BC.

Methods: Our initial cohort of 9415 pts included all women who underwent surgery for early ER+/HER2- BC at IEO. Then, the cohort was restricted to 3986 pts in the period 1998-2002, and with whom long-term follow-up available. A case-cohort was built by randomly selecting approximately 17% of the above cohort (680 pts). 307 additional pts with an event were added to this cohort. TILs were assessed for 987 cases. TILs were considered both as continuous variable, and dichotomized in low (<5%) vs high (⩾5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1-10). Differences between BC subtypes were assessed using the log-rank test. Univariable and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups.

Results: Median TILs was 2%. Higher TILs were positively associated with pN (p = 0.003), tumor grade (p<.0001), peritumoral vascular invasion (p=.003), Ki-67 (p=.0001), luminal B (p<.0001), and chemotherapy (p<.0001), while they were inversely associated with ER expression (p<.0001) and age (p=.02). There was no association with type of endocrine therapy. In multivariable regression analysis, only Ki-67 expression retained significant association with TILs. Age and ER showed a trend towards negative association with TILs. In univariate Cox regression, TILs expression ( = 5% vs. <5%) was not associated with DDFS (p=.62). At stratified cox exploratory analyses, high TILs were correlated with low risk in very young women (p=.03) and G3 tumors (p=.047), and high TILs with worse outcome in G1 tumors (p=.05). We evaluated TILs by treatment group (chemo vs no chemo). TILs were not associated with DDFS in the no-chemotherapy group. Instead, in the chemotherapy group, high TILs were associated with better DDFS (p=.006), particularly in the group with ki67 = 20% (p=.01).

Conclusions: High TILs in ER+/HER2- BC are significantly associated with several clinico-pathological features of dismal outcome. In this group, treatment escalation might be worthy. Our findings suggest that this subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches. The prognostic value of TILs seems to be different in patients treated with or without chemo.

ROLE OF A SET OF GENE POLYMORPHISMS IN THE ONSET OF NEUROPATHY (N) IN METASTATIC BREAST CANCER (MBC) PATIENTS (pts) TREATED WITH ERIBULIN IN THE PAINTER STUDY (POLYMORPHISM AND INCIDENCE OF TOXICITY IN ERIBULIN TREATMENT)

Farina G.¹, Damia G.², Garrone O.³, D’Onofrio L.⁴, Fabi A.⁵, Ciccarese M.⁶, Cappelletti M.R.⁷, Nunzi M.⁸, Poletto E.⁹, Pedrazzoli P.¹⁰, Cretella E.¹¹, Scandurra G.¹², Meattini I.¹³, Menatti E.¹⁴, Cavanna L.¹⁵, Romagnoli E.¹⁶, Legramandi L.¹⁷, Guffanti F.¹⁸, Bocci B.¹⁹, Rulli E.¹⁷, La Verde N.M.²⁰

¹Oncologia Medica ASST Fatebenefratelli Sacco PO Fatebenefratelli, Milano; ²Laboratorio di Farmacia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ³Oncologia Medica Ospedale Santa Croce e Carle, Cuneo; ⁴Oncologia Medica Policlinico Universitario Campus Biomedico, Roma; ⁵Istituto Nazionale Tumori Regina Elena, Roma; ⁶A. O. Vito Fazzi, Lecce; ⁷Istituti Ospitalieri di Cremona via Concordia, 1, Cremona; ⁸A.O. Santa Maria di Terni, Terni; ⁹AOU Santa Maria della Misericordia, Udine; ¹⁰Fondazione IRCCS Policlinico San Matteo, Pavia; ¹¹Comprensorio Sanitario Oncologia, Bolzano; ¹²Ospedale Cannizzaro, Catania; ¹³Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Università di Firenze, Firenze; ¹⁴ASST Valtellina e Alto Lario, Sondrio; ¹⁵Azienda Ospedaliera di Piacenza, Piacenza; ¹⁶Oncologia medica Ospedale Provinciale di Macerata, Macerata; ¹⁷Unità di Statistica, Laboratorio di Metodologia della ricerca clinica - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ¹⁸Laboratorio Farmacologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ¹⁹Oncologia Medica ASST Fatebenefratelli - Sacco P.O. Fatebenefratelli, Milano; ²⁰Oncologia Medica ASST Fatebenefratelli - Sacco P.O. Sacco, Milano

Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increases overall survival in pretreated pts. E peripheral N is reported in 4-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N.

Patients and methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E (dose 1.4 mg/m² day 1 and 8 every 21 days) after taxanes and antracyclines. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment. N was evaluated by medical examination. The associations between peripheral N and the selected polymorphisms were evaluated with Fisher exact test.

Results: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian hospitals and 159 were evaluated for genetic analysis. Pts and tumor characteristics were as follow: median age 60 years, ductal carcinoma 75.9%, visceral disease 68.6%, luminal type 63.2%, Her2 positive 18.8%, triple negative 18.1%, median of previous treatment lines for MBC 5, previous N reported in 17.8% of pts (all N were sensory and 22.2% were also motor). N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (p <0.001) and the allelic variant C of the polymorphism rs7214723 in CAMKK1 gene (p = 0.04), showed a higher and statistically significant N occurrence; see table below.

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rs2233335 - NDRG1	G0n(%)	G1n(%)	G2n(%)	G3n(%)
G/G	25 (78.1)	2 (6.3)	3 (9.4)	2 (6.3)
G/T	54 (77.1)	10 (14.3)	4 (5.7)	2 (2.9)
T/T	26 (45.6)	18 (31.6)	12 (21.1)	1 (1.8)
rs7214723 - CAMKK1	G0n(%)	G1n(%)	G2n(%)	G3n(%)
C/C	32 (68.1)	8 (17.0)	5 (10.6)	2 (4.3)
C/T	32 (68.1)	12 (18.2)	3 (4.5)	3 (4.5)
T/T	23 (52.3)	10 (22.7)	11 (25.0)	0 (0.0)

Conclusions: The results suggest that the SNP rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene are associated with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial registration: NCT0286403

IMPACT OF BODY COMPOSITION PARAMETERS ON TUMOR RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN OPERABLE BREAST CANCER PATIENTS

Palumbo P.¹, Draisci S.¹, Barbolini M.¹, Nasso C.¹, Isca C.¹, Bocconi A.¹, Balduzzi S.¹, Pecchi A.¹, Galetti S.¹, Torricelli P.¹, Piacentini F.¹, Moscetti L.¹, Cascinu S.¹, Omarini C.¹

¹University Hospital of Modena, Modena

Background: Overweight is a known risk factor for various health disorders, including breast cancer (BC). Preclinical evidence shown how endogenous factors released from fat tissue are involved chemo resistance and cells survival. Sarcopenia seems to be a negative prognostic factor too. Computed tomography (CT) imaging instead of body max index (BMI) gives a reliable measure of muscles mass and body fat distribution. The impact of body composition parameters (BCPs) on chemo sensitivity is still debated. We examined the associations between BCPs and tumor response to neoadjuvant chemotherapy (NC) in patients treated for operable breast cancer (BC).

Patients and methods: BMI value, Visceral Fat Area (VFA), Subcutaneous Fat Area (SFA), Lumbar Skeletal Muscle Index (LMCI), Liver/Spleen Ratio (L/S) were collected, besides clinical parameters. BCPs were calculated from pre-treated CT scan images, and correlated to pathologic complete response (pCR) and with survival outcomes.

Results: 407 patients were included in the study: 55% with BMI < 25 and 45% with BMI >25. 137 of them had pre-treatment CT scan imagines. Overweight was significantly associated with postmenopausal status and older age. Hormonal receptor positive BC were more frequent in overweight patients (p<0.05). Post-menopausal women had higher VFA, fatty liver disease and obesity compared to premenopausal patients. 34% of patients had criteria for obesity disease while 48% of them were sarcopenic. Overall, 25% of women achieved pCR. No association between BMI classes and tumor response was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 35% normal VFA vs 20% high VFA, no steatosis 32% vs steatosis 13%; p<0.05). Neither BMI classes nor BCPs significantly influenced overall survival and relapse free survival.

Conclusions: Visceral adiposity as well as steatosis were closely involved in chemo sensitivity in BC patients treated with NC. Their measures from clinically acquired CT scans provide significant predictive information that outperform BMI value. More research is require to evaluate relationship among adiposity site and survival outcomes.

REAL WORLD EVIDENCE ON HR+/HER2- METASTATIC BREAST CANCER: EPIDEMIOLOGY, CLINICAL PRACTICE AND DIRECT COSTS FROM A LARGE ITALIAN DATABASE

Piccinni C.¹, Ronconi G.¹, Calabria S.¹, Dondi L.¹, Pedrini A.¹, Esposito I.², Marangolo M.¹, Marchetti P.³, Martini N.¹

¹Fondazione ReS (Ricerca e Salute), Casalecchio di Reno (Bologna); ²Drugs and Health, Roma; ³Oncologia Medica B, Sapienza Università di Roma e Oncologia Ospedale S. Andrea, Roma

Background: The epidemiology knowledge of different breast cancer types is crucial for planning and funding effective health services. The aim of this study was to estimate the burden of HR+/HER2- metastatic breast cancer (MBC) in Italy, in terms of incidence, prescription patterns, healthcare resource utilisation and costs for the National Health System (NHS).

Methods: A cohort study based on healthcare administrative data (ReS database), covering >10 millions of Italians, was performed. Incident cases of HR+/HER2- MBC were identified among adult women, in 2013. A woman was defined affected by MBC if she was hospitalized with concomitant diagnosis of “Malignant neoplasm of female breast” and “Secondary and malignant neoplasms”. Incident cases were identified by excluding women responding to these criteria in the previous year. The cohort was followed-up for 2 years to describe healthcare utilisation and integrated costs (pharmaceuticals, hospitalisations and outpatients services) paid by the NHS. Prescription patterns were described as first-line choice and therapeutic changes. Specific changes of therapy were used as proxies of disease progression. A survival analysis was performed to estimate the time from diagnosis to first disease progression.

Results: Out of 5,174,723 adult women, 355 new cases of HR+/HER2- MBC were selected (incidence: 6.9 per 100,000). These generated a mean cost of €3,888 due to the diagnoses used to identify the cohort. During the 1^st follow-up year, they on average costed €7,543, whereas €4,834 in the 2^nd year. The 85.9% of the cohort received a monotherapy, while the 14.1% a combination therapy. The most used monotherapy was nonsteroidal aromatase inhibitors (45.9%), while the most prescribed combination was tamoxifen + LHRH analogues (6.2%). Therapeutic changes occurred in 45.4% of the cohort, especially from chemotherapy to nonsteroidal aromatase inhibitors, after on average 276.8 days from the first treatment. Disease progression was identified in 22.5% of patients and it occurred after a mean of 13±6 months from diagnosis.

Conclusions: The study provided a detailed picture of HR+/HER2- MBC, by using real-world data. These findings could be helpful in health technology assessments and expenditure forecasts of future therapeutic strategies for HR+/HER2- MBC, particularly in the field of “precision medicine” or “personalized medicine”.

THE ROLE OF DOSE-DENSE (DD) ADJUVANT CHEMOTHERAPY (CT) IN HER2-POSITIVE (HER2+) EARLY BREAST CANCER (BC) PATIENTS (pts) BEFORE AND AFTER THE INTRODUCTION OF TRASTUZUMAB (T): EXPLORATORY ANALYSIS OF THE GIM2 TRIAL

Poggio F.¹, Lambertini M.², Bruzzone M.³, Conte B.⁴, Bighin C.¹, De Azambuja E.⁵, De Placido S.⁶, De Laurentiis M.⁷, Cognetti F.⁸, Fabi A.⁹, Bisagni G.¹⁰, Durando A.¹¹, Turletti A.¹², Defraia E.¹³, Garrone O.¹⁴, Puglisi F.¹⁵, Montemurro F.¹⁶, Ceppi M.³, Del Mastro L.¹⁷

¹Department of Medical Oncology, UO Oncologia Medica 2, Policlinico San Martino-IST, Genova; ²Department of Medical Oncology, U. O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova; ³Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova; ⁴Department of Medical Oncology, UO Oncologia Medica 2, Policlinico San Martino-IST; Translational Genomics and Targeted Therapeutics in Solid Tumors, August pi I Sunyer Biomedical Research Institute, Genova; Barcellona; ⁵Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B), Genova; ⁶Department of Clinical Medicine and Surgery, University Federico II, Napoli; ⁷Department of Senology, Istituto Nazionale Tumori - Fondazione Pascale, Napoli; ⁸Università La Sapienza di Roma, roma; ⁹Division of Medical Oncology, Regina Elena National Cancer Institute, Roma; ¹⁰Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia; ¹¹Citta’ della Salute e della Scienza, Torino. ASO S Anna, Breast Unit, Torino; ¹²Oncology Unit, Martini Hospital ASL Città di Torino, Torino; ¹³Businco Hospital, Cagliari; ¹⁴Department of Medical Oncology, S. Croce e Carle Teaching Hospital, Cagliari; ¹⁵Medical Oncology, Department of Medicine, University of Udine; Unit of Medical Oncology and Cancer Prevention, IRCCS Oncologico Aviano-National Cancer Institute, Aviano; ¹⁶Candiolo Cancer Institute, FPO-IRCCS, Candiolo; ¹⁷Department of Medical Oncology, U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova

Background: DD adjuvant CT is standard of care in high-risk early BC pts. However, the role of DD CT in HER2+ BC pts remains uncertain, particularly when T is administered. In this exploratory analysis of the GIM2 trial (Del Mastro et al, Lancet 2015), we investigated the efficacy of DD CT in the subgroup of HER2+ BC pts with or without subsequent exposure to T.

Methods: Using a 2x2 factorial design, the GIM2 trial randomized node-positive early BC pts to receive 4 cycles of (fluorouracil)epirubicin/cyclophosphamide (F)EC every 2 (DD) or every 3 (standard interval [SI]) weeks followed by 4 cycles of DD or SI paclitaxel (P). The same number of cycles (4 (F)EC and 4 P) and doses (FEC 600/90/600 mg/m2, P 175 mg/m2) were used in all treatment arms. After the approval of adjuvant T, protocol was amended in April 2006 to mandate use of T for 1 year after CT completion in all HER2+ pts.

The efficacy of DD CT in terms of disease-free survival (DFS) and overall survival (OS) was compared between HER2+ pts with or without subsequent exposure to T and those with HER2-negative /HER2-unknown (HER2-/unk) status.

Results: Out of 2,003 pts randomized to DD or SI CT in the GIM2 study, HER2 status was positive in 452 (22.6%) pts, negative in 1,243 (62.0%) and unknown in 308 (15.4%). Among 452 pts with HER2+ disease, T was administered to 132 (29.2%) pts. Overall median follow-up was 8.1 years (interquartile range: 7.0-9.3).

No significant interaction between T therapy and the effect of DD CT, (p_interaction = 0.603 for DFS and p_interaction = 0.776 for OS) was observed; however, among pts treated with T, the effect of DD CT appeared to be smaller as shown in the table.

OPEN IN VIEWER

	% 7-year DFS SI	% 7-year DFS DD	HR (95% CI)
HER2+ NO trastuzumab	67.0	72.1	0.84 (0.56-1.24)
HER2+ with trastuzumab	72.3	70.4	0.80 (0.40-1.59)
HER2-/unk	73.3	79.9	0.72 (0.59-0.88)
	% 7-year OS SI	% 7-year OS DD
HER2+ NO trastuzumab	78.6	85.2	0.67 (0.39-1.16)
HER2+ with trastuzumab	86.1	84.9	1.04 (0.36-3.00)
HER2-/unk	85.3	90.9	0.64 (0.49-0.84)

Conclusions: In HER2+ early BC pts, DD adjuvant CT appears to have a role only in pts without subsequent exposure to T.

THE PREGNANCY AND FERTILITY (PREFER) STUDY: AN UPDATE ON FERTILITY-PRESERVING (FP) STRATEGIES IN YOUNG EARLY BREAST CANCER (EBC) PATIENTS (pts)

Dellepiane C.¹, Lambertini M.¹, Fontana V.¹, Giannubilo I.¹, Francesca P.¹, Buzzatti G.¹, Blondeaux E.¹, Conte B.¹, Molinelli C.¹, Alessia D.¹, Bighin C.¹, Abate A.¹, Anserini P.¹, Del Mastro L.¹

¹Ospedale Policlinico San Martino IRCCS, Genova

Background: Young early breast cancer (EBC) patients relevant concerns are fertility issues due to oncology treatments. Limited data are available on pts and their oncologists attitude about FP strategies. The PREFER study was developed as a national comprehensive program aiming to optimize care and improve knowledge around this topic.

Methods: This is a prospective cohort study ongoing across 20 Italian centers affiliated to the GIM (Gruppo ItalianoMammella) study group. Oncologists offer the available FP strategies to young EBC pts undergoing (neo)adjuvant CT: oocyte cryopreservation (OC), ovarian tissue cryopreservation (OTC) and LHRH analogue (LHRHa) during CT. Eligible pts are premenopausal, ⩽ 45 years, no previously exposed to CT and/or radiotherapy. Primary objective is to obtain data about preferences and choices of young EBC pts on the FP strategies. Secondary objectives are to evaluate the success and safety of FP strategies, hormonal changes during CT and survival outcomes. The present analysis reports preliminary results of the study including pts enrolled at the coordinating center from November 2012 to May 2019, an update of previous data 2017.

Results: A total of 204 EBC pts were enrolled; median age was 38.77 years (24.80- 45.34). Patients interested in Fertility Preservation were 193 (94.61%); patients not interested were 11 (5.39%) Reasons for refusal were: no interest in fertility preservation 7 pts (3.43%); previous pregnancy 3 pts (1.47%), no interest in having children 1 pt (0.49%). FP strategies: 133 pts (65.19%) accepted only LHRH a, 2 pts (0.98%) counseling only, 57 pts (27.94%) both of them. Only 29 (14.22%) pts accepted OC or OTC after gynecologic counseling. Main reason for refusal of cryopreservation procedures was fear of delaying cancer treatment (3 pts). Median number of oocytes yielded was 13.50 (0-42); median number of mature oocytes yielded and cryopreserved was 10 (0-24).

Conclusions: LHRHa is the fertility-preserving strategy accepted by the majority of young early breast cancer patients, cryopreservation procedures are accepted by nearly 15% of patients.

A PHASE 2 STUDY OF ABEMACICLIB IN PATIENTS (pts) WITH BRAIN METASTASES (BM) SECONDARY TO HR+, HER2- METASTATIC BREAST CANCER (MBC)

Anders C.¹, Le Rhun E.², Bachelot T.³, Yardley D.⁴, Awada A.⁵, Conte P.F.⁶, Kabos P.⁷, Bear M.⁸, Yang Z.⁸, Chen Y.⁸, Tolaney S.⁹, Dieci M.V.¹⁰

¹Duke Cancer Institute, Durham, NC, USA, Durham; ²Lille University Hospital, Lille, France, Lille; ³Centre Léon Bérard, Lyon, France, Lyon; ⁴Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, TN, USA, Nashville; ⁵Institut Jules Bordet, Brussels, Belgium, Brussels; ⁶University of Padova and Istituto Oncologico Veneto, Padova, Italy, Padova; ⁷University of Colorado Denver, Greenwood Village, CO, USA, Greenwood Village; ⁸Eli Lilly and Company, Indianapolis, IN, USA, Indianapolis; ⁹Dana-Farber Cancer Institute, Boston, MA, USA, Boston; ¹⁰University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy, Padova

Background: Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat HR+, HER2- MBC pts on a continuous dosing schedule as monotherapy or in combination with endocrine therapy (ET). Clinical data demonstrate that abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma.

Materials and Methods: JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ MBC, non-small cell lung cancer, or melanoma. Here, we report on HR+, HER2- MBC pts. Eligible pts had ⩾1 new or not previously irradiated measurable BM ⩾10mm or a progressive previously irradiated BM. Pts receiving ET at the time of enrollment were permitted to continue the same ET provided that extracranial disease was stable ⩾3 months and the CNS progression occurred on the ET. Abemaciclib was orally administered 200mg BID. Primary endpoint was objective intracranial response rate (OIRR; [CR+PR]) based on Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, and safety.

Results: 58 HR+, HER2- MBC pts were enrolled and 52 pts were evaluable. Pts had a median of 4 prior systemic therapies, 75% of pts had prior chemotherapies (0-6, median 2), and 71% of pts had prior ET (0-4, median of 1) in the metastatic setting. 50% of pts had prior whole brain radiotherapy, 39% stereotactic radiosurgery, and 8% surgical resection of BM. Median time from radiation to study enrollment was 9.4 months. Out of the 52 evaluable patients, 3 pts had a confirmed intracranial response (6% OIRR), and 38% of pts showed a decrease in the sum of their intracranial target lesions. Intracranial clinical benefit rate (CR+PR+SD persisting for ⩾6 months) was 25%. Median PFS was 4.4 months (95% CI, 2.6-5.5). Safety and tolerability were similar to previous reports for abemaciclib.

Conclusions: Abemaciclib demonstrated intracranial clinical benefit in heavily pretreated HR+, HER2- MBC pts with BM in this study. Further evaluations are ongoing to identify ABC patients with BM who might benefit most from abemaciclib.

© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 American Society of Clinical Oncology - 55th Annual Meeting. All rights reserved.

CORRELATION BETWEEN WEIGHT LOSS AND OUTCOME IN METASTATIC BREAST CANCER PATIENTS TREATED WITH EVEROLIMUS: RESULTS FROM A RETROSPECTIVE EXPLORATORY ANALYSIS OF A BALLET STUDY COHORT

Corona S.¹, Giudici F.¹, Strina C.², Milani M.², Madaro S.², Cappelletti M.R.², Bernocchi O.¹, Dester M.², Cervoni V.², Generali D.¹

¹Università degli studi di Trieste, Trieste; ²Unità Multidisciplinare di Patologia Mammaria e Ricerca traslazionale, Cremona

Background: Notwithstanding the encouraging results seen with everolimus in advanced BC, reliable biomarkers of response to mTOR inhibitors are yet to be identified. Drug-induced toxicities have raised interest as surrogate biomarkers of activity. Here, we present the results of a retrospective analysis evaluating the impact of BMI/weight variation during everolimus therapy on survival in a subgroup of patients recruited in the BALLET trial, whose disease progressed during the study.

Patients and Methods: BALLET evaluated the safety of everolimus plus exemestane in post-menopausal women with advanced hormone positive BC which recurred or progressed on NS-AIs. A total of 685 patients recruited on the trial in Italy were included in our analysis and BMI/weight recorded at baseline till end of treatment (EOT). Metabolic treatment-related adverse events (TrAEs) were considered of “special interest” and obtained at each time-point. BMI was calculated with the formula Kg/m2. The Wilcoxon matched-pairs test was used for the statistical analysis and the Kaplan-Meier to analyse the correlation between BMI/weight and overall survival (OS), defined as the time between the start of everolimus and death.

Results: we found no correlation between BMI measurements and outcomes. To look at weight, we divided the study population in four subgroups according to their absolute weight loss (Δ) during treatment: Δ pre-post ⩾0 kg; Δ >0⩽2 kg; Δ >2⩽5 kg; Δ >5 kg. 68.7% of patients showed a measurable weight-loss. We found a positive correlation between a Δ >5 kg and the outcome, with a median OS of around 180 days in comparison to 120 days for a Δ <5 kg or 0 (p = 0.0). Cholesterol (C) and Triglycerides (T): 85.8% of patients suffered at least a grade 1 TrAE during therapy with everolimus. The great majority were grade 1 or 2 events, with only 0.87% of patients developing a grade 3 AE and 0.14% a grade 4. We found a statistically significant difference between pre- and post-treatment values, with higher C and T recorded at EOT in comparison to baseline (C: 5.44 ± 1.04 at baseline vs 5.84 ± 1.27 at EOT, p<0.001; T: 1.36 ± 0.66 at baseline vs 1.77 ± 1.03 at EOT, p<0.001).

Conclusions: even with the limitations of an exploratory retrospective study, our analysis suggests weight-loss of more of 5 kg as a putative prognostic biomarker of everolimus efficacy in patients with metastatic BC. Prospective studies are needed to confirm the findings and validate the predictive/prognostic value of these biomarkers.

ROLE OF ANTHRACYCLINES IN NEOADJUVANT ANTI-HER2 REGIMENS FOR HER2-POSITIVE BREAST CANCER (BC): A NETWORK META-ANALYSIS (NMA)

Pelizzari G.¹, Gerratana L.¹, Basile D.¹, Bartoletti M.¹, Lisanti C.¹, Giavarra M.², Bertoli E.², Bortot L.¹, Corvaja C.¹, Fanotto V.¹, Vitale M.G.², Garutti M.³, Da Ros L.⁴, Di Nardo P.⁴, Bonotto M.⁵, Bolzonello S.⁶, Miolo G.⁷, Minisini A.M.⁸, Mansutti M.⁵, Spazzapan S.⁷, Puglisi F.¹

¹Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Dipartimento di Medicina, Università degli studi di Udine, Udine, Italy, Aviano; ²Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy; Dipartimento di Medicina, Università degli studi di Udine, Udine, Italy, Udine; ³Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; U. O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy, Aviano; ⁴Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy, Aviano; ⁵Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy, Udine; ⁶ Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy, Aviano; ⁷ Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy, Aviano; ⁸ Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy, Udine

Background: It is matter of current debate which would be the best chemotherapy backbone of neoadjuvant HER2-targeted therapy for HER2-positive BC. The TRAIN 2 trial showed no significant difference in terms of pathological complete response (pCR) when anthracycline-based (CTA) or anthracycline-free regimens (CT) were combined with dual HER2 blockade. However, it remains unclear how anthracyclines may influence the relative benefit across different anti-HER2 treatments.

Methods: A systematic review was conducted which included all phase II/III randomized clinical trials (RCTs) comparing different neoadjuvant regimens for HER2-positive BC. pCR (yT0/isN0) was the outcome of interest. Indirect comparisons of all combinations of anti-HER2 agents with CTA or CT were estimated with a random-effects frequentist NMA. Estimated pCR rates were inferred adopting a Bayesian NMA.

Results: 17 RCTs (3933 patients) were included. Overall, 8 arms were identified, comprising all possible combinations of CTA and CT with trastuzumab (H), lapatinib (L) and dual HER2 blockade (D) but also CTA and D only. Odds ratios (OR) for pCR and 95% confidence interval (CI) of selected NMA comparisons are shown in the table. Estimated rates of pCR for each treatment and 95% credible interval (CrI) are reported in the table.

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NMA Comparisons	OR (95% CI)	Estimated pCR rates (95% CrI)
D-CTA vs D-CT	0.88 (0.64-1.20)	D-CTA	58% (45-71%)
H-CTA vs H-CT	1.22 (0.77-1.92)	D-CT	54% (40-67%)
L-CTA vs L-CT	1.33 (0.77-2.30)	H-CTA	44% (35-54%)
D-CTA vs H-CTA	1.39 (1.03-1.87)	H-CT	36% (23-53%)
D-CT vs H-CTA	1.58 (1.06-2.38)	L-CTA	35% (23-50%)
H-CTA vs CTA	2.21 (1.47-3.33)	L-CT	26% (12-46%)
H-CT vs CTA	1.82 (0.99-3.35)	CTA	24% (13-42%)

Conclusions: In these indirect comparisons, we did not find a significant pCR gain for CTA vs CT when combined to D, H and L. Considering double vs single-agent anti-HER2 regimens, D-CT remains superior to H-CTA, supporting a possible omission of anthracycline when a dual anti-HER2 block is used. On the contrary, our pooled estimate suggests a more relevant role for anthracycline when comparing H-CT or H-CTA vs CTA. Moreover, we estimated a 4% pCR gain for D-CTA vs D-CT, and an 8% higher pCR rate for H-CTA vs H-CT.

PALBOCICLIB-FULVESTRANT (PALBO-FUL) AND EVEROLIMUS -EXEMESTANE (EVE-EXE) FOR SECOND LINE HORMONAL TREATMENT (HT) OF METASTATIC BREAST CANCER (MBC) WITH LOBULAR HISTOLOGY: A PROPENSITY SCORE MATCHED ANALYSIS

Orlandi A.¹, Iattoni E.¹, Pizzuti L.², Fabbri A.³, Botticelli A.⁴, Di Dio C.¹, Palazzo A.¹, Garufi G.¹, Indellicati G.⁵, Alesini D.³, Carbognin L.¹, Paris I.¹, Vaccaro A.⁶, Magrì V.⁴, Naso G.⁴, Cassano A.¹, Vici P.², Giannarelli D.², Marchetti P.⁴, Bria E.¹, Tortora G.¹

¹Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Roma, Roma; ²Istituto Nazionale Tumori Regina Elena, Roma, Roma; ³Ospedale Belcolle, Viterbo, Viterbo; ⁴Università Sapienza di Roma, Roma; ⁵Fondazione Policlinico Universitario, Roma; ⁶Ospedale di Frosinone, Frosinone

Background: In the last years, CDK4/6i showed to improve efficacy of HT in HR-positive/HER2-negative MBC patients (pts). Up to date, no data are available about the best sequence of HT according to MBC histotype. Alterations in the AKT pathway are known to be implied in acquired endocrine resistance and represent a main driver of proliferation in metastatic lobular breast cancer (MLBC). In this contest, the overexpression of cyclin E through the dysregulation of AKT may lead to an intrinsic resistance to CDK4/6i in MLBC previously exposed to HT. Instead, the inhibition of the AKT pathway could represent a better strategy in this setting. Thus, we performed a multicentric retrospective study to compare the efficacy of PALBO-FUL versus EVE-EXE as second line HT of MLBC.

Patients and Methods: From 2013 to 2018 patients with diagnosis od MLBC were collected from databases of 7 Italian centers. Progression free survival (PFS) was the primary endopoint. Results were adjusted through a propensity score (PS) for the final analysis of survival.

Results: Of 376 MLBC pts screened, seventy-four were elegible; 46 and 28 pts received PALBO-FUL or EVE-EXE as second line HT, respectively. Pts characteristics were well balanced between the two groups. Pts receiving EVE-EXE resulted to have significantly longer PFS than pts treated with PALBO-FUL (6.1 vs. 4.5 months, HR 0.58, 95% CI 0.35-0.96; p = 0.025). At the multivariate analysis, previous exposure to chemotherapy was significantly correlated with PFS (HR 0.41, 95% CI 0.24-0.72, p = 0.002). Finally, the PFS benefit for EVE-EXE was confirmed independently from previous chemotherapy exposure and stage at diagnosis at the PS analysis (6.0 vs. 4.6 months, p = 0.04)

Conclusions: This retrospective analysis indicates a potential benefit of EVE-EXE in comparison with PALBO-FUL as second line HT of MLBC. The small pts’ cohort calls for a larger and adequately sized prospective validation. However, these early data allow to speculate on the best hormonal therapeutic sequence in MLBC. Indeed, in this setting a late exposure to CDK4/6i might not allow to exploit its efficacy, while once hormonal resistance is acquired the inhibition of AKT/m-TOR pathway may represent the best option.

NEXTMONARCH 1: PHASE 2 STUDY OF ABEMACICLIB PLUS TAMOXIFEN OR ABEMACICLIB ALONE IN HR+, HER2- ADVANCED BREAST CANCER

Hamilton E.¹, Cortes J.², Dieras V.³, Ozyilkan O.⁴, Chen S.⁵, Petrakova K.⁶, Manikhas A.⁷, Jerusalem G.⁸, Hegg R.⁹, Lu Y.¹⁰, Bear M.¹⁰, Johnston E.¹⁰, Martin M.¹¹, Arpino M.G.¹²

¹Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville, TN, USA, Nashville; ²Ramon y Cajal University Hospital, Madrid, Spain; Vall d’Hebron Institute of Oncology, Barcelona, Spain, Madrid, Barcelona; ³Centre Eugene Marquis UNICANCER, Rennes Cedex, France, Rennes Cedex; ⁴Baskent University Department of Medical Oncology, Adana, Turkey, Adana; ⁵Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan, Taoyuan City; ⁶Masarykuv Onkologický Ustav, Brno, Czech Republic, Brno; ⁷City Clinical Oncology Dispensary, St. Petersburg, Russia, St. Petersburg; ⁸Centre Hospitalier Universitaire, Liege, Belgium, Liege; ⁹Hospital Pérola Byington/FMUSP, Centro de Referência da Saúde da Mulher, São Paulo, Brazil, São Paulo; ¹⁰Eli Lilly and Company, Indianapolis, IN, USA, Indianapolis; ¹¹Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERONC, Madrid, Spain, Madrid; ¹²Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy, Naples

Background: NextMONARCH 1 evaluated abemaciclib (2 monotherapy arms); 200mg Q12H abemaciclib+prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments; and abemaciclib+tamoxifen as a strategy to overcome endocrine resistance.

Material and Methods: NextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib+tamoxifen in women with HR+, HER2- advanced breast cancer (ABC) who have progressed on or after prior endocrine therapy and previously received chemotherapy. Patients (Pts) were stratified by presence of liver metastases and prior use of tamoxifen in advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H+daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B) or abemaciclib 200mg Q12H+prophylactic loperamide (Arm C). Key eligibilities: ⩾2 chemotherapy regimens, measurable disease & no prior treatment with CDK4&6 inhibitors. Primary objective: progression-free survival (PFS); key secondary objectives: objective response rate (ORR), clinical benefit rate (CBR) and safety. PFS analysis tested superiority of Arm A to C at one-sided alpha of.10 with ~110 events across the 2 arms assuming a hazard ratio (HR) of.667 to achieve ~80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2.

Results: 234 pts were randomized to Arms A (n = 78), B (n = 79), C (n = 77). PFS events: 166 (A:57/B:54/C:55); median PFS: 9.1 months (A)/6.5 (B)/7.4 (C; A vs C: HR=.815, 95%CI,.556-1.193, p=.293; B vs C: HR = 1.045, 95%CI,.711-1.535 p=.811). Investigator-assessed ORR: 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR: 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced incidence and severity of diarrhea (C: 62.3%, Gr3: 7.8%) vs MONARCH 1 (90.2%, Gr3: 19.7%) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr3: 1.3%; B: 67.1%, Gr3: 3.8%).

Conclusions: NextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Abemaciclib+tamoxifen did not demonstrate a statistically significant improvement in PFS vs abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis.

MANAGEMENT OF ABEMACICLIB-ASSOCIATED ADVERSE EVENTS IN PATIENTS WITH HORMONE RECEPTOR-POSITIVE (HR+), HER2- ADVANCED BREAST CANCER: ANALYSIS OF THE MONARCH TRIALS

Rugo H.¹, Huober J.², Llombart-Cussac A.³, Toi M.⁴, Tolaney S.⁵, André V.⁶, Barriga S.⁷, Forrester T.⁸, Sledge G.⁹, Goetz M.¹⁰, Guarneri V.P.¹¹

¹University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA, San Francisco; ²University of Ulm, Ulm, Germany, Ulm; ³Hospital Arnau de Vilanova, Valencia, Spain, Valencia; ⁴Kyoto University, Kyoto, Japan, Kyoto; ⁵Dana-Farber Cancer Institute, Boston, MA, USA, Boston; ⁶Eli Lilly, Paris, France, Paris; ⁷Eli Lilly, Madrid, Spain, Madrid; ⁸Eli Lilly, Indianapolis, IN, USA, Indianapolis; ⁹Stanford University, Stanford, CA, USA, Stanford; ¹⁰Mayo Clinic, Rochester, MN, USA, Rochester; ¹¹University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy, Padova

Background: Abemaciclib demonstrated efficacy and acceptable safety profile in HR+, HER2- advanced breast cancer patients (pts) as monotherapy (MONARCH 1) and in combination with endocrine therapy; with fulvestrant (MONARCH 2) or non-steroidal aromatase inhibitors (MONARCH 3). We describe timing and management of common AEs in MONARCH trials.

Material and Methods: Study designs and key eligibility criteria of MONARCH 1,2,3 have been reported. Pts were advised to initiate antidiarrheal therapy at first sign of diarrhea and notify the investigator, drink fluids. If not improved within 24 hours to ⩽ grade 1, treatment was suspended until diarrhea resolved. Dose reductions required for grade ⩾3 or persistent grade 2 diarrhea. For grade 3 neutropenia, abemaciclib was held until ⩽ grade 2. Dose was reduced for recurrent grade 3 or 4 neutropenia.

Results: Across MONARCH, median time to onset of diarrhea was between days 6&8. First dose reductions for diarrhea occurred at a median of 28-41 days. Dose holds for diarrhea were brief, constituting 1.7-3.8% off total treatment time. Median time to onset of grade 3/4 neutropenia was 29-36.5 days, and resolved at a median of 11-15 days. AEs were managed by dose adjustments and/or supportive medication (Table).

OPEN IN VIEWER

Summary of dose adjustments for diarrhea or neutropenia

Characteristics	MONARCH 1 AbemaciclibN = 132	MONARCH 2 Abemaciclib+FN = 441	MONARCH 3 Abemaciclib+NSAIN = 327
Diarrhea (any grade), n(%)	119(90.2)	381(86.4)	269(82.3)
Grade 3	26(19.7)	59(13.4)	31(9.5)
Incidences per patient, n(%)
1	60(50.4)	185(48.6)	124(46.1)
2	29(24.4)	90(23.6)	52(19.3)
⩾3	30(25.2)	106(27.8)	93(34.6)
Outcome, number (%) of events	263	995	802
Not recovered/resolved	15(5.7)	106(10.7)	70(8.7)
Treatment change a , n(%)
Dose reduction of study drug	27(22.7)	83(21.8)	45(16.7)
Dose omission	32(26.9)	83(21.8)	51(19.0)
Antidiarrheal medication, n(%)	80(60.6)	333(75.5)	226(69.1)
Neutropenia (any grade), N(%)	49(37.1)	203(46.0)	143(43.7)
Grade ⩾3	32(24.2)	117(26.5)	78(23.9)
Treatment change, n(%)
Dose reduction of study drug	14(10.6)	44(10.0)	42(12.8)
Dose omission	21(15.9)	72 (16.3)	57(17.4)

a

Based on patients who had diarrhea

Conclusions: The dose adjustment strategy used in the MONARCH studies was effective at managing AEs by dose adjustment and/or supportive medication. Understanding the safety profile of abemaciclib can inform AE management and can extend time on treatment.

FERTILITY CONCERNS AND DESIRE OF PREGNANCY IN YOUNG BREAST CANCER PATIENTS: A SINGLE INSTITUTE EXPERIENCE

Pistelli M.¹, Pellegrini C.¹, Savini A.¹, Merloni F.¹, Tassone L.¹, Crocetti S.¹, Bastianelli L.¹, Cantini L.¹, Della Mora A.¹, Maccaroni E.¹, Berardi R.¹

¹Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Ancona, AOU Ospedali Riuniti-Ancona, Ancona

Background: Although the use of adjuvant therapies with cytotoxic drugs can significantly reduce breast cancer (BC) mortality, it raises issues of the long-term toxicity, such as induction of an early menopause and fertility impairment in young women. The risk of infertility is a potential hardship to be faced by the patients following treatment of BC. Preservation of fertility in BC survivors of reproductive age has become an important issue regarding the quality of life. We conduct this prospectively observational study with the following aims: 1) to estimate the desire of pregnancy in young women with BC; 2) to evaluate the need to adopt appropriate fertility preservation techniques; 3) to evaluate the possible influence of pregnancies preceding the disease; 4) to analyze the implications of ovarian function recovery after adjuvant therapies.

Patients and Methods: We prospectively analyze pathological and clinical data about all consecutive patients younger than 40 years with diagnosis of invasive BC referred to our Institution from january 2013 to december 2017. All patients fill in a questionnaire at diagnosis and then once a year for 5 years after diagnosis that collect data about pregnancies, desire of maternity, using of fertility preservation techniques and menstruation history.

Results: 73 (5.7%) of 1265 patients referred to our Institution are included. The age at diagnosis correlates with the desire of pregnancy (p = 0.0018). About 40% of them had no pregnancies before the diagnosis of BC, consequently more than 60% of patients reveal desire of maternity at the beginning of the treatments and decide to preserve fertility. LH-RH analogue and cryopreservation procedures are used to preserve fertility. However, at the end of the adjuvant therapies only 37% of patients preserve the desire of pregnancy. Among patients who have a free interval ⩽24 months between the last pregnancy and the diagnosis of BC (23.3% of cases), tumors are predominantly ER-negative (60% of cases). Ovarian function recovery occurs early and more frequently in ER-negative BC patients (p<0.0001).

Conclusions: Our results reveal that an higher proportion of young BC women lost the desire of pregnancy during the adjuvant treatments; it may depends on type and duration of oncological therapies and side effects of treatments. A multidisciplinary approach and an adequate psychological support need to encourage young BC patients to pursuing their future aims, including motherhood.

ABEMACICLIB WITH FULVESTRANT IN PATIENTS WITH HORMONE RECEPTOR POSITIVE (HR+), HER2- ADVANCED BREAST CANCER (ABC) THAT EXHIBITED PRIMARY OR SECONDARY RESISTANCE TO PRIOR ENDOCRINE THERAPY

Grischke E.¹, Pivot X.², Llombart-Cussac A.³, Neven P.⁴, Lin Y.⁵, Kaufman P.⁶, Sledge G.⁷, Guarneri V.P.⁸

¹Universitätsklinikum Tübingen Frauenklinik, Tübingen, Germany, Tübingen; ²CHU de Besancon Hopital Jean Minjoz, Besancon Cedex, France, Cedex; ³Hospital Arnau Vilanova, Valencia, Spain, Valencia; ⁴Universitaire Ziekenhuizen Leuven – Campus Gasthuisberg, Leuven, Belgium, Leuven; ⁵Eli Lilly, Indianapolis, IN, USA, Indianapolis; ⁶Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA, Lebanon; ⁷Stanford University, Stanford, CA, USA, Stanford; ⁸University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy, Padova

Background: Abemaciclib, a selective inhibitor of CDK4 & 6, dosed on a continuous schedule is approved for the treatment of HR+, HER2- ABC. In the intent-to-treat population, abemaciclib with fulvestrant (F) demonstrated improved progression-free survival (PFS) and objective response rate (ORR) compared to placebo (P)+F (16.4 vs 9.3 months, HR: 0.553; P<.0000001; ORR in measurable disease 48.1 vs 21.3%; P<.001). ET resistance (ETR) were classified into primary ETR, which includes patients (pts) whose disease relapsed while receiving the first 2 years of (neo)adjuvant ET or progressed while receiving the first 6 months of ET for ABC, and secondary ETR. Here, we compare the efficacy and safety of abemaciclib+F vs P+F in the primary and secondary ETR subgroups.

Material and Methods: MONARCH 2 was a phase 3 randomized, double-blind, placebo-controlled study of abemaciclib+F vs P+F in pts with HR+, HER2- ABC that progressed on ET. Key eligibility criteria were previously discussed. Pts received orally administered abemaciclib 150 mg Q12H + 500 mg F (per label) or P+F. Pts were stratified by sensitivity to ET. Primary objective was investigator-assessed PFS. Secondary objectives included efficacy, safety and tolerability.

Results: 169 pts (25.3%) had primary ETR and 489 pts (73.1%) had secondary ETR. Key efficacy endpoints are summarized (Table). The most frequent adverse events in primary and secondary ETR population are similar. For primary ETR, abemaciclib+F vs P+F were diarrhea (87.3 vs 22.4%), neutropenia (43.6 vs 5.2%), nausea (41.8 vs 25.9%), abdominal pain (36.4 vs 13.8%), and anemia (31.8 vs 5.2%), respectively.

OPEN IN VIEWER

Summary of PFS and ORR in primary and secondary ETR population.

	Primary Resistance		Secondary Resistance
	Abemaciclib + F	Placebo + F	Abemaciclib + F	Placebo + F
PFS
Median (months)	15.3	7.9	16.6	9.6
HR (95% CI)	0.45 (0.31, 0.67)		0.59 (0.46, 0.75)
P-value	<.001		<.001
ORR in measurable disease (%)	53.9	17.9	46.2	22.6
P-value	<.001		<.001

Conclusions: Abemaciclib+F improved PFS and ORR in pts with primary and secondary ETR, and had a generally tolerable safety profile. Although pts with primary ETR typically have poor prognosis the benefit for abemaciclib+F was maintained in pts HR+, HER2- ABC.

THE NEUTROPHIL-TO-LYMPHOCYTE, PLATELET-TO-LYMPHOCYTE AND MONOCYTE-TO-LYMPHOCYTE RATIOS PREDICT EFFICACY OF CDK 4/6 INHIBITORS IN WOMEN WITH HORMONE RECEPTOR-POSITIVE/HER2-NEGATIVE ADVANCED BREAST CANCER

Zattarin E.¹, Fabbroni C.¹, Ligorio F.¹, Nichetti F.¹, Peverelli G.¹, Lobefaro R.¹, Maggi C.¹, Mariani G.¹, Capri G.¹, Rivoltini L.², De Braud F.¹, Bianchi G.V.¹, Vernieri C.¹

¹Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy, Milano; ²Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy, Milano

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapies are a mainstay of treatment for patients (pts) with advanced hormone receptor-positive breast cancer (HR+ BC). Preclinical evidence indicates that the ability of CDK 4/6 inhibitors to stimulate antitumor immunity may crucially contribute to their anticancer activity. Although peripheral blood-derived markers reflecting systemic inflammation and immune system activation, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR) and the platelet-to-lymphocyte ratio (PLR), have been associated with patient prognosis in several malignancies, their role in predicting CDK 4/6 inhibitor efficacy in HR+ BC pts remains unknown.

Patients and Methods: We performed a retrospective, monocentric study in advanced HR+ BC pts treated with CDK 4/6 inhibitors at our Institution. We assessed the association between NLR, MLR or PLR, as measured two weeks after treatment initiation or at the fist disease re-evaluation, and patient progression free survival (PFS). The threshold for NLR (2.5) was chosen on the basis of literature data, whereas MLR and PLR thresholds were calculated through maximally selected rank statistics. The impact of these parameters on PFS was evaluated at univariate and multivariable analysis by using Cox proportional hazard models.

Results: A total of 92 pts treated with palbociclib or ribociclib plus aromatase inhibitors or fulvestrant between January 2017 and December 2018 at our Institution were included in the analysis. When measured two weeks after treatment initiation, NLR, MLR and PLR were not associated with PFS. Conversely, high NLR (> 2.5), high MLR (> 0.19) and high PLR (> 323), as measured at the first disease re-valuation, were associated with significantly higher risk of disease progression (HR 3.12; 95% CIs: 1.06-9.16; HR 2.38; 95% CIs: 1.06-5.34 and HR 3.89; 95% CIs: 1.53-9.9, respectively). Multivariable analysis confirmed an independent association between high MLR or PLR and lower PFS, and a trend towards statistical significance for NLR.

Conclusions: This is the first study to show a significant association between high NLR, MLR or PLR values and lower PFS in HR+ BC pts treated with CDK 4/6 inhibitors. Further studies are warranted to prospectively validate these biomarkers, and to investigate if patients with poorer predicted prognosis may benefit from alternative endocrine, cytotoxic or biological agents.

BRCA MUTATIONS AMONG TRIPLE NEGATIVE BREAST CANCER, EARLY ONSET BREAST CANCER, MALE BREAST CANCER AND OVARIAN CANCER WITHOUT FAMILY HISTORY OF BREAST AND/OR OVARIAN CANCER: THE MODENA FAMILY CANCER CLINIC EXPERIENCE

Eleonora M.¹, Venturelli M.¹, Domati F.¹, Barbieri E.¹, Marchi I.², De Matteis E.³, Cascinu S.¹, Toss A.¹, Cortesi L.¹

¹Department of Oncology and Hematology, University Hospital of Modena and Reggio Emilia, Modena; ²Center for Genome research, University Hospital of Modena and Reggio Emilia, Modena; ³Department of Oncology, Vito Fazzi Hospital, Lecce, Modena

Because of the high costs associated with genetic analyses, BRCA-testing has traditionally been restricted to breast cancer (BC) patients having an a priori high risk of being a carrier. According to the National Institute for Health and Care Excellence (NICE) in the UK, BRCA testing should be offered to BC patients with a probability of having a mutation = 10%. Regardless of family history, International Guidelines include among the BRCA testing Criteria personal history of triple-nagtive BC (TNBC) diagnosed = 60 years, early onset BC ( = 35 years according to the Italian Criteria), male BC and epithelian ovarian cancer (OC).

In the archives of the Modena Family Cancer Clinic, we identified 258 early onset BCs, 126 TNBCs < = 60 years, 44 male BCs and 99 OCs without any breast and/or ovarian family history, which underwent BRCA-genetic testing. BRCA detection rate among eorly-onset BCs was 15.5% (12% BRCA1, 3.5% BRCA2), among TNBCs was 15.8% (14.3% BRCA1, 1.5% BRCA2), among male BCs was 18.2% (18.2% BRCA2) and among OCs was 19.2% (11.1% BRCA1, 8.1% BRCA2). BRCA-associated early-onset BC showed significantly higher MIB-1. The other clinical-pathological characteristics were equally distributed between carriers and non-carriers and will be detailed in the final presentation.

Our analyses highlighted a mutational rate greater than 10% in all the four categories considered. These results confirm the indication to test TNBC = 60 years, early onset BC ( = 35 years), male BC and epithelian ovarian cancer (OC) regardless their family history.

FEASIBILITY OF AUTOMATED DATA EXTRACTION AND ELECTRONIC PHENOTYPING USING THE i2b2 PLATFORM FOR OUTCOMES RESEARCH ANALYSIS, IN A LARGE COHORT OF HER2+ EARLY-STAGE BREAST CANCER

Zambelli A.¹, Ghirardi A.², Bucalo M.³, Chiudinelli L.⁴, Rota Caremoli E.¹, Moro C.¹, Negrini G.¹, Poletti P.¹, Milesi L.¹, Tasca C.¹, Chirco A.¹, Sfreddo E.², Bellazzi R.⁴, Tondini C.¹

¹Department of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italy, Bergamo; ²FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy, Bergamo; ³BIOMERIS, Pavia, Italy, Pavia; ⁴Dipartimento di Ingegne-ria Industriale e dell’Informazione, Università di Pavia, Pavia, Italy, Pavia

Background: With the widespread adoption of electronic health records, large repositories of structured and unstructured patient data are becoming available to conduct observational studies. This single-centre study aimed to evaluate the feasibility of the Harvard-academic, open-source, i2b2 (Informatics for Integrating Biology & the Bedside) platform to support an outcomes research study, through the automated reconstruction of individual pathways of care and long-term survival of a large cohort of HER2+/eBC, based on an electronic phenotyping approach.

Material and Methods: To test the i2b2 platform, we identified a 10-year dataset of consecutive HER2+/eBC patients treated at Papa Giovanni XXIII Hospital (Bergamo), with an automated multiple temporal electronic phenotyping, according to the main clinico-pathological characteristics. In this unselected cohort of patients, the Kaplan-Meier estimates were used to evaluate cumulative incidence of relapse and survival, stratifying for the tumor burden (T, N) and tumor biology (Grade, ER). Multivariable Cox proportional-hazard models were apply to estimate HRs of relapse and death adjusting for potential confounders.

Results: From Sept 2007 to Sept 2017, 531 HER2+/eBCs, out of >5000 consecutive eBCs, were identified and the individual-data automatically analyzed through the i2b2 open-source platform. At a first preliminary analysis, the 10-year OS of trastuzumab-treated patients (391) was 68.3%. According to the multiple electronic phenotyping, OS was significantly affected by lymph node involvement (N-: 79.0% vs. N+: 58.7%, p = 0.0001), tumor size (T1: 76.7% vs. T2-4: 68.4%, p = 0.039) and ER status (ER-: 63.2% vs. ER+: 69.7%, p = 0.012). Similarly, the 10-year cumulative incidence of relapse was mainly associated to lymph node involvement (N-: 26.5% vs. N+: 51.9%, p = 0.0001), ER status (ER-: 51.4% vs. ER+: 30.8%, p = 0.001) and tumor grade (G1-2: 20.7% vs. G3: 45.5%, p = 0.003). The adjusted multivariable analysis confirmed N+, ER- and age>65 as independent risk factors of BC relapse and death, in line with the previously reported evidences.

Conclusions: This real-life experience shown the exportable, open-source i2b2 platform is able to automatically rebuilt the individual pathways of care and clinical outcomes of a large and unselected cohort of HER2+/eBCs. Actually, the i2b2 platform supported the automated data extraction and the phenotyping approach and can be considered as a relevant tool for multiple outcomes research studies.

IMPACT OF ESTROGEN RECEPTOR LEVELS ON OUTCOME AND PATHOLOGICAL COMPLETE RESPONSE IN TRIPLE NEGATIVE BREAST CANCER (TNBC) PATIENTS TREATED WITH NEOADJUVANT CHEMOTHERAPY

Giorgi C. A.¹, Dieci M.V.², Giarratano T.¹, Angelini S.¹, Mioranza E.¹, Gaia G.¹, Federica M.², Tasca G.¹, Faggioni G.¹, Falci C.¹, Piccin L.², Vernaci G.², Mantiero M.², Menichetti A.², Genovesi E.², Frezzini S.², Saibene T.³, Michieletto S.³, Guarneri V.²

¹Medical Oncology 2, Veneto Institute of Oncology IOV – IRCCS, Padova; ²Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova; ³Breast Surgery Unit, Veneto Institute of Oncology IOV – IRCCS, Padova

Background: Although 1% has been proposed as cut-off for estrogen receptor (ER) positivity, the 10% cut-off is often used in clinical practice based on several studies showing that breast cancers with ER<1% have biological characteristics similar to those with ER⩾1%&<10%. Our aim was to compare pathological complete response (pCR) rates and disease-free survival (DFS) according to ER level in a cohort of patients with HER2-negative, ER<10% and progesterone receptor <10% undergoing neoadjuvant chemotherapy (NACT).

Patients and Methods: Clinicopathological data of patients with triple negative breast cancer (TNBC, defined as ER and progesterone receptor <10% and HER2-negative) treated at our Institution with anthracycline and taxane-based NACT were collected. Patients were categorized according to ER expression; <1% or ⩾1%&<10%. pCR was defined as ypT0/is and ypN0. DFS was calculated from the date of diagnosis to the date of relapse (locoregional or distant), death or last follow up.

Results: 184 patients were included: 157 with ER<1%, 27 with ER⩾1%&<10%. Main characteristics: median age 50 years, ductal histology 93%, grade 3 90%, cT>2cm 86%, cN+ 56%, median ki67 60%, BRCA mutated 9%. There was no significant difference in clinicopathological characteristics according to ER level. With regards to adjuvant therapy, 27% (n = 50) of patients underwent chemotherapy after surgery: 29% in the ER<1% and 19% in the ER⩾1%&<10% cohort, p = 0.317. More patients in the ER⩾1%&<10% cohort received adjuvant endocrine therapy (15% vs 6%, p = 0.078). Reason to prescribe endocrine therapy in ER<1% patients was residual disease with ER⩾1%. pCR rate was similar in the two cohorts (38% in ER<1% cohort, 44% in ER⩾1%&<10% cohort, p = 0.498). With a median follow up of 48 months, no difference was observed in DFS: 2-year DFS was 80.9% in ER<1% and 82.9% in ER⩾1%&<10% cohort (HR 1.04, 95%CI 0.46-2.3, p = 0.928).

Conclusions: Early HER2-negative primary breast cancer with ER <10% behaves clinically like ER<1% breast cancer in terms of pCR after NACT and DFS. Our results support the definition of TNBC as HER2-negative breast cancer with ER<10% and PgR<10%, rather than <1%.

AN ANALYSIS OF THE RELATIONSHIP BETWEEN ABDOMINAL FREE FLAP WEIGHT AND MASTECTOMY WEIGHT AND THE EFFECT OF ADJUVANT RADIOTHERAPY ON THE AESTHETIC OUTCOMES OF IMMEDIATE BREAST RECONSTRUCTION: A MULTICENTRE STUDY

Di Pace B.¹, Kahn F.², Patel M.², Serlenga G.³, Sorotos M.⁴, Santanelli di Pompeo F.⁴, Rubino C.⁵, Malata C.M.⁶

¹Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, PhD School of Translational Medicine of Development and Active Aging, Università degli Studi di Salerno, Salerno, Italy; Plastic & Reconstructive Surgery Department, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Salerno; Cambridge; ²University of Cambridge, School of Clinical Medicine, Cambridge, UK., Cambridge; ³Plastic Surgery Unit, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, San Giovanni di Dio e Ruggi D’Aragona University Hospital, University of Salerno, Salerno, Italy., Salerno; ⁴Plastic Surgery Unit, Sant’Andrea Hospital, School of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy., Rome; ⁵Plastic Surgery Unit, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, San Giovanni di Dio e Ruggi D’Aragona University Hospital, University of Salerno, Salerno, Italy; Plastic Surgery Unit, Department of Surgery, Microsurgery and Medical Sciences, University Hospital Trust, University of Sassari, Sassari, Italy, Salerno; Sassari; ⁶Plastic & Reconstructive Surgery Department, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Anglia Ruskin University School of Medicine, Cambridge & Chelmsford, UK., Cambridge

Background: Breast cancer is the most common malignancy in women (25% of all cancers). In the UK, its incidence has increased by 4% over the last 10 years, while it is estimated that in Italy 1 in 8 women will be affected by breast cancer in her life. It has however, the highest survival rate amongst all types of female cancers. In view of this and the fact that today breast reconstruction is a significant component of breast cancer treatment, improving reconstruction outcomes needs to be an ongoing goal.

Material and Methods: Between May 2004 and August 2018, 423 women, who underwent immediate abdominal free flap breast reconstruction (FFBR), were enrolled in our multicentre study (UK and Italy). Abdominal free flap weights were compared with mastectomy weights with a view to analysing the rates of contralateral balancing and ipsilateral revision surgeries based on the relative magnitudes of the weights. Patients were thus divided into two groups: Group A mastectomy weight > flap weight; Group B mastectomy weight < flap weight. The influence of post-mastectomy radiotherapy on the incidence of contralateral balancing and ipsilateral revision surgeries was also studied. Fisher’s Exact test was used to analyse the comparative requirements for these aesthetic adjustment procedures.

Results: In Group A, the incidence of adjustment surgery was dominated by balancing surgeries on the contralateral breast (37%) versus 14% revisions of the reconstructed breasts. In Group B, the rate of contralateral balancing surgery was much less: 11% versus the above 37% (p value = 0.00001). The revision surgery rate on the index breasts in Group A (14%) was double that of Group B (7%) [p value = 0.003]. For all patients, post-operative radiotherapy significantly increased the number of ipsilateral revisions (p value = 0.048) compared with contralateral balancing surgeries.

Conclusions: When performing immediate FFBR, where the flap weight is smaller than the mastectomy weight, surgeons can reasonably expect an increased need for subsequent adjustments on both the contralateral and ipsilateral breasts (revisions and balancing surgeries respectively). Furthermore, post-operative irradiation predisposes to ipsilateral revisions. We believe that these findings are important in patient counselling before and after reconstruction. They may also play a role in planning subsequent aesthetic refinements.

NODE-NEGATIVE BREAST CANCER AND LONG-TERM PROGNOSIS

Agostinetto E.¹, Giordano L.¹, De Sanctis R.¹, Torrisi R.¹, Masci G.¹, Losurdo A.¹, Zuradelli M.¹, Tinterri C.¹, Santoro A.¹

¹Humanitas Research Hospital, Rozzano

Background: Early breast cancers (BC) are associated with a risk of relapse which may vary according to clinical-pathological features of disease. Thanks to a wider diffusion of screening, incidence of node-negative BC has increased in the recent decades and it is expected to further increase in the next future. Aim of our study was to evaluate prognosis of node-negative BC and to evaluate which factors are associated with an increased risk of relapse.

Methods: BC operated at our institution with evidence of negative nodes and with a potential follow-up of at least 5 years were retrospectively reviewed. OS was estimated by Kaplan Meier method and differences between groups by log-rank test. Cox proportional Hazard model was used to estimate Hazard ratio (HR) with 95% confidence intervals (CI). Significance was set at 0.05.

Results: We analyzed 1276 patients (pts) affected by node-negative BC, operated at our institution between April 1999 and December 2013. With a median follow-up of 71.6 months (range 1-227.2 months), we observed 159 events of relapse or death. Median PFS was 170 months. Median OS was 192 months. At univariate analysis, older age, negative hormonal receptors, larger tumor size and higher proliferation index (ki67) were significantly associated with worse PFS and OS (p<0.05); higher grading was significantly associated with worse PFS (p = 0.01). At multivariate analysis for PFS, age, ki67 and tumor size confirmed their independent prognostic role (HR 1.035, 95% CI 1.021-1.048, p<0.001; HR 1.012, 95% CI 1.004-1.021, p = 0.005; HR 1.020, 95% CI 1.004-1.037, p = 0.018, respectively). At multivariate analysis for OS, age and positive hormonal receptors showed an independent prognostic role (HR 1.104, 95% CI 1.079-1.129, p<0.0001, HR 0.426, 95% CI 0.224-0.809, p = 0.0092, respectively). In order to compare prognosis of triple negative BC (TNBC) with non-TNBC subtypes, a subgroup of 71 TNBC pts were matched according to age, ki67 and tumor size with 71 non-TNBC pts. We observed no statistically significant difference in terms of prognosis (72-months PFS 89.6% vs 92.9% in TNBC and non-TNBC, respectively, p = 0.232; 72-months OS 90% vs 98% in TNBC and non-TNBC, respectively, p = 0.1779).

Conclusions: In our retrospective analysis of node-negative BC, age, hormonal receptor status, tumor size and ki67 showed a significant association with prognosis. TNBC subtype was not associated with a statistically significant worse prognosis, compared to non-TNBC subtypes.

EFFICACY AND SAFETY OF ORAL CAPECITABINE-VINORELBINE COMBINATION VERSUS SINGLE-AGENT CAPECITABINE OR VINORELBINE IN METASTATIC HER2-NEGATIVE BREAST CANCER: A RETROSPECTIVE, MONOCENTRIC STUDY

Prisciandaro M.¹, Vernieri C.², Nichetti F.¹, Lobefaro R.¹, Peverelli G.¹, Maggi C.¹, Cona M.S.¹, Corti F.¹, Mariani G.¹, Capri G.¹, Bianchi G.V.¹, Celio L.¹, Rivoltini L.³, De Braud F.⁴

¹Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy, Milano; ²Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; IFOM, the FIRC Institute of Molecular Oncology, Milano; ³Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy, Milano; ⁴Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Oncology and Haemato-Oncology Department, University of Milan, Italy, Milano

Background: Despite the introduction of new treatments, chemotherapy (ChT) still plays a pivotal role in HER2- negative metastatic breast cancer (mBC). Although single-agent capecitabine (C) and vinorelbine (V) are effective agents in mBC treatment, the capecitabine-vinorelbine (CV) combination is frequently used despite the lack of data demonstrating its superiority over single-agent C/V. In this study, we retrospectively compared the efficacy and safety profile of CV and single-agent C/V.

Patients and Methods: We collected data of 310 patients (pts) with HER2-negative mBC treated between April 2012 and December 2018 with C 2000 mg/m2 on days 1-14 of every-three weeks cycles, V 60 mg/m2 on days 1 and 8 of every-three weeks cycles, or the CV combination. We compared progression-free survival (PFS), overall survival (OS) and rate of adverse events (AEs) in pts treated with CV or single-agent C/V. Subgroup analysis was conducted in pts with hormone receptor-positive (HR+) and triple negative breast cancer (TNBC). Propensity score analysis was used to confirm results of OS analyses in pts matched for clinical/tumor characteristics. As an exploratory analysis, we evaluated the impact of single versus combination treatments on the neutrophil-to-lymphocyte ratio (NLR) after one treatment cycle.

Results: We found no differences in median PFS between pts treated with CV vs. single-agent C/V, while CV was associated with significantly longer OS in pts with HR+ BC (27.6 vs. 22.7 moths; p = 0.016). These results were confirmed at multivariable analysis when balancing for known prognostic factors in mBC, as well as after propensity score-based matching of pts with similar clinical/tumor characteristics. Pts treated with CV had higher incidence of any-grade and G3/G4 neutropenia, whereas the incidence of other AEs was similar in the two treatment groups. A NLR higher than 3.67 before treatment initiation was associated with worse OS; of note, the CV combination reduced the NLR significantly more than single-agent C/V.

Conclusions: When compared with single-agent C/V, the CV combination was independently associated with significantly longer OS in the subgroup of HR+ BC pts. However, this potential advantage comes at the cost of increased incidence of neutropenia. Prospective studies are required to confirm the observed association between CV and better OS in HR+ BC patients, as well as to explore the potential immunomodulatory effect of this combination chemotherapy.

LIQERBCEPT: INTERCEPTING MUTATIONAL TRAJECTORIES OF HER2+ BREAST CANCER PATIENTS UNDERGOING T-DM1 ADMINISTRATION

Allegretti M.¹, Giordani E.¹, Taraborelli E.¹, Ercolani C.¹, Romania P.¹, Casini B.¹, Buglioni S.¹, Gasparro S.¹, Russillo M.¹, Pescarmona E.¹, Cognetti F.¹, Ciliberto G.¹, Giacomini P.¹, Fabi A.¹

¹IRCCS Regina Elena National Cancer Institute, Rome

Background: Trastuzumab Emtansine (T-DM1) is standard of care (SOC) in HER2⁺ breast cancer on progression following previous lines of HER2-targeted therapies. Despite clinical benefit, some patients display primary resistance, and the majority relapse within 1 year due to acquired resistance. The underlying mechanisms remain ill-defined. Liquid biopsy (LB) may help to uncover genomic alterations linked to T-DM1 resistance.

Methods: Tissue DNAs (tDNAs) from the latest available primary and/or metastatic lesions (n = 23), and circulating tumor DNAs (ctDNAs) from plasma (n = 157) were collected from 13 patients. tDNAs and ctDNAs were analyzed by ultra-deep NGS (IonTorrent S5) and dPCR (QuantStudio3D). Genomic data were matched with radiomics (PET/CT).

Results: Nine out 13 patients progressed within 1 year (mean 306±209 days). At least 1 mutation per patient (range = 1-64) was identified in tDNAs, and multiple sequential tDNAs documented clonal selection prior to T-DM1 administration. At baseline, 9/13 patients showed at least 1 ctDNA (VAF = 0.1-15.2%), and tDNA/ctDNA mismatches were common. Increases and de novo ctDNA appearance (indicative of primary and adaptive resistance, respectively) were seen by LB in 5/8 relapsing patients, 2.0 months on average before radiomic progression (range 0.7-2.8). The remaining 3 patients developed brain (n = 2) or skin (n = 1) metastases not captured by the available ctDNAs, that registered clonal regression instead. Remarkably, 6/8 relapsing patients displayed actionable (OncoKB levels ⩽3) ctDNAs. As to responders, outcome was anticipated in all (4/5) patients in whom a ctDNA was detectable at baseline. In two of them, ultra-fast ctDNA clearance (<2 months) of two HER2 mutations was observed. Finally, intersecting, divergent ctDNA trajectories were noted in a patient.

Conclusions: Although non-informative in 4/13 patients, our study provides proof of principle for tumor evolution, outcome anticipation, and divergent/accelerated clonal selection. Vulnerabilities only seen in blood may offer unprecedented non-SOC therapeutic opportunity upon T-DM1 progression.

TOXICITY (T) OF ERIBULIN (E) IN METASTATIC BREAST CANCER (MBC) PATIENTS (pts). RESULTS OF THE PHASE IV PAINTER (POLYMORPHISM AND INCIDENCE OF TOXICITY IN ERIBULIN TREATMENT) STUDY

La Verde N. M.¹, Damia G.², Vandone A.M.³, D’Onofrio L.⁴, Fabi A.⁵, Ciccarese M.⁶, Dester M.⁷, Sabatini S.⁸, Poletto E.⁹, Pedrazzoli P.¹⁰, Cretella E.¹¹, Scandurra G.¹², Meattini I.¹³, Menatti E.¹⁴, Cavanna L.¹⁵, Romagnoli E.¹⁶, Legramandi L.¹⁷, Guffanti F.², Moretti A.¹⁸, Rulli E.¹⁷, Farina G.¹⁸

¹Unità Operativa Complessa Oncologia ASST Fatebenefratelli Sacco PO Luigi Sacco Via G. B. Grassi, 74, Milano; ²Laboratorio Farmacologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ³Ospedale Santa Croce e Carle, Cuneo; ⁴Oncologia Medica Policlinico Universitario Campus Biomedico, Roma; ⁵Istituto Nazionale Tumori Regina Elena, Roma; ⁶A.O. Vito Fazzi, Lecce; ⁷Istituti Ospitalieri di Cremona, Cremona; ⁸A.O. Santa Maria di Terni, Terni; ⁹AOU Santa Maria della Misericordia, Udine; ¹⁰Fondazione IRCCS Policlinico San Matteo, Pavia; ¹¹Comprensorio Sanitario Oncologia, Bolzano; ¹²Ospedale Cannizzaro, Catania; ¹³Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Università di Firenze, Firenze; ¹⁴ASST Valtellina e Alto Lario, Sondrio; ¹⁵Oncologia Medica Azienda Ospedaliera di Piacenza, Piacenza; ¹⁶Oncologia Medica Ospedale Provinciale di Macerata, Macerata; ¹⁷Unità di Statistica, Laboratorio di Metodologia della ricerca clinica - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; ¹⁸Oncologia Medica ASST Fatebenefratelli - Sacco P.O. Fatebenefratelli, Milano

Background: MBC is a deathly disease. Treatments in this setting have a palliative aim, therefore the management of drug related adverse events (AE) is very important. E is a microtubule inhibitor, approved for the treatment of MBC. The most common AE reported in the literature are fatigue, neutropenia and peripheral neuropathy.

Material and Methods: PAINTER is a multicenter, interventional, single arm, phase IV study, aimed to survey the tolerability of E, at conventional dose, in an unselected population of pts with MBC. T was reported according to the NCI CTCAE v4.0.

Results: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centers and 170 were evaluated for the safety analysis. Pts and tumors characteristics were as follow: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1, mean BMI 25.5, with 27.2% overweight and 19.5% obese pts. Previous neuropathy was reported in 15.9% of pts. The table shows the incidence of expected AEs. Other G1-G4 toxicities were: gastrointestinal in 30.9% pts, dermatological in 8.6%, liver injury in 13.6%, pulmonary in 13.6%.

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AEsn = 170	G1n. (%)	G2n. (%)	G3n. (%)	G4n. (%)	Severe T(G3+G4)% [%95%CI]
Neurotoxicity	31 (18.2)	20 (11.8)	5 (2.9)	0 (0.0)	14.7 [9.75 - 20.9]*
Neutropenia	15 (8.8)	11 (6.5)	16 (9.4)	10 (5.9)	15.3 [10.2 - 21.6]
Constipation	16 (9.4)	8 (4.7)	1 (0.6)	0 (0.0)	0.6 [0.02 - 3.23]
Alopecia	25 (14.7)	13 (7.6)	0 (0.0)	0 (0.0)	0.0
Asthenia	38 (22.4)	38 (22.4)	10 (5.9)	0 (0.0)	5.9 [2.86 - 10.6]
Nausea	19 (11.2)	6 (3.5)	0 (0.0)	0 (0.0)	0.0

*

G2 for neoropathy was considered as severe T.

Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and in tumor site. 48.8% of pts experienced a schedule modification, mainly at the 2nd cycle, due to neutropenia (23.9%) and liver injury (12%). 37.3% had a modification of timing, mainly for logistic reasons (19.4%) or previous reactions (3.2%). Ten serious AEs were reported, only two E related. 5.2% of pts discontinued E for T and for pts refuse.

Conclusions: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pretreated pts, but T rarely lead to treatment discontinuation.

AGREEMENT BETWEEN THE MULTIDISCIPLINARY TEAM MEETINGS PROPOSAL AND FINAL THERAPEUTIC CHOICE IN EARLY BREAST CANCER

Giavarra M.¹, Bertoli E.¹, Buono V.¹, Zara D.¹, Targato G.¹, Palmero L.¹, Vitale M.G.¹, Pelizzari G.², Basile D.², Gerratana L.², Bonotto M.³, Andreetta C.³, Cinausero M.³, Pascoletti G.³, Poletto E.³, Russo S.³, Puglisi F.², Fasola G.³, Mansutti M.³, Minisini A.M.³

¹Università degli Studi di Udine, Dipartimento di Area Medica; Azienda Sanitaria Universitaria Integrata di Udine “Santa Maria della Misericordia”, Dipartimento di Oncologia Medica, Udine; ²Università degli Studi di Udine, Dipartimento di Area Medica; Centro di Riferimento Oncologico di Aviano IRCCS, Dipartimento di Oncologia Medica, Aviano; ³Azienda Sanitaria Universitaria Integrata di Udine “Santa Maria della Misericordia”, Dipartimento di Oncologia Medica, Udine

Background: A multidisciplinary team meetings (MDMs) approach to breast cancer (BC) management is a standard of care. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early BC. The purpose of this study was to define whether there was agreement between the planned program (i.e. MDMs-based decision) and that actually applied. In addition, the study explored factors associated with discordance.

Methods: We conducted a retrospective study of a consecutive series of 291 pts with new diagnosis of early BC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. The association between clinico-biological factors and discordance was explored through uni- and multi-variate logistic regression analysis.

Results: Median age was 62 years (range 27-88 years). Among invasive early BC patients, the most frequent phenotype was luminal A (38%), followed by luminal B (33%), HER2-positive (12%) and triple negative (5%). In situ carcinoma (DCIS) represented 12% of cases. Median time from MDMs discussion to first oncologic examination was 2 weeks. Rate of discordance between MDMs-based decision and final choice, during face to face consultation with the oncologist, was 15.8% (46/291). The most frequent reason for changing the MDMs-based program was clinical decision (87%). Follow-up was preferred to the chemotherapy (CT) proposed within the MDMs in 15% of cases, and to the endocrine therapy (ET) in 39% of cases (among these, 44.5% had diagnosis of DCIS). Therapeutic change from sequential CT-ET to Et alone was chosen in 16/46 pts (35%): among these pts, 7 had a luminal B disease and 6 had a HER2-positive disease. On univariate analysis, factors associated with discordance were values of Ki-67 14-30% (OR 3.91; 95%CI 1.19-12.9), age⩾70 years (OR 2.44, 95%CI 1.28-4.63), housewife/retired status (OR 2.35, 95%CI 1.14-4.85), polypharmacy (OR 1.95; 95%CI 1.02-3.72), postmenopausal status (OR 4.15; 95%CI 1.58-10.9), high Charlson Comorbidity Index (OR 1.31; 95%CI 1.09-1.57). Association with marital status, educational level, alcool and smoke habits, presence of caregiver, parity, grading, histotype and phenotype, stage were not statistically significant. On multivariate analysis, only ki-67 value maintained its statistical significance.

Conclusions: The results of our study could be useful for enhancing the role of MDMs in clinical decision making process in early BC.

ASSESSING THE IMPACT OF 12 MONTHS LIFESTYLE INTERVENTIONS ON BREAST CANCER SECONDARY PREVENTION: A MODELING APPROACH

Bastianelli L.¹, Pistelli M.¹, Natalucci V.², Della Mora A.¹, Belelli R.¹, Romeo M.¹, Ballatore Z.¹, Capecci M.³, Ceravolo M.G.³, Serrani R.⁴, Ricci M.⁴, Fumelli D.⁵, Taus M.⁵, Nicolai A.⁵, Berardi R.¹

¹Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Ancona, AOU Ospedali Riuniti-Ancona, Ancona; ²Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Urbino; ³Clinica di Neuroriabilitazione, Università Politecnica delle Marche, Ancona, AOU Ospedali Riuniti-Ancona, Ancona; ⁴Medicina Riabilitativa, AOU Ospedali Riuniti-Ancona, Ancona; ⁵Dietetica e Nutrizione Clinica, AOU Ospedali Riuniti-Ancona, Ancona

Background: Healthy lifestyle, including caloric restriction, balanced diet and physical activity, is important in primary and secondary prevention of breast cancer (BC). Since January 2014, at our Institution we promoted a project named “Lifestyle Program” for high risk BC patients underwent to primary surgery. Here we presented the results of 12 months of “Lifestyle Program”.

Patients and Methods: Since January 2014 we have prospectively enrolled all high risk patients between 18 and 70 years treated to our department for invasive early-stage breast cancer (stage I-III). High risk has been defined by one or more of the following inclusion criteria: body mass index (BMI)> 25, diagnosis of metabolic syndrome, increased level of blood testosterone and/or insulin. All high risk patients receive a periodical personalized educational intervention by a physiatrist for physical activity and by a nutritionist for a mediterranean diet low in animals fat and enriched of fibers, fruits and vegetables. All patients underwent to screening for anxiety and depression through HADS questionnaire scores.

Results: 98 BC patients were included; 21.4% of them had a metabolic syndrome. Median age was 56 years old (range 27-75). Most of patients enrolled had ER+ (85.7%), Her2/neu negative (79.6%), stage I (48%) BC. We observed a statistically significant reduction of BMI (BMI>25 in 94.9% of pts at baseline vs 63.2% after 12 months of lifestyle; p=<0.0001), glycemic (>110 mg/dl in 23.5% of pts at baseline vs 10.2% at 12 months; p=<0.0001), insulin levels (>27 uU/ml in 20.6% of pts at baseline vs 2.9% after 12 months; p<0.0001), testosterone (>1,2 ng/ml in 17.6% of pts at baseline vs 4.1% at 12 months; p<0.0001), cholesterol (>200 mg/dl in 46.9% of pts at baseline vs 35.7% at 12 months; p<0.0001), triglycerides (>170 mg/dl in 13.3% of pts at baseline vs 10.2% at 12 months; p<0.0001) and arthralgia (37.7% at baseline vs 17.3% at 12 months; p = 0.0008). We also noted a significantly reduction of anxiety and depression after 12 months of lifestyle program (25.4% and 12% respectively at diagnosis vs 13.4% and 4.5% at 12 months respectively; p = 0,0064 and p<0.0001).

Conclusions: Promoting healthy lifestyle can reduce risk factors involved in BC recurrence and ensure psychological benefit and compliance to endocrine therapy. A multidisciplinary approach allows greater adherence to healthy attitudes in BC high risk patients.

BASELINE SUVMAX AS A PREDICTOR OF PATHOLOGICAL COMPLETE RESPONSE (pCR) FOR PATIENTS (pts) WITH BREAST CANCER (BC) TREATED WITH PREOPERATIVE SYSTEMIC THERAPY (pst)

Inno A.¹, Turazza M.¹, Salgarello M.¹, Bogina G.¹, Lunardi G.¹, Massocco A.¹, Carbognin G.¹, Gorgoni G.¹, Olivari L.¹, Diodato S.¹, Severi F.¹, Alongi F.¹, Mazzola R.¹, Valerio M.¹, Marchetti F.¹, Gori S.¹

¹IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona

Background: PST is the standard of care for inoperable locally advanced or inflammatory BC and it is also an option for operable BC in order to improve breast conservation. Achieving a pCR to PST is associated with better DFS and OS. In this retrospective study, we assessed the potential role of baseline SUVmax as a predictor of pCR for BC pts treated with PST.

Methods: We retrospectively reviewed medical charts of pts with stage II-III BC who underwent a baseline FDG-PET/CT scan before PST. Categorical data were compared with chi-square test and a multivariate logistic regression analysis was performed to investigate the association of clinicopathologic variables and pCR. Kaplan-Meier method with log rank test was used for DFS analysis. Cox multivariate analysis was performed to evaluate the association of clinicopathological variables with DFS.

Results: From 2010 to 2019, 140 pts received a baseline FDG-PET/CT scan before starting PST for stage II-III BC. Among them, 30 (21%) achieved a pCR. pCR rates were 42% (24/57), 27% (6/22), and 0% (0/61) for pts with HER2+, TN and luminal A/B BC, respectively (p<0.001). Median baseline tumor SUVmax was 10, median post-treatment delta SUVmax was 68%: these were considered as cut-off values. SUVmax was more frequently high ( = 10) in HER2+ (57%) and TN (68%) than in luminal BC (24%, p = 0.30). High SUVmax was associated with G3 (p<0.001) and Ki67 = 20% (p = 0.001). At univariate analysis, pCR was significantly associated with HER2+ and TN subtype (HER2+ vs luminal, OR 89; p = 0.002; TN vs luminal, OR 48; p = 0.009), high grade (G3 vs G2, OR 6; p = 0.002), and high baseline SUVmax ( = 10 vs <10, OR 1.6, p = 0.001). At multivariate analysis, only BC subtype and SUVmax were significantly associated with pCR. After a median follow-up of 27 months, 28/140 pts relapsed locally (6) or at a distant site (22). No pts who achieved pCR had recurrence, and median DFS was NR vs 56 months (p = 0.0011) for pts with pCR compared to those with no pCR. Among pts who did not achieve pCR, stage (III vs II, HR 30, p = 0.007), grading (G3 vs G2, HR 3.7, p = 0.045), HER2 status (HER2+ vs luminal, HR 0.28, p = 0.016) and deltaSUVmax ( = 68% vs <68%, HR 0.11, p = 0.002), but not baseline SUVmax ( = 10 vs <10, HR 0.46, p = 0.324), were significantly associated with DFS.

Conclusions: High baseline SUVmax ( = 10) and BC subtype could represent predictive factors of pCR for BC pts receiving PST. At a median follow-up of 27 months, no relapse was observed among pts who achieved pCR.

CLINICAL PATHWAYS (PERCORSO DIAGNOSTICO-TERAPEUTICO-ASSISTENZIALE O PDTA) AND MULTIDISCIPLINARY APPROACH IN BREAST CANCER UNIT: A MODEL BASED ON CENTRO ACCOGLIENZA E SERVIZI (CAS) AND GRUPPI INTERDICIPLINARI E CURE (GIC) IN RETE ONCOLOGICA DEL PIEMONTE E VALLE D’AOSTA (ROPEVDA)

Malossi A.¹, Cursio O.E.¹, Battaglia A.¹, Courthod G.¹, Peretto S.¹, Buzzelli C.¹, Cascarano T.¹, Carbone E.², Poussin V.³, Schena M.³

¹SC Oncologia ed Ematologia Oncologica, Ospedale Parini, AUSL Valle d’Aosta, Aosta; ²SC Chirurgia Toracica, Ospedale Parini, AUSL Valle d’Aosta, Aosta; ³ SC Oncologia ed Ematologia Oncologica, Ospedale Parini, AUSL Valle d’Aosta, Aosta

Background: Detailed clinical pathways (PDTA) and multidisciplinary approach represent two instrument keys faced to improve local organizational model, healthcare [1] quality and clinical outcomes. At Parini’s Hospital in Aosta, we implemented a Breast Unit with CAS and GIC activity in order to manage breast cancer patients(pts) across the entire process from diagnosis, staging and therapies, according to a shared PDTA. The aim of this study is to present a preliminary analysis of process indicators from our model of breast cancer management.

Patients and Methods: Pts were referred from the breast cancer screening program, the senologist or the [2] general practitioner. As indicated by the ROPeVDA, the oncologist or the surgeon performed the first clinical evaluation at CAS. In the meanwhile the CAS nurse collected clinical, pharmacological, social and personal informations and provided the correct planning of clinical and histological staging. The GIC discussion was performed after completing the first step evaluation defining the following therapeutic approach. The GIC was composed by oncologists, radiotherapists, surgeons, radiologists, pathologists, psicologists, palliative care medicine and a case manager nurse. Results: Here we report data of our activity in January-December 2018. We observed 120 women with hystologically proven breast cancer, median age 61 years. Hormonal receptor positive pts were 82%, Her2 positive 23%; triple negative 6%. Six pts had metastatic disease at diagnosis. 100 pts underwent surgical intervention as primary treatment; 21/100 pts had a pre-surgical GIC discussion, 79/100 were discussed after surgery. The median time from diagnosis to surgery was 36 days (range 19-67), from surgery to adjuvant chemotherapy or hormonal therapy was 46 days (35-60) and 36 day (20-73) respectively. 13 pts received neoadjuvant chemotherapy (neoadj CT) followed by surgery. All of them had a GIC discussion before CT. The median time from diagnosis to neoadj CT was 29 days (11-80), while from GIC discussion to neoadj CT it was 22 days (5-45).

Conclusions: The Breast Unit model based on CAS, GIC and PDTA allows to measure the time frame between the different steps of breast cancer management showing the respect of guidelines and PDTA parameters in most but not all patients. Further analysis of the delay reasons in single cases are needed in order to adopt corrective actions. [1]Healthcare quality and [2]General practitioner (medico di base).

ITALIAN BONE METASTASES (BM) DATA BASE (DB): FIRST PROSPECTIVE DATA ON BREAST CANCER (BC) PATIENTS (pts)

Bongiovanni A.¹, Foca F.¹, Forcignanò R.², Artioli F.³, Procopio G.⁴, Fantini M.⁵, Berardi R.⁶, Silvestris F.⁷, Campadelli E.⁸, Riva N.⁹, Recine F.⁹, Lorena G.⁹, Fausti V.⁹, Di Menna G.⁹, Debonis S.A.⁹, Vespignani R.⁹, Ibrahim T.⁹

¹Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori IRST, IRCCS, Meldola; ²Ospedale Vito Fazzi, Lecce; ³Ospedale Ramazzini, Carpi; ⁴Istituto Nazionale Tumori, Milano; ⁵Ospedale Infermi, Rimini; ⁶Ospedali Riuniti, Ancona; ⁷Policlinico Universitario, Bari; ⁸Ospedale Umberto I, Lugo; ⁹Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori, IRST IRCCS, Meldola

Introduction: BM are still the main cause of morbidity and morbility in cancer pts because of their complications defined as skeletal-related events (SREs).SREs reduce pts quality of life and are associated with an increasing in social and health costs.

Materials and Methods: This is a multicentric prospective observational study on pts with BM from BC with at least 6 months follow-up, enrolled into the BMDB. From October 2014 pts were recruited at the first BM occurrence by 14 Italian hospitals.The DB will allow to gather information on BM pts medical history using an online tailored software. The platform consists of 4 files containing information regarding pts demographics, primary tumors and BM characteristics and their evolution,in particular the onset and the types of SREs.Data are updated every 6 months by the participating centers and reviewed by coordinator center.The study was approved by ethical commitee.All pts have signed an informed consent.

Results: Since October 2014, 814 pts with BM from solid tumors were enrolled of whom 192 have BC as primitive site.Median age was 62 years (range 26-86). Median follow up was 34 months (range 6-149). At enrolment 97 pts (51%) had only BM, 67 (35%) had concomitant non-skeletal and BM and 28(14%) had previous non-skeletal metastases. Median time to first BM was 53 months (range 0-312). At first BM diagnosis, SREs were present in 75 pts (39%). Zoledronate was used in 51% and Denosumab in 21% of cases. Treatment was hormone-based (n = 96, 52%) chemo-based(n = 71, 39%) and chemo+ormono based therapy (n = 15, 8%). During follow up,67 new SREs were observed.Pts’ characteristics were resumed in table 1. Progression occurred mainly in skeletal sites (n = 107, 73%). Median progression-free (PFS) and overall survival (OS) were 13.7 (95%CI 11.3-17.1) and 56.8 months (95%CI 46.4-72.4),respectively.The 2-year survival according to the presence of nonskeletal metastases and the time of BM appearance was 87.8% (95%CI 77.6-93.5) for BM only,78.9% (95%CI 56.6-90.7) for previous non-skeletal BM and 87.2% (95% CI 74.4-93.9)for concomitant nonskeletal and BM pts.

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Table 1.

	N (192)	%
PS ECOG 0-1	144	75.0
Number of BM
1	33	17.9
2-6	52	28.3
>6	99	53.8
Type
Litic	98	60.1
Osteoblastic	42	25.8
Mixed	23	14.1
Pain at diagnosis	40	20.0
SRE at diagnosis
Radiotherapy	49	24.5
Pathological fracture	21	10.5
Surgery	4	2.0
Spinal cord compression	1	0.5

Conclusions: This study presents prospective data about a cohort of BC pts enrolled at the first BM occurrence and followed over the time, extrapolated by the multicentric observational BMDB.

REAL-LIFE DATA ON THE SAFETY OF TRASTUZUMAB BIOSIMILAR IN HER2-POSITIVE BREAST CANCER PATIENTS IN DEPARTMENT OF ONCOLOGY (DO) OF AZIENDA USL TOSCANA NORD OVEST (ATNO)

Bertolini I.¹, Coltelli L.², Muttini M.P.³, Giovanelli S.⁴, Tanganelli L.⁴, Donati S.⁵, Musettini G.⁶, Fontana E.¹, Bona E.¹, Biasco E.⁷, Di Marsico R.², De Maio E.², Finale C.², Masini L.C.², Dargenio F.⁸, Caparello C.⁸, Taurino G.⁹, Torracca M.T.¹⁰, Arrighi G.¹¹, Allegrini G.²

¹Division of Medical Oncology, Cecina Hospital, Italy; Department of Oncology, ATNO, Cecina; ²Division of Medical Oncology, Civili Hospital, Livorno, Italy; Department of Oncology, ATNO, Livorno; ³Division of Medical Oncology, Apuane Hospital, Massa, Italy; Department of Oncology, ATNO, Massa; ⁴Division of Medical Oncology, S. Luca Hospital, Lucca, Italy; Department of Oncology, ATNO, Lucca; ⁵Division of Medical Oncology, Versilia Hospital, Italy; Department of Oncology, ATNO, Camaiore; ⁶Division of Medical Oncology, F. Lotti Hospital, Italy; Department of Oncology, ATNO, Pontedera; ⁷Division of Medical Oncology, Portoferraio Hospital, Italy; Department of Oncology, ATNO, Portoferraio; ⁸Division of Medical Oncology, Piombino, Italy; Department of Oncology, ATNO, Piombino; ⁹ Department of Drug, Division of Pharmacy, Apuane Hospital, Massa, Italy, Massa; ¹⁰Department of Drug, Division of Pharmacy, F. Lotti Hospital, Pontedera, Italy, Pontedera; ¹¹Division of Medical Oncology, F. Lotti Hospital, Pontedera, Italy; Department of Oncology, ATNO, Pontedera

Background: Biosimilars are biologic products designed to mimic existing approved biologic agents. Trastuzumab biosimilars (TB) have been approved in the treatment of HER2-positive breast cancer (BC) based on the evidence of the same efficacy to trastuzumab originator (TRZ). Few data from real-life are available regarding toxicities associated with TB administration.

Methods: The DO of ATNO was established in 2016 and incorporates 5 Divisions of Medical Oncology. For what concern the oncologic field, ATNO presents an unique working group on breast cancer with a referring physician in each hospital. In order to offer an homogeneus service also in terms of therapeutic options, our clinical practice is based on specific predefined protocols, also named PDTA (Percorsi Diagnostici Terapeutici e Assistenziali). In our study we retrospectively collected all consecutive HER-2 positive BC patients (pts) treated with TB in the (neo)adjuvant or metastatic setting from 2018 to now in theoncology units of the DO, of Massa Carrara, Lucca, Livorno (including also Piombino, Portoferraio and Cecina units) and Versilia hospitals. We reported pts characteristics and adverse events (AEs) graded according CTCAE v 4.0.

Results: A total of 196 HER2-positive BC pts receiving a TB were analyzed. Median age was 56.3 years (range 29-83 years). 130 (66%) pts received TB in the (neo)adjuvant setting, 76 (34%) in the metastatic setting, among them 37 (19%) received TB in combination with pertuzumab as first line therapy. 90% pts had shifted from TRZ to TB, 10% received directly TB. The overall incidence of AEs was low. The most common AE reported was infusion related reaction (IRR), that was observed in 6 pts (3%): 3 pts G1, 1 pt G2, 1 pt G3, 1 pt G4; a permanent discontinuation of anti-HER2 therapy was required in case of G3-4 IRR. An asymptomatic left ventricular systolic dysfunctionwas observed in 2 (0.7%) pts; in both cases a complete resolution of the event was obtained with a temporary suspension of TB. Only one patient was shifted from TB to TRZ, due to the onset of a stomatitis G2. Interestingly no AE was observed when TB was administered in combination with pertuzumab.

Conclusions: In our real life experience TB showed a good toxicity profile, with a low incidence of AEs. Our preliminary results confirm the safety of TB, despite the retrospective nature of the trial and the limited sample size.

SAFETY OF ANTHRACYCLINES REGIMENS IN PATIENTS WITH EARLY BREAST CANCER AND GLUCOSE-6-PHOSPHATE-DEHYDROGENASE (G6PD) DEFICIENCY

Donisi C.¹, Persano M.¹, Francesca B.¹, Camera S.¹, Impera V.¹, Liscia N.¹, Mariani S.¹, Musio F.¹, Pretta A.¹, Soro P.¹, Tolu S.¹, Lai E.¹, Dessì M.¹, Scartozzi M.¹, Atzori F.¹

¹AOU Cagliari, Cagliari

Background: Anthracyclines are considered a cornerstone in the adjuvant treatment of breast cancer. Due to their oxidative properties, they are contraindicated in G6PD deficient patients. Considering the high frequency of breast cancer and G6PD deficiency worldwide, there is little to no information about that.

The aim of this study is to evaluate the hematologic and non-hematologic toxicity of adjuvant treatment with anthracyclines in G6PD deficient patients affected by breast cancer.

Material and Methods: From July 2009 to May 2019, we enrolled 52 Caucasian female patients carrier of G6PD deficiency with early breast cancer. Anthracyclines’ toxicities were evaluated with clinical assessments and blood test analyses. In this study, the median age of the patients was 52,5 years (28 to 69). As for adjuvant treatment, 23,1% of patients were treated with FEC regimen (Fluoruracil 500 mg/m² i.v., Epirubicin 75-100 mg/m² i.v., Cyclophosphamide 500-600 mg/m² i.v. every three weeks) for 6 cycles; 70% of the women received chemotherapy including anthracyclines and taxanes: 65,4% with EC regimen (Epirubicin 90 mg/m² i.v. and Cyclophosphamide 600 mg/m² i.v. every two weeks) for 4 cycles and Paclitaxel 80 mg/m² i.v. weekly for 12 cycles; 11,5% were treated with FEC regimen for 3 cycles and Docetaxel 100 mg/m² i.v. every three weeks for 3 cycles.

Results: Anemia of grade 1 (48,1%) or 2 (15,4%) occurred in 63,5% of patients. In 36,5% of patients no anemia occurred. None of them have had acute hemolytic anemia or G3 neutropenia/thrombocytopenia. Bilirubin levels were normal in all patients (0.2-1,2 mg/dl) such as reticulocytes count (0,5-1,5%). Haptoglobin levels (50-150 mg/dl) were normal too.

In 67,3% of cases LDH levels were lightly increased (200-500 U/L), but this result was due to a G-CSF injection.

A common trait that occurred in 100% of the patients was alopecia. Only 21,2% of patients reported fatigue of grade 1 while in 1,9% of cases fatigue G2 were reported; 34,6% reported nausea of grade 1 and 2; 3,8% of patients presented vomit; 5,8% of patients reported constipation of grade 1 or 2, 3,8% presented diarrhea of grade 1 and 2 and 7,7% of patients reported oral mucositis of grade 1 or 2.

Conclusions: Despite this is a retrospective study, anemia percentages reported are similar in patients with enzymatic deficiency and those who do not have any. Therefore, it appears safe to use chemotherapy regimens containing anthracyclines in G6PD- deficient patients.

TEN-YEARS RETROSPECTIVE ANALYSIS ON THE EFFICACY OF SHORT-COURSE VS.STANDARD ANTHRACYCLINE-TAXANE-BASED NEOADJUVANT CHEMOTHERAPY IN TRIPLE NEGATIVE AND HORMONE RECEPTOR-POSITIVE BREAST CANCER

Lobefaro R.¹, Vernieri C.¹, Sepe P.¹, Brambilla M.¹, Nichetti F.¹, Prisciandaro M.¹, Corti F.¹, Ligorio F.¹, Zattarin E.¹, Maggi C.¹, Celio L.¹, De Braud F.¹, Mariani G.¹, Bianchi G.V.¹, Capri G.¹

¹Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano

Background: Neoadjuvant anthracycline-taxane-based chemotherapy is one standard treatment option for patients with stage II-III breast cancer (BC). Patients achieving pathological complete response (pCR) after neoadjuvant chemotherapy have significantly longer disease-free survival (DFS) and overall survival (OS) when compared to patients with residual disease. However, the optimal duration of neoadjuvant anthracycline-taxane chemotherapy has not been investigated so far.

Material and Methods: We retrospectively collected clinical data about patients with stage II-III TNBC and hormone receptor-positive (HR+) BC who were treated at our Institution between October 2007 and January 2018 with neoadjuvant AT (doxorubicin 60mg/m²i.v. plus paclitaxel 175 mg/m²i.v. every 3 week) for 3 cycles (group A: 5,5 months) or 4 cycles (group B: 7 months) followed by CMF (cyclophosphamide 600 mg/m² i.v. plus methotrexate 40 mg/m2 i.v. and 5FU 600 mg/m2 i.v. on days 1 and 8 every 4 weeks) for 3 cycles (group A) or 4 cycles (group B). The aim of our study was to assess the impact of neoadjuvant chemotherapy duration (group A vs group B) on pCR rate, DFS and OS in the whole patient population, as well as in patients with TNBC and HR+ BC.

Results: A total number of 209 patients were included in our analysis; of these, 62 had TNBC and 147 had HR+ BC. Median age was 50 years (range 30-74). 111 patients belonged to group A and 98 patients to group B. We observed a total of 29 pCRs (13,9%), of which 25 (40%) occurred in the TNBC subgroup and 4 (3%) in the HR+ BC subgroup (p = 0.009). As expected, pCR was associated with better DFS and OS, with statistical significance reached only in patients with TNBC (DFS: p = 0.0012; OS: p = 0.0025). We observed no differences in terms of pCR between patients in group A and group B (17 and 12 patients respectively, p = 0.552). Local or distant relapse occurred in 56 patients (26,8%), with no significant differences between groups A and B when considering the whole patient population (p = 0.62), as well as TNBC (p = 0.22) and HR+ BC (p = 0.56) patients. DFS and OS rates at 5 years were 74,8%/70,7% (group A/B) and 86,4%/85,7% (group A/B) respectively.

Conclusions: Shorter duration of neoadjuvant doxorubicin-paclitaxel followed by CMF chemotherapy was not associated neither with lower pCR rate nor with worse DFS/OS in TNBC and HR+ BC patients. Prospective studies are needed to evaluate if the duration of neoadjuvant anthracyclines-taxane-based chemotherapy can be shortened.

THE EARLY CHANGES OF THE STANDARDIZED UPTAKE VALUES (SUVMAX) IS A PREDICTIVE MARKER OF RESPONSE AND OUTCOME IN EVEROLIMUS-BASED TREATED PATIENTS WITH BREAST CANCER

Sirico M.¹, Generali D.¹, Bernocchi O.², Giudici F.², Vernieri C.³, Milani M.¹, Strina C.¹, Madaro S.¹

¹Breast Cancer Unit and Translational Research Unit, Azienda Socio-Sanitaria Territoriale Cremona, Italy, Cremona; ²Dipartimento di medicina e chirurgia, Università degli studi di triste, Trieste; ³ Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Italy, Milano

Background: ¹⁸F-Fluorodeoxyglucosepositron-emission tomography (¹⁸F-FDG PET/CT) is one of the essential imaging modalities for establish the efficacy of breast cancer therapy and the measures of tumor burden showed promises to predict survival in patients with metastatic breast cancer (mBC). Everolimus inhibits mammalian target of rapamycin (mTOR) and leads to decreased protein synthesis, cell metabolism and cancer cell proliferation in solid tumors. Identification of predictive markers for everolimus-based treatment remains a major issue, but to date, no predictive markers have been established. The aim of this study is to evaluate an optimal SUV% [(SUV baseline-SUV 3 months)/SUV baseline] as a predictive factor of response and disease progression in patients with mBC receiving the combination of everolimus and exemestane in first line treatment.

Patients and methods: The study included 31 patients with a new diagnosed luminal B phenotype mBCs treated with everolimus and exemestane in ASST of Cremona and Istituto Nazionale Tumori of Milano between May 2013 and March 2108. The ¹⁸F-FDG PET/CT and glycemia were performed at baseline and after three months of treatment. Patients who stopped treatment before 10 months were considered as in a progressive disease (PD) status, otherwise a duration of therapy > 10 months was scored as no PD. ROC analysis was performed to determine the optimal cut-off value of SUV% to differentiate PD from non-PD women using Youden Index. Time to progression survival (TTP) was estimated by Kaplan-Mayer method. Spearman’s rank correlation coefficient (rho) was calculated to describe correlation between SUV% and glycemia.

Results: An optimal cut-off SUV% value of 29% was proposed for discriminate patients with PD from those without PD: patients with SUV%<29% had a median TTP of 3.11 months versus 9.29 months for patients with SUV%>29% (p = 0.0036) and more frequently had PD within 10 months: 100% vs 53%, respectively (p = 0.005). There was a negative correlation between SUV% and glycemia (rho=-0.32, p = 0.15)

Conclusions: Our results showed that SUV> 30% tested with ¹⁸F-FDG PET/CT after 3 months of treatment identified patients who had benefit from the everolimus-exemestane combination in term of response and TTP (>10 months). Moreover we have observed an inverse correlation between SUV and glycemia. These results warrant further validation with a potential integration with molecular biomarkers related to tumor metabolism and mTOR signalling.

IDENTIFICATON OF HER2 POSITIVE PROGNOSTIC SUBGROUPS USEFUL FOR ADJUVANT THERAPY DECISION MAKING. RESULTS OF A MONOCENTRIC OBSERVATIONAL STUDY

Molinelli C.¹, Giraudi S.², Del Mastro L.³, Ballestrero A.⁴, Carli F.⁵, Poggio F.³, D’Alonzo A.³, Dellepiane C.³, Buzzatti G.³, Blondeaux E.³, Conte B.⁶, Pastorino S.³, Gallo M.⁴, Bighin C.³

¹Ospedale Policlinico San Martino, Genova; ²UO Oncologia Medica, Ospedale San Paolo, Savona; ³UO Oncologia Medica 2, Ospedale Policlinico San Martino, Genova; ⁴UO Clinica di Medicina Interna ad Indirizzo Oncologico, Ospedale Policlinico San Martino, Genova; ⁵UO Anatomia Patologica, Ospedale Policlinico San Martino, Genova; ⁶Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi I Sunyer Biomedical Research Institute, Barcellona

Background: The clinical magnitude of the benefit observed with the addition of Pertuzumab (P) to Trastuzumab (T) and chemotherapy (CT) in early HER2-positive (HER2+) breast cancer (BC) is debated, particularly in patients (pts) with 1-3 positive nodes (N1-3) or node negative (N-). In this retrospective study, we analyzed HER2+ BC pts with N1-3 and N- tumors treated with adjuvant CT and T at the Breast Unit of our Institute to identify possible eligibility criteria for adjuvant dual HER2 blockade.

Methods: From 1992 to 2016, 694 consecutive HER2+ early BC pts were registered in a monocentric observational study. For this analysis we excluded pts who underwent neoadjuvant CT (113 pts), pts who were metastatic ab initio (21 pts), pts receiving treatment with adjuvant P or Lapatinib (31 pts), not receiving adjuvant T (81 pts), and missing baseline data (63 pts). 5-years (yrs) disease free survival (DFS) rates analyses were compared using Kaplan Meyer method to evaluate differences between the following groups: node positive vs N-, N1-3 and N- according to hormone receptor (HR) status.

Results: A total of 385 pts with HER2+ BC treated with adjuvant T was identified, with a median follow-up of 7 yrs (6.5-7.4). Median age was 56 yrs (28-85), 123 pts (32%) were premenopausal and 262 pts (68%) were post-menopausal. 201 pts (53%) were N- and 179 (47%) were N+. 114 pts (30%) were N1-3, 64 (17%) had more than 4 positive nodes. HR were negative in 127 pts (33%) and positive in 258 pts (67%). As expected, 5yrs DFS in N+ group was significantly lower (83.2%) than N- group (93.5%) (p = 0.005). N1-3 HR- pts had a 5yrs DFS lower than N1-3 HR+ pts (86% vs 88%; p = 0.583). The limited number of events didn’t allow statistical analyses in N- subgroup according to HR status.

Conclusions: Our results confirmed that HER2+ BC N+ pts are at higher risk of relapse than N-. Moreover, among N1-3 pts, HR status seems not to give useful information to add single or dual HER2 blockade to CT.

THE PARADOX OF AROMATASE INHIBITORS (AI) INDUCED BONE RESORPTION AND BONE RECURRENCE IN EARLY BREAST CANCER (EBC) PATIENTS: A SINGLE-INSTITUTION STUDY

Pavese F.¹, Cortellini A.¹, Rotondaro S.¹, Cocciolone V.¹, Irelli A.¹, Pierorazio G.¹, Sidoni T.¹, Patruno L.¹, Agostinelli V.¹, Pensieri M.V.¹, Parisi A.¹, Lanfiuti Baldi P.¹, Venditti O.¹, D’Orazio C.¹, Verna L.¹, Porzio G.¹, Ficorella C.¹, Cannita K.¹

¹UOC Oncologia Medica, Ospedale S. Salvatore, L’Aquila

Background: Several trials of adjuvant bisphosphonates showed a disease-free survival improvement in early breast cancer (EBC) patients, treated with endocrine therapy. In a cohort of EBC “luminal-like” patients with bone recurrence, we found that median time to skeletal recurrence (TSkR) was shorter for those who received adjuvant AIs.

Patients and Methods: A retrospective analysis of EBC “luminal-like” patients with bone recurrence was performed, to evaluate the impact of adjuvant AI on the TSkR. Patients were categorized according to the adjuvant hormonal therapy: AI (exclusively), tamoxifen (exclusively), AI/tamoxifen, and no-treatment. Binary logistic regression and χ2 were used to evaluate relationships between age, menopausal status and adjuvant AI. Baseline TNM stage (AJCC 8^th edition) was used as pre-planned adjusting factor in the multivariate analysis.

Results: From May 1995, to March 2019, 143 patients experienced bone recurrence (Table 1). There was a significant association between age and adjuvant AI (χ2 = 20.9, p<0.0001), and between menopausal status and adjuvant AI (p = 0.0067). At median follow-up of 178 months, median TSkR and median Overall Survival were 54 months (95%CI: 45 – 65) and 120 months (95%CI: 99 – 147; 54 censored), respectively. Among patients who received adjuvant AI median TSkR was 35 months (95%CI: 25-54), while among patients who did not received adjuvant AI was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p = 0.0644). After adjusting for TNM stage, adjuvant AI was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p = 0.0244). Adjuvant Tamoxifen, adjuvant AI/Tamoxifen and no-treatment did not revealed to be associated to TSkR.

OPEN IN VIEWER

Age, years
Range	29 – 87
Median	53
Menopausal status	93 (65%)
Histology
Ductal	107 (75%)
Lobular	33 (23%)
Others	3 (2%)
“Luminal subtype”
Luminal A	70 (49%)
Luminal B	35 (24%)
Luminal HER2	18 (13%)
N.A.	20 (14%)
TNM Staging
I	27 (19%)
II	61 (43%)
III	55 (38%)
Grading
1	10 (7%)
2	64 (45%)
3	41 (29%)
N.A.	28 (19%)
Adjuvant hormonal therapy
AI only	33 (23%)
TAM only	61 (43%)
AI + TAM	33 (23%)
No adjuvant hormonal therapy	16 (12%)
(Neo)Adjuvant chemotherapy
Yes	102 (71%)
No	41 (29%)

Conclusions: In our cohort (selected for bone recurrence), AI treatment is related to a shorter TSkR. AI-induced bone resorption could be the underlying mechanisms, thus antiresorptive adjuvant treatments should be always taken into account.

THE ASSOCIATION OF IMMUNE CHECKPOINT INHIBITOR PEMBROLIZUMAB AND TRASTUZUMAB HAS ADDITIVE CARDIOTOXIC AND PRO-INFLAMMATORY EFFECTS IN PRECLINICAL MODELS

Maurea N.¹, Quagliariello V.², Coppola C.², Passariello M.³, Barbieri A.⁴, Rea D.⁵, Monti M.G.⁶, De Lorenzo C.³, Iaffaioli R.V.⁷, De Laurentiis M.⁸, Ascierto P.⁹, Botti G.¹⁰

¹Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia, Napoli; ²Division of Cardiology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italia, Napoli; ³CEINGE – Biotecnologie Avanzate s.c.a.r.l., Naples, Italy, Napoli; ⁴AnimalFacility, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia., Napoli; ⁵Animal Facility, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia., Napoli; ⁶Department of Translational Medical Sciences, University Federico II, Naples, Italy, Napoli; ⁷Association for Multidisciplinary Studies in Oncology and Mediterranean Diet, Piazza Nicola Amore, Naples, Italy, Napoli; ⁸Breast Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia, Napoli; ⁹Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia, Napoli; ¹⁰Scientific Direction, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia, Napoli

Background: The association of Pembrolizumab and Trastuzumab was recently proposed for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer patients, with extremely interesting therapeutic perspectives. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiotoxicity has not been properly studied. We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab

Materials and Methods: Cell viability, intracellular calcium overload and pro-inflammatory studies (analyzing the production of Interleukin 1β, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes exposed to Pembrolizumab or Trastuzumab alone or in combination. Preclinical studies were also performed in C57BL6 mice treated with Pembrolizumab (10 mg/kg, i.p, for the first dose, followed by a dose of 5 mg/kg every 5 days until the study end point) or Trastuzumab (10 mg/kg/day, according to literature) alone or in combination. After treatments, we studied cardiac fibrosis (by quantifying collagen fibers) and expression of pro-inflammatory interleukins in heart tissues.

Results: The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40-50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased. The histological analysis showed an increased amount of collagen fibers in mice treated with Pembrolizumab and Trastuzumab, compared to the single treatments.

Conclusions: Pembrolizumab associated to Trastuzumab leads to significant cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways.

EXPRESSION OF ER, PGR, HER-2, AND KI-67 IN CORE BIOPSIES AND IN DEFINITIVE HISTOLOGICAL SPECIMENS IN PATIENTS (pts) WITH LOCALLY ADVANCED BREAST CANCER (BC) TREATED WITH NEOADJUVANT CHEMOTHERAPY (NACT)

Verrico M.¹, Rossi L.², Ricci F.², Fontana A.², Colonna M.², Spinelli G.P.², Busco S.², Fara M.A.², De Masi C.², Calogero A.², Fanelli G.P.², La Manna A.², Di Filippo S.², Dorkin M.², Ulgiati M.A.², Tozzi R.², Gozzi E.², Sinjari M.², Tomao S.²

¹Universita Sapienza, Roma; ²Universita Sapienza, Aprilia

Background: Pathologic response to NACT differ among BC subtypes and reported changes in expression of estrogen-receptor (ER), progesterone-receptor (PgR), HER-2 and Ki-67 following NACT. The aim of our study is to evaluate effect of NACT on expression of ER and PgR, Her-2 and Ki67.

Material and Methods: 93 pts with BC stages IIB, IIIA, and IIIB were treated with anthracycline and paclitaxel based NACT. In pts with HER-2 amplification, trastuzumab was added.ER, PgR, HER-2 and Ki-67 status were evaluated before and after NACT.

Results: Of 93 pts, 29% achieved a pathologic complete response(pCR). In pts luminal A(28%) pCR occurred in 15%; luminal B HER2 –(35%) in 28%; luminal B HER2+(15%) in 28%; HER2 +(8%) in 50% and triple negative (14%) in 46%.

We evaluated changes in hormone receptors, ki-67 and HER2 in 56 pts in correlation with pathological response, excluding pts with pCR.

ER modified expression from positive to negative in 8% pts and from negative to positive in 22%. Mean value of ER positivity remained unchanged before and after NACT(54,5% vs 54,7%).In pathological responders group (pPR) median value of 43,9% was observed before NACT and 43% after; in non-pPR median value of 62% was observed before NACT and 63% after. PgR changed from positive to negative in 21% cases and from negative to positive in 37%. Mean value of PgR positivity was different before and after NACT (36,7% vs 28%). In pts with pPR, mean value was 28% before vs 16,5% after NACT; in pts non-pPR, mean value was 42,9% before vs 36,3% after NACT. Median Ki-67 value was 20,9% before NACT and 18% after. In pPR ki-67 median value was 25% before and 12,8% after NACT. In non-pPR median ki-67 was 18% before and 21,8% after NACT. HER-2 expression changed in 46% pts, 30,7% pts with HER-2 positive before NACT had HER-2 negative after.Conversely, 15,3% pts HER-2 negative became HER-2 positive.

Conclusions: We identified a Ki-67 reduction after NACT in pts whit pathological response. Ki-67 could predict pCR and identify pts most likely to benefit from NACT. NACT can change status of ER, PgR, Ki-67 and HER

2. After NACT, PgR+ expression decreased while ER positivity remained. We identified a prognostic role of decreased expression of PgR and Ki-67.

LIFESTYLE ASSESSMENT IN EARLY-STAGE BREAST CANCER (EBC): RESULTS OF A TELEPHONE SURVEY

Lanza M.¹, Avancini A.², Trestini I.³, Tregnago D.³, Fiorio E.³, Parolin V.³, Carbognin L.⁴, Bria E.⁴, Milella M.⁵, Pilotto S.⁵

¹Department of Neuroscience, Biomedicine and Movement, Unviersity of Verona, Verona; ²Biomedical, Clinical and Experimental Sciences, Department of Medicine, University of Verona, Verona; ³Medical Oncology, University of Verona Hospital Trust, Verona; ⁴Fondazione Policlinico Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma; ⁵Department of Oncology, University of Verona Hospital Trust, Verona

Background: Weight gain, overweight and lack of physical activity (PA) are associated to an increased risk of recurrence and mortality in pts affected by EBC. This preliminary study explores the levels and the association of PA, emotional functioning, nutritional status in a sample of EBC pts.

Methods: A telephone survey was conducted in a sample of EBC pts by a trained staff. The eligible pts received a nutrition evidence-based tailored educational intervention by a skilled dietitian. The telephone questionnaire included anthropometric measures, the validated International Physical Activity Questionnaire (IPAQ) telephone short version, the Med-Diet 14 items (MDS), while the questions about emotional functioning (EF) were drawn from EORTC QLQ C30 Quality of Life questionnaire. Clinical and demographic variables were obtained by Hospital registry. Descriptive analysis, absolute frequencies and Spearman Rank Correlation test were used.

Results: With a response rate of 76%, 136 women (median age 52 years) were included in the analysis. The median time since diagnosis was 1.96 year. Nearly all the participants had received surgery (93%), 71% chemotherapy, 58% radiotherapy and 82% hormonotherapy. Over the half (55%) of patients were normal weight, 28% and 15% presented overweight and obesity status, respectively. With a median of energy expenditure for PA low/moderate [769.5 MET-min/week (metabolic equivalent of task)], 43% of women resulted to be in low category for PA, 40% in moderate and only 17% in high, according to IPAQ scoring protocol. The half of participants reported a high adherence at MDS (defines as a MDS ⩾10), while 49% an average adherence (MDS 6-9). Increasing of PA level (rs = 0.17; p = 0.04), better scores of MDS (rs = 0.16; p = 0.05) and a decrease in sedentary time (rs=-0.20; p = 0.02) were significantly related to high score of EF. Body mass index resulted inversely associated with PA (rs=-0.16; p = 0.05) and correlated with time since diagnosis (rs = 0.20; p = 0.01). MDS was inversely associated with weight gain from diagnosis (rs = 0.22; p = 0.01).

Conclusions: Despite the validated importance of PA and weight control, a large portion of EBC pts did not engage in enough PA and nearly 45% were either overweight or obese. Healthy lifestyle modifications should be incorporate into EBC care, in order to increase PA levels, manage body weight control, allowing also an improvement in term of emotional functioning.

CIRCULATING TGFß AND TNFA DURING ERIBULIN TREATMENT IN METASTATIC BREAST CANCER PATIENTS. THE TRANSERI PROJECT

Garrone O.¹, Michelotti A.², Abbona A.¹, Montemurro F.³, Vandone A.M.¹, Paccagnella M.¹, Falletta A.¹, Geuna E.³, De Angelis C.², Lo Nigro C.¹, Vanella P.¹, Merlano M.C.¹

¹A. O. S. Croce e Carle, Cuneo; ²AOU Pisana, Ospedale S. Chiara, Pisa; ³Candiolo Cancer Institute, FPO-IRCCS, Candiolo

Background: Eribulin (E) is approved for the treatment of metastatic breast cancer (mBC) patients (pts) after failure of antracyclines and taxanes. E interferes with microtubule leading to apoptosis and G2/M cell cycle arrest. In human cancer cell lines and in mice, it reverses epithelial mesenchimal transition (EMT) and reduces metastases in mice. TGFβ, an immunosuppressive cytokine, acts as growth factor for cancer-associated fibroblasts (CAFs) and promotes EMT. TNFα synergizes with TGFβ to promote EMT. The TRANSERI study investigates the modifications of TGFβ and TNFα levels in 42 mBC pts treated with E.

Methods: Plasma levels of TGFβ and TNFα were determined by ELISA assay at baseline, before cycle (C) 3, 5 and at disease progression in mBC pts treated with E at 1.23 mg/m2, d 1–8 every 21 days. Statistical analysis of the changes in the longitudinal samples was performed by GraphPad 5. Clinical outcome was monitored according to standard internal follow up procedure.

Results: At baseline the median (M) TGFβ value was significantly higher in pts than in 7 healthy volunteers (203,4 pg/ml vs 113,0 pg/ml respectively; p<0.0001). At C 5, 17 pts had a decrease in TGFß with a M value approaching the one of healthy controls (152,8 pg/ml vs 113,0 pg/ml respectively). Twenty-five pts progressed before C 5. The M value of TGFß in pts at disease progression was 297,3 pg/ml. A significant difference of TGFß was observed between non progressed vs progressed pts (p = 0.01). The M TNFα value at baseline was higher in pts than in healthy volunteers, even if in both groups it was close to the lower sensitivity cut-off of the assay. Intriguingly, at C 5, the TGFß/TNFa ratio was significantly lower in pts who did not progressed compared to the value at progression (p = 0.01). We did not observe any relationship between the number of metastatic sites and the amount of circulating TGF-β. Similarly high tumor burden did not account for an increased level of TGF-β at baseline. Indeed the level of the cytokine, in patients who gained benefit from therapy, decreased irrespective of the objective response or disease stabilization.

Conclusions: TGFβ levels changed during treatment with E and correlate with outcome. We are evaluating the role of tumor burden in modulating the TGFβ/TNFα ratio.

POTENTIAL IMPACT OF MIGRAINE ON THE COURSE OF BREAST CANCER PATIENTS: A PILOT SURVEY

De Sanctis R.¹, Torrisi R.¹, Masci G.¹, Agostinetto E.¹, Losurdo A.¹, Zuradelli M.¹, Viganò A.², Tinterri C.¹, Testori A.¹, Santoro A.¹

¹Istituto Clinico Humanitas, Rozzano (MI); ²Ospedale L. Sacco, Milano

Background: Recently, large registry-based studies highlighted an interplay between breast cancer (BC) and migraine (M). In particular, M seems to be associated to a better overall BC prognosis, and menstrual migraine (MM) to luminal rather than triple-negative disease, albeit not in all studies. We aimed to investigate BC-M relationship in a clinical setting, with strict data check and clinical evaluation.

Methods: Consecutive BC patients filled a custom-made questionnaire to obtain a diagnosis of M according to Migraine-ID and International Headache Society (IHS) criteria. Clinical data on BC type, treatments and prognosis were collected together with phenotypic and clinical data on M. Parametric and nonparametric statistics were used according to data distributions to investigate differences in BC features between patients with and without M.

Results: Presently, 50 patients completed 1-year follow-up. Median age was 51.5 years (range, 27-79); 11 patients were diagnosed as Luminal A (LA), 9 as Luminal B (LB), 24 HER-2 positive (H2), and 6 as Triple Negative (TN). Thirty-eight (76%) patients had hormone-receptor positive disease. Thirty (60%) had a G3 BC, 18 (36%) G2 and 2 (4%) G1. M was diagnosed in 29 patients (18 with MM), tension-type headache (TTH) in 9 and no headache at all in 12; 19 out of 29 M patients still had migraine attacks at the time of the survey; 10 no longer had attacks. Seven patients had migraine with aura. All patients with migraine had an episodic pattern (less than 15 days/month), no one were under treatment for headache except acute treatments. Regarding demographics, patients with M were younger (48.4 ± 10.7 vs. 60.5 ±12, p<0.01) than patients without M. No association between migraine diagnosis and BC characteristics was found. However, patients with active M at recruitment had higher levels of HER-2 and ER expression than patients with prior M (p<0.05 for both).

Conclusions: Our preliminary survey showed no direct impact of M on the course of BC. However, patients with an active migraine at recruitment had higher ER and HER-2 expression levels; furthermore, BC patients with M were younger than BC patients without M, with no interaction with other variables. Results on HER-2 are in line with new researches on the use of EGFR inhibitors in pain management. Larger sample and longer follow-up are needed to confirm these preliminary results.

BREAST CANCER IN WOMEN AGING 40 YEARS OLD AND YOUNGER: CLINICOPATHOLOGICAL PROFILE AND IMPLICATIONS ABOUT ADJUVANT TREATMENTS AND SCREENING

Merloni F.¹, Pistelli M.¹, Pellegrini C.¹, Savini A.¹, Tassone L.¹, Crocetti S.¹, Bastianelli L.¹, Cantini L.¹, Della Mora A.¹, Maccaroni E.¹, Berardi R.¹

¹Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Ancona, AOU Ospedali Riuniti-Ancona, Ancona

Background: Differences in the clinical and biological characteristics between young and older breast cancer patients have been observed. Breast cancers (BCs) in young women are more often hereditary and express different genes compared with breast cancers in older patients. The purpose of this study was to evaluate the clinicopathological profile of BC in younger women (⩽ 40 years) and their implications on choosing adjuvant treatments and screening.

Patients and Methods: We prospectively analyzed pathological and clinical data about all consecutive patients younger than 40 years with diagnosis of invasive BC referred to our Institution from january 2013 to december 2017. All the patients’clinical data were collected at their first visit, and information about their pathological characteristics and treatment history was obtained after surgery and following subsequent visits.

Results: We selected 73 patients from a database of 1265 patients. Median age at diagnosis was 38 (range 26-40). 40% of them had no pregnancies before BC diagnosis. 84% of patients had invasive ductal carcinoma. The main pathological features were G3, ER+, HER2+ (74%, 65% and 30%, respectively). Interestingly, at diagnosis 56% of the patients had tumors size greater than 2 cm with an higher incidence of metastatic axillary nodes (53% of cases). Consequently the major part of patients (63%) underwent to adjuvant chemotherapy in addiction to endocrine therapy and anti-HER2-blockade treatment based on biological features of disease.

Conclusions: Our results confirmed that younger women tend towards an increased risk of developing biologically aggressive BC subtypes (especially HER2+ subtype tumors) with worse prognosis. Furthermore, this young population is actually excluded from the mammography screening programs making an early diagnosis very difficult to reach. The low percentage of pregnancies before BC needs a multidisciplinary approach to evaluate strategies to preserve ovarian function and the desire to become pregnant at the end of adjuvant therapies.

ERIBULIN MESYLATE-TREATED METASTATIC BREAST CANCERS DEVELOP PROGRESSION MAINLY ON PRE-EXISTING LESIONS

Bordonaro R.¹, Castagna F.¹, Russo A.¹, Commendatore O.¹, Lavenia G.¹, Salice P.¹, Ursino M.G.¹, Carmela F.¹, Fassari G.E.¹

¹ARNAS Garibaldi Struttura Complessa di Oncologia Medica, Catania

Background: Eribulin mesylate (EM) provided survival advantage in metastatic or locally advanced breast cancer (MBC) previously treated with anthracicline and taxanes, mainly in several subgroups like triple-negative ones. Epithelial-to-mesenchymal transition (EMT) is a crucial process in breast tumour progression; the adoption of EMT phenotype is responsible of enhancing invasivity and metastatic potentialities. In preclinical observations EM showed the ability to reverse EMT and consequently to reduce the capacities of in vitro migration and invasion of MX-1 cells xenografts.

Matherial and Methods: In the aim to find clinical implications of EM-induced inhibition of tumour cells ability to metastasize, we retrospectively analyzed the records of 38 pts with MBC that underwent EM administration. The median age of the series was 51 years (r. 33-74); ECOG-WHO PS distribution was 39.5, 57.9 and 2.6% for 0,1 and 2 respectively. Thirty-five (92.1%) of pts were ER and/or PgR positive, three (7.9%) were triple-negative and seven (18.4%) overexpressed Her-2. Twelve (32%) pts had only one site of disease,whereas 26 (68%) had more than one site of disease. At the time of the censorship of data, four patients were still on treatment.

Results: The entire series of pts had a median-overal survival (mOS) of 10.5 (r. 1 – 56) months, with a median progression-free-survival (mPFS) of 4 (r. 1-17) months. The 82% (28/34) of the pts developed progression of disease (PD) on a pre-existing lesion (PEL); 1/34 (3%) developed a new lesion in a pre-existing site of disease (PESD), and only 5/34 (15%) progressed on a site not previously involved by the tumor (NL).The mOS of the NL-progressive-pts was 9 months (r. 8-22), whereas the mOS of the PEL-progressive-pts was 15.5 months (r.2-56)

Conclusions: In our retrospective series, MBC pts exposed to EM developed progression of disease mainly on PEL showing a mOS of 15.5 months; only a minority of pts progressed on new sites, with a mOS of 9 months. This observation could be interpreted as being linked to an inhibition of the metastatic capacity of the tumor induced by the drug and is consistent with preclinical findings; furthermore, the better survival of PEL-progressive-pts could be interpreted as related to the acquisition of a more indolent phenotype caused by the exposure to EM. Further studies aimed to investigate the correlations between EM-induced bio-molecular modifications and clinical observations are needed.

CARDIAC SAFETY OF ADJUVANT TRASTUZUMAB AND PACLITAXEL FOR HER2+ EARLY BREAST CANCER PATIENTS

Frezzini S.¹, Giarratano T.², Griguolo G.², Piccin L.¹, Mioranza E.², Giorgi C.A.², Miglietta F.¹, Menichetti A.¹, Genovesi E.¹, Cumerlato E.¹, Bottosso M.³, Angelini S.³, Vernaci G.³, Dieci M.V.³, Guarneri V.³

¹Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche, Università di Padova, Padova; ²Oncologia Medica 2, Istituto Oncologico Veneto IOV - IRCCS, Padova; ³Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova

Background: Trastuzumab (T) improves outcomes of HER2+ early breast cancer (eBC) patients (pts). However, it may lead to left ventricular ejection fraction (LVEF) decline, mostly reversible. As anthracycline administration increases the risk of cardiac toxicity, anthracycline-free regimens, such as weekly paclitaxel (P)-T are increasingly used for low-risk HER2+ eBC. Little evidence exists regarding cardiac safety of this regimen in real-life pts. Here, we report cardiac outcomes of pts treated with adjuvant P-T in our institution.

Methods: We included HER2+ eBC pts planned to receive weekly P-T for 12 weeks followed by T up to 1 year between 2014 and 2019. LVEF assessment was performed by two-dimensional echocardiography at baseline and months 3, 6, 9, 12, as by clinical practice. LVEF reduction (% points from baseline) was calculated. Significance of changes in LVEF from baseline were determined by paired Wilcoxon test. Heart failure (HF) was defined by New York Heart Association (NYHA) class (I asymptomatic, II-IV congestive HF [CHF]).

Results: Data from 127 HER2+ eBC were available. Pts characteristics were: median age 57 (range 26-87), postmenopausal 67%, Tumor⩽2cm 90%, N0 86%, G3 67%, hormone-receptor positive 78%. Cardiovascular risk factors at baseline were: dyslipidemia 33%, hypertension 30%, history of tobacco use 24%, diabetes 10%, and BMI⩾30 15%. Five pts (4%) had an history of arrhythmias and 49 pts (39%) were receiving cardiologic therapy. Median LVEF at baseline was 64% (range 55-73). Table 1 reports LVEF reductions from baseline. Overall, 2 pts (1.6%) presented CHF, while 3 (2%) presented NYHA I. As of April 2019, T was ongoing for 24 pts (18%). Three pts (2%) discontinued T due to cardiac toxicity.

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	3 months	6 months	9 months	12 months
LVEF reduction from baseline	N (%)	N (%)	N (%)	N (%)
5-9%	25 (22%)	26 (27%)	23 (27%)	18 (20%)
10-15%	2 (2%)	2 (2%)	1 (1%)	1 (1%)
Not evaluated	16	33	41	37
Median (range)	63(50-74)	62(55-70)	62.5(55-72)	63(55-72)
Change from baseline (Wilcoxon test p-value)	0.001	<0.001	<0.001	0.007

Conclusions: LVEF decreases during adjuvant P-T. However, LVEF decrease of more than 10% points and HF are uncommon. These results confirm that P-T treatment retains cardiovascular safety even in real-life pts with cardiovascular risk factors.

SAFETY AND EFFICACY OF CDK4/6 INHIBITORS IN PATIENTS WITH ADVANCED BREAST CANCER: A REAL WORD EXPERIENCE

Isca C.¹, Piacentini F.¹, Bocconi A.¹, Toss A.¹, Barbieri E.¹, Cortesi L.¹, Moscetti L.¹, Cascinu S.¹, Omarini C.¹

¹Azienda Ospedaliero-Universitaria di Modena, Modena

Background: CDK4/6 inhibitors plus endocrine treatments are the standard of care in hormonal receptors positive metastatic breast cancer (MBC) due to the positive results of Paloma, Monaleesa and Monarch trials. Our aim was to audit the real life experience of treating MBC with CDK4/6 inhibitors.

Methods: All patients receiving CDK4/6 inhibitors at the University Hospital of Modena were registered in a database. At the time of analysis, all women were evaluated for safety and efficacy. Treatment toxicities were graded according to CTCAE v5. Efficacy was assessed using routinely performed imaging.

Results: 87 patients have been treated with CDK4/6 inhibitors, in particular 78 with Palbociclib and 9 with Ribociclib. Considering first line setting, 43 patients received CDK4/6 inhibitors: 74% of them with aromatase inhibitors (AI) and 26% with fulvestrant, respectively. More than half of them received neo/adjuvant chemotherapy and 70% adjuvant endocrine therapy (ET) too. Only bone disease was present in 70% of patients. All patients were assessed for efficacy with 79% of them exhibiting ORR (CR+PR), 3% SD and 18% PD as best response. The clinical benefit rate (CBR: CR+PR+SD>6months) was 81%. At the time of the analysis, 9 patients (21%) progressed with a median time to progression of 5 months (2-7 months), all the others are ongoing. Regarding second line, 19 women were treated: 32% with AI and 68% with Fulvestrant. All women were pre-treated with ET in adjuvant setting and/or 1^st line and more than half of them with chemotherapy too. 63% of patients had visceral disease. ORR was 53%, 11% SD and 36% PD. The clinical benefit rate was 68% Moreover, in naïve patients the CBR was 100% with no tumors progression. Neutropenia was the most common side effect observed in 95% of the patients. 60% were G3 with only 5% of febrile neutropenia. 65% and 40% of patients had delay in treatment administration and first dose reduction due to neutropenia, respectively. In 16% of them a second dose reduction was performed too. All other toxicities reported were all grade 1-2. Diarrhea and nausea determined dose reduction in 3% of women. No treatment discontinuation due to toxicity were observed.

Conclusions: CDK4/6 inhibitors administered outside the context of a clinical trial was safe, well tolerated and with significant efficacy. Our results were consistent with those published in the phase III clinical trials.

EFFICAY OF ERIBULIN MESYLATE IN ELDERLY PATIENTS WITH BREAST CANCER: A POOLED ANALYSIS OF 5 REAL WORLD STUDIES

Petrelli F.¹, Parati M.C.¹, Ghidini A.², Amoroso V.³, Lonati V.¹, Cabiddu M.¹, Borgonovo K.¹, Ghilardi M.¹, Berruti A.³, Barni S.¹, Pedersini R.³

¹ASST Bergamo ovest, Treviglio; ²Casa di cura Igea, Milano; ³ASST Spedali Civili di Brescia, Brescia

Introduction: Eribulin Mesylate (EM) is a nontaxane microtubule inhibitor approved for the for use in in patients with metastatic breast cancer (BC).

This pooled analysis of retrospective published series aims to evaluate efficacy and toxicities of EM in elderly patients in the “real-world”.

Material and Methods: A systematic review for studies reporting outcome and adverse events with EM in elderly BC patients (⩾70 years) was performed up to March 2019. Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were described and aggregated in a pooled analysis. Main toxicity rates (G1-2 & G3-4) were described.

Results: A total of 5 studies (3 retrospective, 1 observational and 1 pooled analysis of 3 prospective studies) were included for a total of 301 patients. Median age ranged from 69 to 74 years. Most patients had performance status 0-1. Estrogen receptor positive disease ranged from 79 to 89%. Triple negative BCs were 12%. The median number of administered cycles was 5. Overall the pooled ORR, median OS and PFS were 23.2%, 13.1 and 4.83 months. The disease control rate was 47%. Grade 3-4 neutropenia ranged from 0 to 49%, G3-4 anemia and thrombocytopenia were rare. Among nonhematological toxicities, the most frequent G3-4 adverse events were fatigue (range 5-16.5%) and neurotoxicity (range 0-10.1%). Dose reduction rate was reported in n = 3 studies and was provided in 40% of patients (range 18.6-84%).

Conclusions: This pooled analysis of 5 studies show that median OS is 13 months with an ORR of 23%. About 50% attained control of disease. Dose reduction was relatively frequent, but severe toxicities were rare. Treatment of elderly patients with EM is so feasible and reflects the results of the general population.

REAL LIFE INCIDENCE AND MANAGEMENT OF ADVERSE EVENTS (AES) IN WOMEN WITH ESTROGEN-RECEPTOR (HR)–POSITIVE AND (HER2)–NEGATIVE ADVANCED BREAST CANCER TREATED WITH PALBOCICLIB: A SINGLE INSTITUTION EXPERIENCE

Sinjari M.¹, Brandi M.², Ceddia S.², Cosimati A.², Verrico M.³, Gozzi E.², Mannino A.², Di Lisa F.S.³, Rossi L.², Tomao S.³

¹Università Sapienza., Aprilia; ²Universita Sapienza, Aprilia; ³Universita Sapien-za, Roma

Background: Palbociclib is selective CDK4/6 inhibitor a cyclin-dependent approved on results of Paloma 2 and Paloma 3 study for the treatment of locally advanced or metastatic breast cancer with hormonal-receptor (HR)–positive and negative human epidermal growth factor receptor(HER2). Inhibition of CDK4/6 prevents cell cycle progression from G1 to the S phase. We present the results on most common AEs, incidence of dose reduction and management in “real life” clinical practice.

Material and methods: We retrospectively reviewed records of all patients who were treated with palbociclib at our institution from 2017-2019. Our aim is to report our experience about the management of adverse event. A total of 51 females received palbociclib in various lines of treatment associated with hormonal therapy. We evaluated AEs, number of delayed cycles and incidence of dose reduction.

Results: About 51 patients analyzed, median age was 66. Histological exam revealed ductal carcinoma in 32 patients and lobular in 14. 26 patients had not performed previous treatment lines. Palbociclib was associated to aromatase inhibitor in 27 (53%) patients and to fulvestrant in 24 (47%). 5 patients had a biopsy-only as they were metastatic at the diagnosis, 7 (13,7%) had a previous neoadjuvant treatment. 19 patients had only one site of metastasis, 11 four sites. The only side effect of a high degree G3- G4 occurred was neutropenia in 21,6% (11) of the patients with a grade G3 and in 3,9% (2) with a G4; there was only 1 case of febrile neutropenia (2%). The other frequent AEs were grade G1-G2: fatigue in 41% (21), thrombocytopenia in 17% (9), anemia in 13,7% of pts (7), stipsis 6% (3), nausea 3% (2), diarrea 2% (1), mucositis 2% (1). 29 pts (56,8%) had to delay at least one subsequent therapeutic cycle, but only 10 out of 51 (20%) had to reduce the dosage of palbociclib.

Conclusions: The most common adverse events with Palbociclib are hematologic, particularly neutropenia.This neutropenia is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. Dose modification occur within the first two cycles. Older age does not affect palbociclib tolerance. Accurate patient monitoring and management of the side effects is crucial.

BREAST CANCER: TIME BETWEEN ACCESS TO RECEPTION SERVICE CENTRE (CAS), INTERDISCIPLINAR TEAM (GIC) VISIT AND SURGERY IN A SPOKE HOSPITAL OF PIEDMONT ONCOLOGY NETWORK (ROP)

Fora G.¹, Gasparre T.¹, Torazzo R.¹, Lattuada S.¹, Manachino D.¹, Posca T.¹, Zecchin D.¹, De Marino E.¹

¹Ospedale Sant’Andrea, Vercelli

Background: Delay of therapies in oncology is one of prognostic factors determining the outcome. The piedmont oncological network has proposed a new organisational model by setting the timing between visits cas and gic

These are affected by the mode of onset of neoplasia. Objective of the study is to assess the adherence to the indications of the rop and the interval between cas gic and surgery for breast cancer in the hospital spoke with the purpose to define classes of priorities for intervention.

Materials and Methods: We evaluated admissions for breast cancer present in reports sent to cas from the medical department of the hospital. We calculated the time between taking charge cas, gic and surgery and we divided into classes of priority related to the mode of onset.

Results: From january to december 2018 246 patients admitted for neoplasia were examined. 75/246 (30%) had breast cancer. 39/75 (52%) performed both cas and gic visits.

14/39 (36%) respected the 24 days waiting time between cas and gic visits as indicated by the rop. 5/75 (7%) had neither a cas visit nor a gic visit, 10/75 (13%) had only gic.

Conclusions: In this initial assessment only a third of patients had conditions indicated by the respected global timing rop. Efforts are needed to improve performance. However examination of medical records has allowed to divide cases into 4 groups related to disease onset.

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Priority	Definition	Time for Surgery	CAS	GIC
1	Strong suspicion of cancer or positive biopsy: the patient experiences symptoms or serious life-threatening signs, and illness or impending death without immediate intervention is high	Within 24 hours	NO	NO
2	High suspicion of cancer or positive biopsy: the patient has a high probability of having a highly aggressive neoplasm	Within 10 days	Yes	NO
3	All patients with high suspicion of cancer that does not meet the criteria of priority 1, 2 and 4	Within 30 days	Yes	Yes
4	All patients with an intermediate level of suspicion of cancer or patients with a positive biopsy, but with a high probability of an indolent (slow-growing) cancer	Within 40 days	Yes	Yes

EVALUATION OF OVARIAN FUNCTION SUPPRESSION (OFS) IN PATIENTS (pts) TREATED WITH EXEMESTANE (E) AND TRIPTORELIN (T) IN PREMENOPAUSAL ADJUVANT SETTING. FROM TRIAL TO CLINICAL PRACTICE: SOMETIMES A CHALLENGE

Cursio O. E.¹, Malossi A.¹, Courthod G.¹, Battaglia A.¹, Trogu A.¹, Cucchi M.¹, Alvaro M.R.¹, Stella A.¹, Mozzicafreddo A.¹, Sirotova Z.¹, Spinazze S.¹, Schena M.¹

¹SC Oncologia ed Ematologia Oncologica, Ospedale Parini, AUSL Valle d’Aosta, Aosta

Background: TEXT and SOFT 8-year update demonstrates that E was superior to tamoxifen alone or plus LHRHa at preventing distant metastases among HER2-negative chemotherapy-treated patients (pts) with a lack of benefit in overall survival(OS), many hypothesis have been proposed to explain it. In SOFT and TEXT OFS was investigated only by amenorrhea, in a SOFT substudy one-third of pts had Estradiol level above 2,72pg/ml, with uncertain clinical implication. No definitive data are emerged to now about the need of monitoring hormone levels. The aim of our analysis is to evaluate OFS by measuring estradiol levels in pts treated with E and T in our Day Hospital

Patients and method: We analyzed the quarterly estradiol values and menstrual documentation of pts treated with E and T off-label, according to TEXT and SOFT criteria.

Results: Since January 2018 we treated 10 pts. Median age 41y (as in TEXT and SOFT trial), 33% were node positive; 78% HER2 negative. Six(67%) received chemotherapy. All are still receiving hormonal treatment. We measured estradiol level every three months since baseline, our laboratory upper limit is 5pg/ml: in two pts the value raised at three months, in one case the dosage fell within the limits at six month; we are waiting for the six-month value of the second pt. Two pts showed a fluctuation of estradiol at 6 months, one returned to normal at 9 month, the other one is ongoing. One patient switched to tamoxifen after six month due to persistent elevation of Estradiol level. All patients maintained amenorrhea despite elevation of estradiol

Conclusions: Preliminary 5-year data of SOFT and TEXT demonstrate a benefit in disease outcome with E plus LHRHa in high risk patients, unconfirmed at 8-year follow up. Through data in our small experience we documented a lack of inhibition of ovarian function in 40% of our pts, whose meaning cannot be fully examined, but it’s not possible to exclude that such fluctuations might negatively affect the efficacy of treatment. Monitoring OFS with amenorrhea could be inaccurate, as we have seen elevations of Estradiol levels despite persistent absence of menses. We argue caution in translating results from trial population into clinical practice, we have to consider unanswered issues, as impact of incomplete OFS and the need of monitoring Estradiol value, pts compliance to scheduled blood examination and visits. Moreover intensifying treatment could increase side effect and reduce adherence to therapy.

TREATMENT WITH ERIBULIN MESILATE(EM) IN NINETIES WOMEN (NW)WITH LOCALLY ADVANCED BREAST CANCER NOT RESPONDING TO ENDOCRINOTHERAPY(NRETH):TOXICITY EVALUATION

Carreca I.U.¹, Bazan V.², Carreca A.P.², Galvano A.², Russo A.²

¹Department of Surgical, Oncological, and Oral Sciences- University-Palermo, Palermo; ²Department of Surgical, Oncological, and Oral Sciences- ^Section of Medical Oncology,- *Medical Oncology Unit, Palermo

Background: Cases of women about 90th with locally advanced breast neoplasms not responding to endocrinotherapy are more and more frequent: These subjects are mostly frail subjects.Therapy must therefore mainly take this condition into account. A synthetic analog of “halichondrin B,” Eribuline Mesilate was defined also to prolong overall survival of heavily pretreated metastatic breast cancer(MBC) patients. Furthermore,the EM limited adverse events like slightly neutropenia, fatigue, and peripheral neuropathy are especially appreciate in the treatment of elderly population. Aim: We plain to use a modified EM schedule to evaluate if is more effective than conventional treatments also in NW withy LABC.

Methods: Treatment plan: EM 0.96-1.0 mg/sqm IV on d1 every 21 (it depend on evaluation of CCl according to Kintzel-Dorr’s way, was delivered until progression or intolerable toxicity. Eligibility criteria: acquired written consensus; confirmed diagnosis of LABC -skin or visceral(one site) measurable lesion, medium age:88; Comprehensive Geriatric Assessment evaluation (CGA) permissive for chemotherapy, adequate renal function (CCl evaluation), proper bone marrow function; adequate liver function. Charlson’s Score Comorbidity Scale 1-3 score points max Evaluations tools: Clinical Benefit (CB) as Stable Disease + Objective Response Rates (ORR) according to ESMO CB scale v.2a; Toxicity Profile using CTCAE v3.0 Criteria; Quality of Life (QoL) score EORTC QLQ-C30 questionnaire.

Results: From 2017 to 2018, 22 women with locally advanced breast cancer were treated.20 of these are still under maintenance therapy (2 pts discontinued treatment for personal reasons). A total of 759 cycles were delivered to pts: 9out of 22 develop G3-4 hematological toxicity, but no delay in therapy delivery was needed. QoL score shows no noticeable decline in comparison with baseline whereas Clinical Benefit was about 65-70%.

Conclusions: EM adj schedule in the treatment of LABC NRETh about ninety women shows good safety also in presence of comorbidity and frailty with 65-70% of Clinical Benefit.These data also show that subjects at a very advanced age better withstand this type of chemotherapy even compared to endocrine therapy [ic1] Authors suggest starting an enlarged polycentric study to confirm these outcomes.

ASSESMENT OF IN VITRO CELL PROLIFERATION RESPONSES: A SINGLE BOUT OF MODERATE INTENSITY AEROBIC EXERCISE SERUM ON TRIPLE-NEGATIVE BREAST CANCER

Emili R.¹, Natalucci V.², Baldelli G.², De Santis M.², Lucertini F.², Vallorani L.², Annibalini G.², Brandi G.², Stocchi V.²

¹Oncologia Ospedale di Urbino, Urbino; ²Department of Biomolecular Sciences - Division of Exercise and Health Sciences, Urbino

Background: Breast cancer (BC) is the most common invasive cancer in women of all age groups, and studies have shown that sedentary women who are overweight or obese, or suffering from metabolic syndrome are more likely to have unfavorable prognoses. The cellular and molecular mechanisms related to this evidence are still unknown. The purpose of the study is to examine if systemic responses to a single bout of vigorous intensity aerobic exercise in sedentary healthy women could modulate cell proliferation, including the Triple-Negative BC (TNBC) subtype.

Methods: Pre-menopausal women performed 65 min of moderate to baseline vigorous intensity aerobic exercise on a treadmill. First 20 minutes subjects run at a heart rate reserve (HRR; ≈42%) corresponding to 50% of their own estimated VO2max, then exercise intensity was increased to 65% of VO2max (60% HRR) and maintained for 45 minutes (Rundqvist H et al., 2013).

Blood samples were collected before exercise, immediately after the end of exercise, and 2h post-exercise. The TNBC MDA-MB-231 cell line was exposed to the three blood samples. TNBC cells were seeded at a density of 2500 cells/well in 96 well plates. After overnight incubation, culture medium was changed with red-phenol free DMEM (0.8 or 1.2 mg/mL glucose) conditioned with 5% of human serum, and cell proliferation was evaluated using MTS assay after 72 hours.

Results: Post exercise sera showed a control on cell proliferation in comparison to sera collected before exercise. Indeed, the proliferation of cells cultured with 2h post-exercise serum lowered about 10%. Data were statistically significant (One-way ANOVA, Bonferroni post-hoc test; p<0.05) with a physiological concentration of glucose (0.8 mg/mL).

Conclusions: The effect of a single bout of moderate-intensity aerobic in sedentary pre-menopausal healthy women, in particular 2h post exercise, reduced TNBC cell proliferation. Therefore, we consider important that even a single exercise session of prolonged moderate exercise seems to have the potential to add a positive effect to the overall beneficial influence of exercise on TNBC. This protocol could be prescribed as MOVEMENT AND HEALTH CARE

STRATEGIES, MoviS within physical activity educational programs for cancer patients.

Rundqvist H et al., (2013) Plos One. 8(7):e67579.

CLINICAL IMPACT OF PACLITAXEL INDUCED PERIPHERAL NEUROPATY (PIPN): MONOCENTRIC EXPERIENCE

Murialdo R.¹, Francesca C.², Tixi L.², Balestra A.², Harusha E.², Zoppoli G.², Gallo M.², Raisi E.², Barbero V.², Isnaldi E.², Lia M.², Mina F.³, Bonalumi B.³, Beltramini S.³, Ballestrero A.²

¹IRCCS Policlinico S Martino, Genova; ²Department of Internal Medicine, University of Genoa. Ospedale Policlinico San Martino, Genova; ³U.O. Farmacia, Ospedale Policlinico San Martino, Genova

Background: Paclitaxel is one of the most used drugs in early and advanced breast cancer treatment. The incidence of all grades of neurotoxicity in patients (pts) treated with paclitaxel is high, ranging from 57%–83% overall and with severity in 2%–33% of patients. Peripheral neurotoxicity was the dose-limiting side effect mostly for weekly regiments. This could decrease total cumulative dose administered which may impair patients outcome as it is described in the literature. Patients receiving chemotherapy at relative dose intensity (RDI; received dose/planned dose) ⩾85% had better clinical outcome. We reviewed retrospectively the clinical impact of PIPN on our patients.

Material and Methods: We conducted a retrospective single institution analysis of 133 newly consecutive diagnosed breast cancer patients treated with paclitaxel-based neoadjuvant/adjuvant regimen (EC90 every 21 days for 4 cycles followed by weekly paclitaxel 80 mg/mq for 12 cycles). 89 pts and 44 pts were treated respectively in adjuvant and neoadjuvant setting.

Results: The median age of patients was 59 years (ranged 34-79). 89 pts (67%) were <65 years (ranged 34-64), 44 pts (33%) were ⩾65 years (ranged 66-79). 42 pts (31%) required discontinuation of paclitaxel for neuropathy (median of 10 cycles, ranged 4-11). 77 pts (58%) reduced paclitaxel dose (60 for PIPN, 17 for other causes). The median RDI for the 73 PIPN-induced dose reduction and/or treatment discontinued pts was 77%. 102 pts (77%) received a RDI ⩾85% while 29 pts (23%) received a RDI < 85%. In pts ⩾65 years (44 pts) 26 pts (59%) received RDI ⩾85% and 18 pts (41%) RDI<85%. In pts <65 years (89 pts) 76 pts (85%) received RDI ⩾85% and 13 pts (15%) RDI<85%.

Conclusions: These results add to a poor body of literature related to the frequency of taxane-associated dose reduction and its impact on the adherence to follow the planned treatment. PIPN seems to have an impact on RDI and maybe on patient outcome. This would seem even more true considering aging patients. Age seems an important factor to consider when we set up a taxane-based regimen above all in adjuvant/neoadjuvant setting even if there is for now controversial evidence of literature.

PALBOCICLIB: CDK4/6 INHIBITORS: EFFICACY AND TOXICITY EVALUATION: OUR EXPERIENCE IN ADVANCED BREAST CANCER

Burattini E.¹, Astone A.¹, Satta F.¹, Pellegrino A.¹, Todi F.¹, Zoffoli M.V.¹, Marchetti L.¹, Ramundo M.², Ludovisi E.²

¹Ospedale San Pietro Fatebenefratelli, Roma; ²Policlinico A. Gemelli, Roma

Introduction: Palbociclib (P) is a highly selective oral inhibitor of cyclin-dependent kinase 4/6 (CDK4/6). Cyclin D1 and CDK4/6 are downstream of signaling pathways that lead to cellular proliferation. Preduce cellular proliferation of estrogen receptor-positive breast cancer cell lines by blocking progression of the cell from G1 into the S phase of the cell cycle.

Methods: Between August 2017 to April 2019, 44 pts with MBC were treated with Palbociclib: 41 female and 3 male PS:0-2 (ECOG).Median age was 61 years (range:36-84). 18 pts received Palbociclib plus Letrozolo as first Line;15 pts received P plus Fulvestrant as first Line (after progression Adjuvant therapy with Aromatase Inhibitor) and 9 pts P plus Fulvestrant as second Line. 8 pts were in pre-menopausal, received LHRH agonist. 43% had visceral metastases; 32% had bone-exclusive metastases and 25% had multiple metastatic sites. HR: POS; HER2: NEG. Dose: P was administered at mg125/die (72% of pts) or 100/die (19% of pts) or 75/die (9% of pts) every day x os:1-21 every 28 days. Toxicity: Main observed toxicities were: neutropenia (G2-3):75% (33/44); thrombocytopenia (G1-2):22% (10/44); anemia (G1-2):27% (12/44); mucositis (G1-2):31% (14/44); fatigue (G2):40% (18/44); nausea (G1-2):34% (15/45); diarrhoea (G1-2):25%(11/44); emesis (G1):11% (5/44); arthromyalgie(G1):15% (7/44); dry skin (G1-2): 11% (5/44). No clinically relevant effect on the QTc interval. In pts with neutropenia G3: delayed treatment for 1 week.

Results: At a median follow-up of 20 months (until April 2019), median PFS was: First Line with P plus Letrozolo: 10,42 months: ORR was 78% (15/19); PR: 21% (4/19); CR: 10% (2/19); SD: 31% (6/19); PRO: 21% (4/19); First Line with P plus Fulvestrant: 11,3 months: ORR was 86% (13/15); PR: 53% (8/15); CR: 13% (2/15); SD: 20% (3/15); PRO: 13% (2/15). Second Line with P plus Fulvestrant: 7 months: ORR was: 50% (5/10); PR: 20% (2/10); SD: 30% (3/10); PRO: 50% (5/10).

Conclusions: Our experience confirm discrete tolerability and efficacy of PALBOCICLIB plus Letrozolo and even more with Fulvestrant. Moreover Palbociclib does not prolong QTc at the recommended therapeutic dosing regimen. Anyway is important to consider medications that could impact QTc, mostly in older pts.

OBSERVATIONAL PROSPECTIVE ITALIAN STUDY ON BREAST CANCER - BRIDE STUDY

Gori S.¹, Turazza M.¹, Gianni L.², Salvini P.³, Cretella E.⁴, Fabi A.⁵, De Rossi C.⁶, Vici P.⁵, Bisagni G.⁷, Aprile G.⁸, Cinieri S.⁹, Amaducci L.¹⁰, Moscetti L.¹¹, Mattioli R.¹², Cinquini M.¹³, Fabiana M.¹, Giugliano V.¹³, Nicolis F.¹⁴

¹IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona; ²Ospedale Infermi, Rimini; ³Humanitas Gavazzeni, Bergamo; ⁴Azienda Sanitaria dell’Alto Adige, Bolzano; ⁵Istituto Regina Elena-IFO, Roma; ⁶Ospedale dell’Angelo Mestre, Venezia; ⁷IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia; ⁸Ospedale San BORTOLO ULSS8 Berica, Vicenza; ⁹Ospedale Antonio Perrino, ASL Brindisi, Brindisi; ¹⁰Ospedale per gli Infermi, Ravenna; ¹¹AOU Policlinico Modena, Modena; ¹²Ospedale S. Croce, Fano; ¹³IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano; ¹⁴Fondazione AIOM, Milano

Backround: Breast cancer (BC) represents the first leading cause of death for cancer disease in the female sex. In Italy, in 2018 were estimated about 52,000 new breast cancers. This can be ascribed to both implementation of screening campaigns and increasing health information. The knowledge of clinical and biological prognostic factors (pT, pN, G, ER, PgR, Ki67 or MIB-1, HER2) is important to evaluate appropriate treatments both in the early and metastatic stages.

The aims of BRIDE study are to evaluate prospectically: 1- the criteria with which the oncologist consider to decide to carry out an adjuvant or neoadjuvant therapy in patients with a stage I-II-III BC; 2- the treatments used in patients with in situ carcinoma; 3- the types of treatment used in stage IV “de novo” and in stage IV as first disease recurrence (locoregional and/or metastatic). Secondary objectives are: disease free survival (DFS), progression free survival (PFS), overall survival (OS) and the evaluation of implementation in the clinical practice of AIOM v. 2017 Breast guidelines.

Methods: BRIDE is an observational, prospective, multicentre study. The sample size chosen is 4,500 patients in the 30 Italian cancer Centers. The oncologic centers are selected according to the geographical distribution, type of institution, listed in the AIOM Report v.2016 and also on the basis of new cases afferent per years. The target population included female patients with age =>18 years with histological diagnosis of carcinoma in situ (DCIS, LCIS) or invasive BC; stage I-III and stage IV (according to TNM v. VII) “de novo” or stage IV as first disease recurrence (loco-regional or metastatic). Clinical characteristics, biological parameters (grading, ER, PgR, Ki67/MIB-1, HER2 on primary tumour and/or metastatic lesion), treatments and outcome of patients were recorded. The accrual period is two years.

Results: From January 2018 to April 2019, 589 patient were enrolled in 13 Italian centers: 365 patients were treated with adjuvant and 44 with neoadjuvant therapy. PFS and DSF will be analyzed. The end of the study is estimated by January 2024.

Conclusions: The BRIDE study is ongoing. The data collected will let know the percentage of stage I-II-III BC patients treated with a systemic adjuvant or neoadjuvant therapy, the parameters that influenced the physician choice and the types of chosen treatments. Moreover the implementation of the AIOM v. 2017 Breast guidelines will be evaluated.

EVEROLIMUS (EVE) IN HORMONE RECEPTOR POSITIVE ADVANCED BREAST CANCER: RETROSPECTIVE REVIEW OF A SINGLE INSTITUTE EXPERIENCE

Chirco A.¹, Milesi L.¹, Moro C.¹, Rota Caremoli E.¹, Tasca C.¹, Zambelli A.¹, Tondini C.¹, Poletti P.¹

¹ASST Papa Giovanni XXIII, Bergamo

Background: EVE is an mTOR inhibitor approved in association with exemestane for advanced breast cancer progressing after non-steroidal aromatase inhibitors (NSAIs). This retrospective analysis was aimed to evaluate clinical activity and tolerability in real life setting.

Material and Methods: Patients (pts) treated at the Oncology Unit of PG23 Hospital in Bergamo from January 2013 to January 2019 were included. We collected data about safety, drug exposure and efficacy.

Results: We treated 73 pts, median age 64 years, 36% had visceral involvement, 23% had ⩾ 3 metastatic sites, previous therapy included NSAIs (100%), fulvestrant (59%), chemotherapy for advanced disease (44%), 71% had a DFI >24 months. The most common grade 3 and 4 adverse events (AE) were stomatitis (7%), anemia (3%), pneumonitis (3%), grade 1-2 AE were stomatitis (67%), asthenia (46%), rash (31%), pyrexia (38%), cough (35%). A dose reduction to 5 mg of EVE was necessary for 47% of the pts, 57% temporary interrupted EVE. The most frequent reason of discontinuation was disease progression (71%). At the cutoff date (January 31,2019) 4 pts were still on treatment. The median duration of exposure of EVE was 6 months (range1-31+). Response rate was 17%, with 2 complete response and 10 (14%) partial response, stable disease was obtained in 44% of the pts. Median progression free survival was 6.5 months (range interquartile: 3.6-14.0).

Conclusions: EVE and exemestane combination is effective and manageable in real life setting, even if it is burdened with many side effects. We experienced that dose reductions and temporary interruptions of EVE, together with symptomatic therapies, can help to overcome toxicities and prolong a potential effective therapy.

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Table 1.

Adverse Events (%) any grade G3/G4.

	N°pts (%)	N°pts (%)
Stomatitis	48(67)	5(7)
Asthenia	33(46)	1(1)
Pyrexia	27(38)	1(1)
Cough	25(35)	0(0)
Rash	22(31)	0(0)
Pneumonitis	16(22)	2(3)
AST increased	16(22)	1(1)
ALT increased	15(21)	1(1)
Anemia	13(18)	2(3)
Hyperglycemia	13(18)	0(0)
Diarrhea	11(15)	1(1)
Decreased appetite	11(15)	0(0)
Nausea/vomiting	11(15)	0(0)
Arthralgia	11(15)	0(0)
Decreased weight	9(13)	0(0)
Thrombocytopenia	9(13)	0(0)

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Table 2.

Treatment.

	N°mo	N°pts (%)
months on treatment%	< 3	19(26)
	3-5	16(22)
	6-9	18(25)
	>9	20(27)
dose reduction (5 mg) %		34(47)
treatment interruption %		41(56)
	1	18(25)
	2	20(27)
	⩾ 3	3(4)
reasons for interruption %	PD	52(71)
	toxicity	13(18)

EFFICACY AND SAFETY OF RIBOCLICLIB AND LETROZOLE IN THE TREATMENT OF LOCALLY ADVANCED AND METASTATIC HR+/HER2 - BREAST CANCER: A REAL WORLD EXPERIENCE

Savastano C.¹, Lombardi F.², Fiorillo C.², Rispoli A.I.², De Divitiis C.²

¹UOSD Oncologia AOU Ruggi di Aragona Salerno, Salerno; ²UOSD Oncologia AOU Ruggi d’Aragona, Salerno

Background: Breast Cancer is the second most common type of cancer worldwide. Targeted therapies have revolutionized the treatment of metastatic breast cancer, improving the life expectancies of many women. Selective CDK 4/6 inhibitors are a new class of drugs that, in addition to hormone therapy in patients with advanced HR + / HER2- breast cancer, have been shown to improve the results obtained with hormone therapy alone and to prolong survival progression free, with a lower level of toxicity and less impacting side effects than the chemotherapy, offering a better quality of life, an early reduction of pain. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and (HER2)negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively.

Methods: From September 2018 to May 2019 in our hospital we have treating thirty women with metastatic or locally advanced breast cancer with expression of hormone receptors and HER2 not amplified with ribociclib 600 mg/day, (3 weeks-on/1 week-off), plus letrozole (2.5 mg/day continuous). Of these thirty patients, 8 have a diagnosis of locally advanced breast cancer not susceptible to surgery.

Results: In our experience, the treatment with ribociclib and letrozole was well tollereted, and the most common Grade 3/4 adverse events observed until today were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA-2 population. In 40% of these patients, and in accordance with the result of the recording study, we found both a clinical and ultrasound imaging examination, after eight weeks of therapy, a volume reduction of breast lesions.

Conclusions: Ribociclib plus letrozole represents an effective and well tollerated therapeutic opportunity in postmenopausal women with HR+, HER2− de novo advanced breast cancer. This therapeutic approach translates into the possibility of administering to women in this setting a treatment that is not, as a first option,chemotherapy, but an oral therapy, with many advantages for patients in terms of quality of life, impact on everyday life and safety. These results, confirmed in our real life experience,open up new horizons, not only for the efficacy observed, but also for the quality of life that this change can offer.

CARDIAC TOXICITY OF ADJUVANT TRASTUZUMAB IN BREAST CANCER PATIENTS AGED ⩾60 YEARS

Spoto C.¹, Calabretta F.¹, Ciorra A.A.¹, Cirino C.¹, Di Cocco B.¹, Di Palma T.¹, Pistillucci G.¹, Salesi N.¹, Sciacca V.¹, Zoratto F.¹, Veltri E.¹

¹Ospedale Santa Maria Goretti – U. O. Oncologia Medica, Latina, Latina

Background: Adjuvant trastuzumab in combination with chemotherapy is the treatment of choice for patients (pts) with human epidermal growth factor receptor positive (HER2+) early breast cancer (EBC). Cardiac toxicity became a major concern in trastuzumab-treated pts but, to date, the incidence of Trastuzumab-mediated cardiotoxicity in older patients is not well defined. Cardiac dysfunction appears to be related to both age and baseline left ventricular ejection fraction (LVEF) values.

Patients and Methods: We conducted a retrospective data analysis of 76 consecutive pts > = 60 years (median age 67 years; range 60-87) with HER2+ EBC treated with adjuvant trastuzumab from June 2009 to December 2017 at our institution. Thirty-five pts received sequential trastuzumab according to HERA trial design, twenty-eight pts received trastuzumab with concurrent taxanes administration and thirteen pts did not receive any adjuvant chemotherapy but undertook adjuvant treatment with trastuzumab and letrozole. Adjuvant antracycline-based chemotherapy was administered in 52 pts. An assessment of LVEF by echocardiography was performed at baseline, and at 3, 6, 9, 12 months during trastuzumab. Pts with an LVEF value > = 55% were eligible to receive therapy. Median LVEF at baseline was 68%.

Results: A total of 1.234 cycles of trastuzumab were administered and 64 pts (84.2%) completed one year of treatment. Seventeen pts (22.4%) interrupted treatment because of asymptomatic LVEF decrease > 10% but thirteen of these resumed trastuzumab after LVEF recovery. Definitive discontinuation occurred in only four pts (5.3%). No clinically significant congestive heart failure and no cardiac death occurred. Eight pts (10.5%) discontinued treatment for no cardiac causes: disease relapse, severe adverse skin reaction, liver toxicity, worsening of chronic renal failure, severe and prolonged asthenia. When compared for trastuzumab treatment duration, LVEF values at baseline, cardiological risk factors and previous exposure to anthracycline or to left-sided chests irradiation, pts who experienced LVEF reduction did not differ from those who do not.

Conclusions: Our results show that, with appropriate pts selection and systematic cardiac assessment, cardiotoxicity in adjuvant trastuzumab therapy is confirmed manageable also in older women. In our experience no serious cardiac events were observed and only 5.3% of pts permanently discontinued treatment because of cardiac toxicity.

BEVACIZUMAB COMBINED WITH PACLITAXEL AS FIRST-LINE TREATMENT OF HER2-neg METASTATIC BREAST CANCER: MONOINSTITUTIONAL EXPERIENCE

Zoratto F.¹, Calabretta F.¹, Ciorra A.A.¹, Cirino C.¹, Di Cocco B.¹, Di Palma T.¹, Pistillucci G.¹, SALESI N.¹, Sciacca V.¹, Spoto C.¹, Veltri E.¹

¹Ospedale Santa Maria Goretti – U. O. Oncologia Medica, Latina, Latina

Background: Bevacizumab + paclitaxel represents a standard of care for HER2-neg metastatic breast cancer (MBC) and has shown an improved progression-free survival (PFS), despite the lack of clear overall survival (OS) benefit. We performed a retrospective analysis to evaluate the efficacy and safety of this combination in patients (pts) no previously treated with chemotherapy for HER2-neg metastatic breast cancer.

Materials and Methods: from October 2011 to April 2018 we identified 33 pts treated at our institution with paclitaxel 90 mg/mq on days 1.8.15 + bevacizumab 10 mg/mq on days 1,15 q28 until disease progression or intolerable toxicity. Patients’ median age was 60.5 years (range 40-79) and 72.7% of them (24 pts) had visceral disease; 11 pts (33.3%) were previously treated with endocrine therapy for metastatic disease. Histology: ductal carcinoma 25 (75.8%), lobular carcinoma 8 (24.2%). Molecular subtype: triple negative 6 (18.2%). 11 pts received maintenance therapy with bevacizumab (4 pts), letrozolo (4 pts) or both (3 pts) after paclitaxel discontinuation due to progression or toxicity.

Results: All the pts were evaluable for toxicity and response. An objective response rate of 45.4% was reached in the whole population (4 complete responses, 11 partial responses), stable disease in 24.3% (8 pts), progression disease (PD) in 30.3% (10 pts). Median PFS was 10 months (range 3-61+), median OS was 23 months (range 9-61+); At 1 and 2 years PFS rates were respectively 39.4% and 18.2% and OS rates 75.8% and 42.5%. At the time of statistical analysis, 4 pts were still receiving maintenance therapy with letrozolo with a PFS of 26 to 61 months and 2 pts were still in treatment with bevacizumab + paclitaxel after 10 and 8 cycles respectively. After disease progression, further anticancer therapy was administered to 19 pts. Grade 3 adverse events occurred in 13 pts (39.4%) and the most common were neutropenia (6 pts), hypertension (5 pts) and peripheral neuropathy (2 pts); no grade 4 adverse events were detected. Five pts (15.1%) interrupted treatment for side effects: 2 because of G3 hypertension, 2 for prolonged G2 proteinuria and 1 for G3 neuropathy; neither vascular thromboembolism nor gastrointestinal perforation or congestive heart failure occurred.

Conclusions: Our small retrospective study conducted on HER2-negative MBC pts confirms the efficacy of bevacizumab-paclitaxel therapy. The regimen is well-tolerated and adverse events are fairly manageable.

A NON STANDARDIZED QUESTIONNAIRE TO INVESTIGATE ADVERSE EVENTS DURING ENDOCRINE THERAPY IN PATIENTS WITH EARLY BREAST CANCER

Persano M.¹, Donisi C.¹, Balconi F.¹, Camera S.¹, Impera V.¹, Liscia N.¹, Mariani S.¹, Musio F.¹, Pretta A.¹, Soro P.¹, Tolu S.¹, Lai E.¹, Dessì M.¹, Scartozzi M.¹, Atzori F.¹

¹Università degli Studi di Cagliari, Cagliari

Background: Breast cancer is the leading neoplasia among women. Endocrine therapy is indicated in all patients with detectable ER expression (⩾1% of invasive cancer cells), irrespective of the use of chemotherapy and / or target therapy. In premenopausal patients, for 5 years is a standard the ovarian suppression with Gonadotropin releasing hormone (GnRH) in combination with Tamoxifen (T) 20mg/day or an Aromatase inhibitor (AI). The aim of this study is to analyse adverse events due to GnRH+T or GnRH + AI.

Material and Methods: From July 2005 to August 2018, we enrolled 90 premenopausal patients with non-metastatic breast cancer.

Patients were treated with adjuvant endocrine therapy (T+GnRH or AI + GnRH). Adverse events were evaluated with clinical assessments and blood samples. We also administered the patients a non-standardized questionnaire to investigate which were adverse events caused by endocrine therapy. The median age of the patients was 48 years (from 32 to 58). Of them, 98% were Caucasian women and 2% Asian women. Our population was split in 4 subgroups, respectively:1. Patients treated with AI+GnRH (62%); 2. Patients treated with T+GnRH (31%); 3. Patients initially treated with T+GnRH and subsequently treated with AI+GnRH for adverse events occurred (3%); 4. Patients initially treated with AI + GnRH, were switched to T+GnRH due to adverse events (4%).

Results:

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	Group 1	Group 2	Group 3	Group 4
Hot flushes	91%	68%	33%	100%
Depression	34%	25%	33%	33%
Anxiety	2%	4%	33%	0
Irritability	9%	10%	33%	33%
Insomnia	77%	61%	33%	33%
Nausea	34%	11%	33%	0
Constipation	27%	36%	0	0
Headache	21%	29%	33%	33%
Vaginal dryness	64%	61%	66%	100%
Vaginitis	16%	18%	33%	33%
Libido decreased	70%	50%	33%	100%
Gain of weight	38%	50%	66%	100%
Joint pain	84%	32%	66%	33%
Paraesthesia	27%	0	33%	33%
No symptoms	48%	57%	0	0

Conclusions: These adverse events irremediably affect quality of life of patients treated with endocrine therapy. It would be advisable to use a standardized questionnaire to investigate adverse events due to endocrine therapy to improve quality of life of these patients.

HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY IN PRETREATED LIVER METASTASES FROM BREAST CANCER

Federici F.¹, Lucchesi M.¹, Bursi S.¹, Ginocchi L.¹, Valsuani C.¹, Auci A.², Ceccherini C.², Della Seta R.¹, Allegrini G.³, Gebbia V.⁴, Liguigli W.⁵, Fiorentini G.⁶, Caparello C.³, Musettini G.⁷, Mambrini A.¹

¹Oncologia Medica Massa Carrara - Azienda USL Toscana Nord Ovest, Massa; ²Radiologia Massa Carrara - Azienda USL Toscana Nord Ovest, Massa; ³Oncologia Livorno - Azienda USL Toscana Nord Ovest, Livorno; ⁴La Maddalena Hospital - Università di Palermo, Palermo; ⁵Oncologia Mantova - Azienda Ospedaliera Carlo Poma, Mantova; ⁶Oncologia Pesaro - Azienda Ospedaliera Marche Nord, Pesaro; ⁷Oncologia Medica Pontedera - Azienda USL Toscana Nord Ovest, Pontedera - PI

Background: The presence of liver metastases in breast cancer is associated with poor outcome. Up to 20% of this patients, will die from hepatic failure. In literature there are limited experiences with hepatic arterial infusion of chemotherapy (HAI) for these patients, in particular without subcutaneous pumps.

Patients and methods: This is an observational, single-center, retrospective analysis of HAI in heavy pretreated patients with breast cancer liver metastases (with only liver metastases or in which disease progression was mainly on liver, or at risk of liver visceral crisis, but always without other organs at risk of visceral crisis). Patients were treated with the combination of 5-fluorouracil (1000 mg), epirubicin (50 mg), and mitomycin-C (10 mg), every 28 days.

Results: From 2011 to 2018, 23 female patients were treated with HAI. The median age was 65 (range 40-77) at treatment, 58 (range 38-71) at breast cancer diagnosis. The most frequent tumor biology was hormone receptors (HR) positive/HER2 negative (56%); triple positive, triple negative, or unknown occurred respectively in 13%, 9%, and 22%. The median Ki-67 was 20% (15-90). Extra-hepatic disease was described in 17 patients (74%). Before HAI patients received a median of 4 (range 2-6) previous lines of treatment for stage IV disease, with a median of 2 (range 1-4) lines of systemic chemotherapy.

Regarding HAI, a median of 3 cycles was administered (range 1-9). The overall response rate (ORR) on liver was 26%, with a disease control rate (DCR) of 56% and a clinical benefit rate (CBR) of 47%. A progressive disease (PD) in liver or other sites was reported in 44% of patients. The median progression-free survival (PFS) was 6,45 months on 20 patients (3 were not evaluable for survival). Response rates and PFS benefit were independent from the number of previous lines (p: 0.26 and 0.56). Grade 3-4 adverse events or injuries linked to the invasive procedure were not reported.

Conclusions: In this series of pretreated patients with breast cancer liver metastases, the treatment with HAI achieved a durable disease control in about one case out of two. Most of them had a HR positive/HER2 negative tumor. Prospective confirmation in clinical trials in the “cyclin inhibitors era” is recommend.

IMMUNOLOGICAL EFFECTS OF ERIBULIN MESYLATE ADMINISTRATION IN PATIENTS WITH ADVANCED BREAST CANCER

Danova M.¹, Comolli G.², Olgiati A.³, Cavalli C.³, Zanirato S.³, Nozza A.³

¹Medicina Interna a indirizzo Oncologico, ASST Pavia, Pavia; ²Laboratori di Ricerca Biotecnologie e UOC Microbiologia e Virologia, Fondazione IRCCS San Matteo, Pavia; ³Medicina Interna a indirizzo Oncologico, ASST di Pavia, Pavia

Background: Anticancer chemotherapy (CT) has been traditionally considered to be strongly immunosuppressive. However, increasing evidences suggest that certain CT agents have the ability to stimulate the immune system, inducing anti-tumor immune responses that contributes to their clinical efficacy. Eribulin mesylate (EM) exerts multiple non-mitotic effects on tumor biology including: tumor vasculature remodeling, reversal of epithelial-to-mesenchymal transition and stimulations of some immune cell-mediated activities.

Patients and Methods: In a study project on the role of CT drugs on the immune system we have studied the effect of EM on different T-cell populations in advanced breast cancer (BC). Using high-resolution multicolor flow cytometry, FOXp3⁺ Treg populations, sub-populations of cytotoxic CD8⁺ T-cells and CD57⁺ NK cells were analyzed in 19 pts (median age 61, range 40-76 yrs) undergoing a 3^rd or 4^th line of treatment. Ten healthy subjects matched for sex and age were utilized as control.

Results: There was a progressive decrease in absolute numbers of leukocytes, lymphocytes and CD8⁺ T-cells during CT courses. Starting from the 3^rd course, Treg populations, that initially were increased compared to the healthy controls (p<.001), significantly decreased (p<.001). Among the T-cells, there was a lower CD8^-/CD8⁺ ratio in pts compared to controls. The proportion of CD28^-CD57⁺ cells also remained higher among pts with cancer throughout the study duration.The number of CD28⁺CD57^- and CD28^-CD5^- cells decreased faster during CT than CD28⁺CD57⁺ and CD2^-CD57⁺ cells.

Conclusions: In pre-treated advanced BC pts, EM elicit several changes of some immune-related parameters including the composition and phenotype of immune cells. In particular, during treatment, regulatory activities in T cells were increased through a decrease of Foxp3⁺Treg cells. These findings suggest a contribution of the immune cells to the antitumor activities of EM and may help to design relevant clinical protocols based on the combination of EM with immune checkpoint blockers.

PROOF-OF-CONCEPT OF SERENITY TRIAL (SECOND LINE ERIBULIN FOR LOCALLY ADVANCED OR METASTATIC BREAST CANCER): FOCUS ON NEUROPATHY AND OVERALL TOXICITY

Becherini C.¹, Michelotti A.², Martella F.³, Desideri I.¹, Scotti V.¹, Maragna V.¹, Ciabatti C.¹, Lo Russo M.¹, Garlatti P.¹, Lucidi S.¹, Lorenzetti V.¹, Meattini I.¹, Livi L.¹

¹AOU Careggi, SODc Radioterapia Oncologica, Firenze; ²AOU Pisana, UO Oncologia Medica I, Pisa; ³Ospedale Santa Maria Annunziata, SOC Oncologia Medica, Firenze

Background: In heavily pre-treated locally-advanced /metastatic breast cancer (LA/MBC) patients, neuropathy frequently occur. This disabling symptom leads to drug delays, dose reductions and discontinuations in addition to a detrimental impact on health-related quality of life (HRQoL). Eribulin mesylate was studied as subsequent line in various murine model with induced paclitaxel neuropathy producing less neuropathy than did paclitaxel. The aim of this study is to assess the toxicity profile of 2nd line chemotherapy with eribulin in a cohort of LA/MBC patients treated in real life setting, focusing on neuropathy-related toxicity assessed by both physician and Patients Reported Outcomes (PROMs).

Patients and Methods: Serenity is a longitudinal, prospective, open label multicentric study investigating tolerability profile and efficacy in a real life setting of eribulin as 2nd line treatment for HER2- LABC/MBC. An overall series of 33 patients is estimated, including a 10% of patients drop out from the study. Eribulin (1.23 mg/m²) is administered as per local practice. Tumor response will be evaluated with clinical, laboratory and imaging evaluations following the local center policy. Peripheral motor and sensory neuropathy will be assessed after clinical examination, using NCI CTCAE (version 5.0). PROMs related to neuropathy will be assessed concurrently, through the following tools: EORTC QLQ-CIPN20, Clinical version of the Total Neuropathy Score clinical version (TNSc), mISS, Visual analog pain scale (VAS).

Results: This study aims to collect data to assess the toxicity profile, the mode and the effectiveness of treatment of LA/MBC with eribulin. Relevant parameters in this respect are the reasons for stopping eribulin as well as the toxicity profile during and after stopping the above-mentioned treatment. Outcome data will be collected, in particular, side effects using the NCI CTCAE v.4 scale. In addition, data will be collected regarding progression-free survival, subsequent therapy lines and time to recurrence.

Conclusions: This study aim observe prospectively heavily pre-treated LA/MBC patients treated with 2nd line eribulin. We want to describe a toxicity profile in detail, comparing clinical assessment and PROMs.

IMMUNE CHECK POINT INHIBITORS IN METASTATIC BREAST CANCER: A REVIEW OF THE AVEILABLE DATA

Ambroggi M.¹, Orlandi E.¹, Citterio C.¹, Cavanna L.¹

¹Ospedale “G. da Saliceto”, UO Oncologia, Piacenza

Background: Immune check point inhibitors have become a standard of care in some tumors, and are emerging as a new treatment modality also in breast cancer, where anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1) antibodies were developed later. Metastatic breast cancer (MBC) remains incurable, and some breast cancer subtypes have a higher TILs expression with greater immunogenic power, like triple negative breast cancer (TNBC), considered the most immunogenic subtype.

Materials and Methods: We review available data from clinical trials regarding safety and efficacy of immune check point inhibitors in MBC.

Results: Eighteen trials were founded, mainly phase I/II. Efficacy data are encouraging, especially in TNBC and in PD-L1+, and when immune check point inhibitors are used in combination with other therapies, like eribulin, radiotherapy like abscopal effect and poly(ADP-ribose) polymerase (PARP) inhibitors, or abemaciclib in hormone receptor (HR) positive tumors. Progression free survival (PFS) and overall survival (OS), in Impassion 130 phase III trial, were better in the nab-paclitaxel plus atezolizumab group, especially in PD-L1+, and atezolizumab has recently been approved by FDA for metastatic TNBC. Pembrolizuamb alone, in TNBC, demonstrated better responses in less pre-treated patients especially in PD-L1+, with a median duration of response higher than standard chemotherapy, also in pre-treated patients, while it demonstrated less efficacy in patients with poor prognostic factors. In human epidermal growth factor 2-neu (HER2) positive tumors there are less data and more controversial, Immune check point inhibitors were well tolerated and the main side effects were similar to those seen in studies conducted in other cancer types.

Conclusions: Available data regarding immune check point inhibitors use in breast cancer are promising, especially in metastatic TNBC. The main biases of the published studies are the small sample size and the early phase of the trials. These drugs are well tolerated, both alone or in combination, and reflect the toxicities already known from studies in other cancer types. Efficacy is interesting, especially in TNBC, early metastatic setting and PD-L1+, even if these drugs need further investigations, that are ongoing. Patients with poor prognostic factors should not be considered for therapy with immune checkpoint inhibitors alone.

FROM AN HOSPITAL TO A NETWORK: SHARING OF AN INTERDISCIPLINARY AND MULTIPROFESSIONAL CARDIO-ONCOLOGY PATHWAY FOR THE MANAGEMENT OF BREAST CANCER PATIENTS IN AZIENDA USL TOSCANA NORD-OVEST (ATNO)

Canale M. L.¹, Camerini A.², Venturini E.³, Sardella S.⁴, Pacetti P.⁵, Colombi L.⁶, Aguzzi G.⁷, Arrighi G.⁸, Di Marsico R.⁹, Giovannelli S.¹⁰, Zavettieri A.¹¹, Coltelli L.¹², De Maio E.¹², Lorenzoni M.⁴, Amoroso D.², Belli L.¹³, Lencioni S.¹⁴, Donati S.¹³, Allegrini G.¹², Casolo G.¹⁴

¹Cardiology, Versilia Hospital - Azienda USL Toscana Nord-Ovest, Lido di Camaiore; ²Medical Oncology, Ospedale Versilia; Oncology Department – Azienda USL Toscana Nord-Ovest, Lido di Camaiore; ³Cardiology, Ospedale Civile, Cecina – Azienda USL Toscana Nord-Ovest, Cecina; ⁴Cardiology, Ospedale Civile, Livorno – Azienda USL Toscana Nord-Ovest, Livorno; ⁵Medical Oncology, Nuovo Ospedale Apuano, Massa – Azienda USL Toscana Nord-Ovest, Massa; ⁶Cardiology, Nuovo Ospedale Apuano, Massa – Azienda USL Toscana Nord-Ovest, Massa; ⁷Cardiology, Ospedale Lotti, Pontedera – Azienda USL Toscana Nord-Ovest, Pontedera; ⁸Medical Oncology, Ospedale Lotti, Pontedera; Oncology Department – Azienda USL Toscana Nord-Ovest, Pontedera; ⁹Medical Oncology, Ospedale Civile, Livorno; Oncology Department – Azienda USL Toscana Nord-Ovest, Livorno; ¹⁰Medical Oncology, Ospedale S. Luca, Lucca; Oncology Department – Azienda USL Toscana Nord-Ovest, Lucca; ¹¹Cardiology, Ospedale Piombino; Azienda USL Toscana Nord-Ovest, Piombino; ¹²Medical Oncology, Ospedale Civile Livorno; Oncology Department – Azienda USL Toscana Nord-Ovest, Livorno; ¹³Medical Oncology, Versilia Hospital – Azienda USL Toscana Nord-Ovest, Lido di Camaiore; ¹⁴Cardiology, Versilia Hospital – Azienda USL Toscana Nord-Ovest, Lido di Camaiore

Background: The impact of cardio-oncology issues in breast cancer patients management has become more and more relevant so making crucial to adopt a dedicated care pathway.

Materials and Methods: In late 2017 an ATNO interdisciplinary and multi-professional working group was established. The group was composed by selected medical oncologists, belonging to the Department of Oncology, cardiologists and nurse representatives from each different hospital. The aim was to create a shared cardio-oncology pathway based on an in-hospital cardio-oncology pathway previously active at Versilia Hospital. The process was divided into three phases: a) cardio-oncology census and inner organization of each hospital (if available); b) oncology-related workload; c) availability of trained and/or interested physicians. Final objectives were: 1) promote the Versilia model in the other hospitals of ATNO; 2) define a shared model to be applied across all ATNO hospitals, to take care of breast cancer patients from a cardiological point of view; 3) encourage clinical research in this unexplored area of clinical oncology.

Results: Baseline cardio-oncology service organization clearly differs among ATNO hospitals ranging from established pathway to no service. On the other hand, the amount of monthly oncology-related workload was relevant with a mean of 40-60 services/month/hospital. The working group so defined cardiac risk toxicity categories, timing and type of cardiology visits and imaging and need for next-level diagnostic tests. The group also focused on network level activities by the identification of some centers with specific expertise on cardiac imaging (cardiac MRI and coronary-CT) and cardiac rehabilitation to be offered to all ATNO breast cancer patients.

Conclusions: A cardio-oncology pathway is now active at ATNO and breast cancer patients cardiac management is based on shared expertises at hospital network level.

SECONDARY ROS1 MUTATIONS AND LORLATINIB SENSITIVITY IN CRIZOTINIB-REFRACTORY ROS1 POSITIVE NSCLC: RESULTS OF THE PROSPECTIVE PFROST TRIAL

Landi L.¹, Tiseo M.², Heukamp L.C.³, Menon R.⁴, Spitaleri G.⁵, Cortinovis D.L.⁶, Delmonte A.⁷, Galetta D.⁸, D’Arcangelo M.⁹, D’Incà F.¹⁰, Bertrand M.⁴, Jori B.⁴, Zacher A.⁴, Gridelli C.¹¹, Pignataro D.¹², Chiari R.¹³, Verusio C.¹⁴, Crinò L.⁷, Cappuzzo F.⁹

¹Dipartimento di Oncologia ed Ematologia, Azienda USL della Romagna, Ravenna; ²2. Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma e Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma; ³3. Lung Cancer Network NOWEL.org, Oldenburg; ⁴4. NEO New Oncology GmbH, Cologne; ⁵5. Thoracic Oncology Division, Istituto Europeo di Oncologia IRCSS, Milano; ⁶6. SC Oncologia Medica, SS Lung Unit Asst Ospedale San Gerardo, Monza; ⁷7. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola; ⁸8. Oncologia Medica Toracica, IRCCS Oncologico Giovanni Paolo II, Bari; ⁹1. Dipartimento di Oncologia ed Ematologia, Azienda USL della Romagna, Ravenna; ¹⁰Fondazione Ricerca Traslazionale (FoRT), Roma; ¹¹10. UOC Oncologia Medica, Azienda Ospedaliera S.G. Moscati, Avellino; ¹²11. Dipartimento di Oncologia, Università di Torino, AOU San Luigi, Orbassano (TO); ¹³12. UOC Oncologia Ospedali Riuniti Padova Sud-AUSLL 6 Euganea, Padova; ¹⁴13. SC di Oncologia Medica, PO Saronno, ASST Valleolona, Saronno

Background: Lorlatinib, an ALK/ROS1 inhibitor, showed activity in ROS1+NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

Material and Methods: The phase II PFROST trial included ROS1+NSCLCs refractory to crizotinib. Eligible patients received lorlatinib 100 mg daily until disease progression. Primary end point was response rate (RR). For all patients, pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

Results: From June 2017 to April 2019, 22 ROS1+crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N = 8; 36.4%), PS 1 (N = 14; 63.6%); The majority had brain metastases at baseline (N = 15; 68.1%), were never smokers (N = 13; 59.1%) and received lorlatinib as third line therapy (N = 16; 72.7%). In all cases crizotinib was the last therapy before lorlatinib. At the time of this analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N = 1) or partial (N = 6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N = 1 ROS1 S1861I, N = 1 ROS1 V2054A, N = 3 ROS1 G2032R). All patients harboring the ROS1 G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of of lorlatinib failure.

Conclusions: In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals harbouring crizotinib-induced secondary ROS1 mutations.

RELAY: A MULTINATIONAL, DOUBLE-BLIND, RANDOMIZED PHASE 3 STUDY OF ERLOTINIB (ERL) IN COMBINATION WITH RAMUCIRUMAB (RAM) OR PLACEBO (PL) IN PREVIOUSLY UNTREATED PATIENTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION-POSITIVE (EGFRM) METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)

Nakagawa K.¹, Garon E.², Seto T.³, Nishio M.⁴, Ponce Aix S.⁵, Chiu C.⁶, Park K.⁷, Novello S.⁸, Nadal E.⁹, Imamura F.¹⁰, Yoh K.¹¹, Shih J.¹², Au K.H.¹³, Moro-Sibilot D.¹⁴, Enatsu S.¹⁵, Zimmermann A.¹⁶, Frimodt-Moller B.¹⁷, Visseren-Grul C.¹⁸, Reck M.¹⁹

¹Kindai University Hospital, Osaka, Japan, Osaka; ²David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles, CA, USA, Los Angeles; ³National Kyushu Cancer Center, Fukuoka, Japan, Fukuoka; ⁴Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan, Tokyo; ⁵Hospital 12 de Octubre, Madrid, Spain, Madrid; ⁶Taipei Veterans General Hospital, Taipei, Taiwan, Taipei; ⁷Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Kore, Seoul; ⁸Department of Oncology, University of Turin, Orbassano, Italy, Orbassano; ⁹Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain, Barcelona; ¹⁰Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan, Osaka; ¹¹National Cancer Center Hospital East, Kashiwa, Japan, Kashiwa; ¹²Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Taipei; ¹³Queen Elizabeth Hospital, Kowloon, China, Kowloon; ¹⁴Service Hospitalier Universitaire Pneumologie Physiologie Pôle Thorax et Vaisseaux Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France, Grenoble; ¹⁵Lilly Research Laboratories Japan, Kobe-shi, Japan, Kobe-shi; ¹⁶Eli Lilly & Co., Indianapolis, IN, USA, Indianapolis; ¹⁷Eli Lilly and Company, Copenhagen, Denmark, Copenhagen; ¹⁸Lilly Oncology Europe, Utrecht, Netherlands, Utrecht; ¹⁹LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, German, Grosshansdorf

Background: Dual blockade of EGFR and VEGFR pathways in EGFRm NSCLC augments anti-tumor efficacy vs EGFR inhibition alone. RELAY evaluated efficacy and safety of ERL, an EGFR TKI standard-of-care, plus RAM, a human IgG₁ VEGFR2 antagonist, or PL in 1L EGFRm metastatic NSCLC.

Materials and Methods: Eligibility included untreated metastatic NSCLC pts with Exon 19 deletion (del) or L858R and no CNS metastasis. Randomized (1:1) pts received ERL (150 mg/day) + RAM (10 mg/kg q2w) or ERL + PL, stratified by gender, geographic region (East Asia v other), EGFRm type (Ex19del v L858R) and EGFR testing method (Therascreen/Cobas v other). The primary endpoint was Investigator assessed progression free survival (PFS). Other objectives included ORR, DoR, PFS2, OS, safety, and plasma T790M mutation (Guardant NGS).

Results: 449 pts were randomized and characteristics were balanced between treatment arms: Asian 77%, Females 63%, Ex19del 54%. RAM + ERL significantly prolonged PFS, DoR, and PFS2 (Table). Grade > = 3 TEAEs were greater with RAM (72%) vs PL (54%), largely driven by hypertension (24 vs 5%, no Gr4); with 1 treatment related on study death (hemothorax) in RAM vs 0 PL. EGFR T790M + rates at progression are forthcoming.

OPEN IN VIEWER

	RAM + ERL (n = 224)	PL + ERL (n = 225)	HR (95% CI)	p-value
PFS			0.591 (0.461–0.760)	<0.0001
Median, months (95% CI)	19.4 (15.4–21.6)	12.4 (11.0–13.5)
Censoring rate	46%	30%
ORR, % (95% CI)	76.3 (70.8–81.9)	74.7 (69.0–80.3)		0.7413
Number of responders	171	168
DoR**			0.619 (0.477–0.805)*	0.0003*
Median, months (95% CI)	18.0 (13.9–19.8)	11.1 (9.7–12.3)
Censoring rate	41%	24%
PFS2			0.690 (0.490–0.972)	0.0325
Median, months (95% CI)	NR	NR
Censoring rate	73%	65%
Interim OS			0.832 (0.532–1.303)	0.4209
Median, months (95% CI)	NR	NR
Censoring rate	83%	81%

Median follow-up: 20.7 months; NR, not reached; * unstratified; **Ns are based on number of responders from the ITT population.

© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the ASCO (2019) American Society of Clinical Oncology - 55th Annual Meeting. All rights reserved.

Conclusions: RAM + ERL led to superior PFS in 1L EGFRm metastatic NSCLC. Safety was consistent with the established safety profiles of the individual compounds.

GEFITINIB PLUS VINORELBINE IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) HARBORING MUTATIONS OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)

Genova C.¹, Rossi G.², Pezzuto A.³, Valmadre G.⁴, Rijavec E.⁵, Biello F.⁶, Barletta G.⁷, Tagliamento M.⁷, Dal Bello M.G.⁷, Boccardo S.⁷, Coco S.⁷, Alama A.⁷, Sini C.⁷, Burrafato G.⁷, Maggioni C.⁷, Bennicelli E.⁷, Cerbone L.⁷, Zullo L.⁷, Ricci A.⁸, Grossi F.⁹

¹Lung Cancer Unit; IRCCS Ospedale Policlinico San Martino, Genova; ²Lung Cancer Unit; IRCCS Ospedale Policlinico San Martino, Genoa; ³Cardiovascular and Respiratory Science Department – Azienda Ospedaliera Sant’Andrea, Roma; ⁴Oncology Unit – Ospedale E. Morelli., Sondalo; ⁵Medical Oncology Unit – Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano; ⁶Oncology Unit - AOU Ospedale Maggiore della Carità, Novara; ⁷Lung Cancer Unit; IRCCS Ospedale Policlinico San Martino, Genova; ⁸Cardiovascular and Respiratory Science Department – Azienda Ospedaliera Sant’Andrea, Roma; ⁹Medical Oncology Unit – Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano

Background: Patients with advanced EGFR-mutant NSCLC are generally destined to experience disease progression in spite of initial benefit from EGFR Tyrosine kinase inhibitors (TKIs). In a preclinical study conducted within our Institution, the administration of vinorelbine followed by gefitinib resulted in increased activity due to synergistic effect of the combined drugs. Here we present the interim analysis of GEfitinib plus viNorelbine in Advanced EGFR mutated NSCLC (GENOA TRIAL), which was designed to investigate the role of oral vinorelbine followed by gefitinib for the management of treatment-naïve patients affected by EGFR-mutant NSCLC (Clinicaltrials.gov: NCT02319577).

Methods: This was an open-label, randomized phase II trial designed to explore activity and tolerability of vinorelbine followed by gefitinib compared to gefitinib alone in patients with EGFR-mutant NSCLC. The estimated enrolment was equal to 80 patients; enrolled patients were randomized (1:1) to receive oral vinorelbine (60 mg/m²) on days 1,8 followed by gefitinib (250 mg) on days 9-21 (Arm A) or gefitinib alone (250 mg) on days 1-21 (Arm B) in three-weekly cycles. The primary end-point of the study was the increase in terms of 6-month progression-free survival (PFS) rate in the experimental arm, while median PFS and median overall survival (OS) were secondary end-points.

Results: Data from 44 patients (Arm A = 23; Arm B = 21) are available for this interim analysis. All the patients had advanced lung adenocarcinoma with EGFR mutation (exon 18 = 2; exon 19 = 16; exon 21 = 21; multiple exons = 5). The 6-month PFS rate was 48% for Arm A compared to 66% for Arm B (p = 0.24). Median PFS was 6.2 months for Arm A vs. 9.5 months for Arm B (p = 0.17), while median overall survival (OS) was 18.2 months for Arm A and not reached for Arm B (p = 0.12). Response rate was 47% for Arm A vs. 55% for Arm B (p = 0.76). Severe adverse events (AEs) were similarly uncommon in both arms: two patients in Arm A experienced grade 3 white blood cells reductions, and two patients in Arm B experienced grade 3 increase of liver alanine aminotransferase. No treatment-related deaths were reported.

Conclusions: At the interim analysis of GENOA Trial, the addition of oral vinorelbine to gefitinib was not associated with increased 6-month PFS rate; similarly, no differences in terms of response, median survival or toxicity was reported. The study was interrupted on the basis of this interim analysis.

CORRELATION BETWEEN MALIGNANT PLEURAL MESOTHELIOMA TREATMENT AND GENOMIC PROFILE: UPDATE RAMES STUDY

Pagano M.¹, Zanelli F.¹, Gnoni R.¹, Bonelli C.¹, Tiseo M.², Pasello G.³, Grosso F.⁴, Garassino M.C.⁵, Soto Parra H.⁶, Zucali P.⁷, Ceresoli G.L.⁸, Torricelli F.¹, Ciarrocchi A.¹, Larocca M.¹, D’Arcangelo M.⁹, Pinto C.¹⁰

¹AUSL-IRCCS, Reggio Emilia; ²Azienda Ospedaliero-Universitaria, Parma; ³IRCCS, Padova; ⁴SS Antonio e Biagio General Hospital, Alessandria; ⁵INT, Milano; ⁶UOC, Catania; ⁷UO Humanitas Cancer Center-IRCCS, Rozzano; ⁸UO Humanitas, Gavazzeni; ⁹AUSL Romagna-Ravenna, RAVENNA; ¹⁰AUSL -IRCCS, Reggio Emilia

Background: MPM is an aggressive tumor mainly caused by asbestos exposure, with a median overall survival ranging from 12 to 18 months. Platinum/pemetrexed regimen is the standard 1°-line chemotherapy (CHT) in advanced disease.

Methods: The RAMES Study evaluated the 2°-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 pts were admitted to this study. We evaluated by NGS the mutational profile of a panel of 34 genes (gs) (ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6). We reported the results of the 103 pts (63%) of both arms with specimen available for molecular analysis. Median age was 63 years (45-81), 24.3% (n = 25) were females and 75.7% (n = 78) males. Histotype was 83.5% (n = 86) epithelioid and 16.5% (n = 17) non-epithelioid. 37.8% (n = 39) were stage IV, 60.2% (n = 62) were stage III, and 1.9% (n = 2) were unknown. In 1°-line platinum/pemetrexed CHT treated pts, the median PFS was 5.75 months (ms) (C.I. 95% 4.75-6.76). 50 pts had PFS <6 ms, while 50 pts had PFS >6 ms (n = 3 not available).

Results: 260 functional somatic mutations were identified in 28 of the 34 gs analyzed. 75pts (72.8%) displayed mutations in 1 to 3 gs while 17 pts (16.5%) showed mutations in at least 4 gs. No mutated gs were detected for 11 pts (10.7%). The number of mutated gs was positively associated with higher stage and metastatic behavior (p = 0.025) and increased 1°-line PFS (p = 0.011). RDX (42.7%), MXRA5 (23.3%), BAP1 (13.6%), PIK3CB (10.7%) and NF2 (10.7%) were the most frequently mutated gs in our pts. Mutations in RAPGEF6 (p = 0.013) and ACTG1 (p = 0.01) were associated with non-epithelioid, while mutations in BAP1 (p = 0.041) were associated with PFS >6 months. A positive trend of association was also observed between mutations in COL3A1 (p = 0.052) and NFRKB (p = 0.052) and stage IV.

Conclusions: In MPM the identification of molecular gene alterations could be an important starting point for understanding the main pathways involved in prognosis and sensitivity/resistance to therapy. In the RAMES Study, the mutation of gene BAP1 is related to a prolonged PFS at the 1°-line CHT (p = 0.041).

CRIZOTINIB IN ROS1 REARRANGED NSCLC: FINAL RESULTS OF THE METROS TRIAL

Chiari R.¹, Landi L.², Tiseo M.³, Spitaleri G.⁴, Chella A.⁵, Cortinovis D.L.⁶, Delmonte A.⁷, Novello S.⁸, Bonanno L.⁹, Grossi F.¹⁰, Gridelli C.¹¹, Galetta D.¹², Morabito A.¹³, Verusio C.¹⁴, Mazzoni F.¹⁵, Gori S.¹⁶, Barbieri F.¹⁷, Borra G.¹⁸, Fontanini G.¹⁹, Crinò L.⁷, Cappuzzo F.²

¹UOC Oncologia Ospedali Riuniti Padova Sud-AULSS 6 Euganea, Padova; ²Dipartimento di Oncologia, Azienda USL della Romagna, Ravenna; ³Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma e Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma; ⁴Divisione di oncologia Toracica, Istituto Europeo di Oncologia IRCSS, Milano; ⁵Pneumologia Universitaria, Dipartimento Cardiotoracico Vascolare, Ospedale Cisanello, Pisa; ⁶SC Oncologia Medica, SS Lung Unit Asst Ospedale San Gerardo, Monza; ⁷Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola; ⁸Dipartimento di Oncologia, Università di Torino, AOU San Luigi, Orbassano (TO); ⁹Oncologia Medica 2, Istituto Oncologico Veneto, Padova; ¹⁰Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano; ¹¹UOC Oncologia Medica, Azienda Ospedaliera S. G. Moscati, Avellino; ¹²Oncologia Medica Toracica, IRCCS Oncologico Giovanni Paolo II, Bari; ¹³Istituto Nazionale Tumori, “Fondazione G. Pascale” IRCCS, Napoli; ¹⁴SC di Oncologia Medica, PO Saronno, ASST Valleolona, Saronno; ¹⁵SC Oncologia Medica, Azienda Ospedaliera Universitaria Careggi, Firenze; ¹⁶Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar (VR); ¹⁷Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliera-Universitaria Policlinico, Modena; ¹⁸AOU Ospedale Maggiore della Carità, Novara; ¹⁹Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università di Pisa, Pisa

Background: The METROS was a phase II, non-parallel, Italian trial, specifically designed to evaluate the activity of crizotinib in two different cohorts of oncogene addicted NSCLC (cohort A=ROS1 rearranged; cohort B=MET amplified or MET Exon14 mutated). Based on positive results obtained in ROS1cohort (Landi L, et al. AIOM 2016), we emended the study to include additional patients. Here we reported results of the whole ROS1 population.

Material and methods Patients with advanced NSCLC and evidence of ROS1 rearrangements on FISH test were treated with crizotinib 250 mg BID orally until disease progression. Primary end point was objective response rate (ORR).

Results: From December 2014 to August 2018, 64 ROS1 rearranged NSCLC patients were included onto the study (N = 26 initial cohort; N = 38 expansion cohort). Median age was 55 years (28-86 years), most were females (65.5%), never/past smokers (90.6%) with ECOG PS 0 (57.8%). All but one case had adenocarcinoma histology and presented with >2 metastatic sites. The most common sites of disease were lung (92.2%), nodes (65.6%), liver (76.6%), bone (35.9%) and brain (26.6%). At data cut-off of 30 March 2019, 19 patients are still receiving treatment. ORR was 65.2%, including 2 (3.1%) complete and 41 (64.1%) partial responses. Twelve patients (18.8%) obtained a stabilization of the disease, resulting in an overall disease control rate of 86%. Depth of response, defined as the median percentage of reduction in target lesions from baseline, was -62% (IQR, -26% - -100%). With a median follow-up of 15 months (95% CI 1 – 52), median PFS was 16.5 months (95% CI 9.4-23.6), whereas median OS was 40.9 months (95% CI 23.1-58.7). Median time to response and median duration of response were 1.9 months (IQR, 1.1-37.8) and 14.9 months (95% CI 1.8 – 36.6), respectively. Safety profile of crizotinib was consistent with literature data and no new safety alert was reported.

Conclusions: Our results confirmed the marked activity of crizotinib in ROS1 rearranged NSCLC. Biomarker analyses on plasma collected at baseline and during treatment are ongoing.

CDKN2A/B GENE LOSS AND MDM2 ALTERATION AS A POTENTIAL MOLECULAR SIGNATURE FOR HYPERPROGRESSIVE DISEASE IN ADVANCED NSCLC: A NEXT-GENERATION-SEQUENCING APPROACH

Giusti R.¹, Filetti M.¹, Mazzotta M.¹, Marinelli D.¹, Scarpino S.¹, Di Napoli A.¹, Scafetta G.¹, Marchetti P.¹

¹AO Sant’Andrea- La Sapienza Università di Roma, Roma

Background: Hyperprogressive disease (HPD) incidence ranges from 8% to 21% in patients treated with anti-PD-1/PD-L1 mAbs in NSCLC and is associated with poor survival. Previously published data underlined a link between HPD across different cancers types and specific genetic alterations, such as MDM2 amplification and EGFR aberrations. We present a single-center cohort of patients with NSCLC and PD-L1>50% treated with 1st-line pembrolizumab. We performed NGS, IHC and FISH analysis to evaluate genetic correlations with the clinical phenotype.

Methods: Clinical data from 20 patients with diagnosis of advanced NSCLC treated with 1^stline immunotherapy pembrolizumab were retrospectively collected. HPD was defined by Time to Treatment Failure ⩽2 months and raising in Tumor Burden ⩾50% compared with basal CT-scan. MDM2 amplification was investigated by FISH on FFPE tissue sections using the MDM2/CON12 break apart FISH Probe. Positive cases were defined as those with >10% positive tumor cells. We performed IHC for MDM2 protein on FFPE tissue sections. The staining was semiquantitatively graded for the intensity as: 0, negative; 1+, weak positive; 2+, moderately positive; 3+, strongly positive, and for the extent as 0–<1% (negative), 1–50% (focal), and >50% (diffuse). We also performed NGS analysis (FoundationOne CDX, Foundation Medicine Inc.) on 324 preidentified genes.

Results: We identified 5 cases of HPD; all five cases showed MDM2 amplification by FISH analysis and a focal protein expression by IHC with the strongest nuclear staining observed in the cases showing a higher degree of MDM2 amplification (8/9 dots) and a weaker expression in those with a lower MDM2 amplification (4/5 dots). NGS analysis showed MDM2amplification in 1/5 HPD patient and a loss of CDKN2A/B in 4/5 patients. None of the non-HPD patients had IHC expression of MDM2 or amplification of the gene. Among the non-HPD patients no genetic alterations regarding MDM2 and/or CDKN2A/B were found on NGS analysis.

Conclusions: Our data suggest a potential role of CDKN2A/B gene loss and alteration of MDM2 on the establishment of HPD in NSCLC patients treated with immunotherapy. Because the HPD logic is not yet clear, more data is needed to better understand the link between this genomic signature and the development of HPD.

IMMUNE CHECKPOINT INHIBITORS IN THE ELDERLY WITH NON-SMALL CELL LUNG CANCER: EFFICACY AND SAFETY

Randon G.¹, De Toma A.¹, Pagani F.¹, Trevisan B.¹, Prelaj A.¹, Ferrara R.¹, Proto C.¹, Signorelli D.¹, Ganzinelli M.¹, Zilembo N.¹, De Braud F.¹, Garassino M.C.¹, Lo Russo G.¹, Galli G.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori, Milan

Background: Data about efficacy and safety of Immune Checkpoint Inhibitors (ICIs) in elderly patients (pts) with Non-Small Cell Lung Cancer (NSCLC) are scarce. However, NSCLC is often diagnosed in pts older than 70. Therefore, we aimed at investigating the topic of Immunotherapy (IO) in the elderly in a real-world case series.

Material and Methods: All consecutive pts with advanced or metastatic NSCLC treated with ICIs at Istituto Nazionale dei Tumori, Milan, between 04/2013 and 03/2019 were retrospectively reviewed. Cases were divided in the following three age classes: <70 year-old (yo), 70-79 yo, ⩾80 yo. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves.

Multivariate analyses were performed with Cox model.

Results: We identified 290 cases, whose median age was 67 (range: 29-89). The aforementioned three age classes included 180, 94 and 16 pts, respectively. IO consisted in anti-PD1 in 205 cases, in anti-PDL1 in 77 cases, in an anti-CTLA4 or in a combo-IO in 8 cases. Main clinico-pathological variables were well balanced among subgroups, except for a higher frequency of male gender (p 0.0228) and squamous NSCLC (p 0.0071) in the class 70-79 yo.

Response Rate (RR) did not show differences across subgroups (21.5% vs 22.3% vs 18.8% for pts aged<70 vs 70-79 vs ⩾80 yo, respectively; p 0.9470). Similarly, no difference was observed in median PFS (2.8 vs 3.5 vs 2.6 mos for pts aged<70 vs 70-79 vs ⩾80 yo, respectively; p 0.2020) and OS (9.1 vs 11.3 vs 9.6 mos for pts aged<70 vs 70-79 vs ⩾80 yo, respectively; p 0.9144), even after stratification according to gender (p 0.516 for PFS, p 0.5154 for OS) and histology (p 0.9057 for PFS, p 0.1002 for OS). Toxicity was comparable across age classes (grade⩾2 adverse events in 35.8% vs 32.7% vs 37.5% for pts aged<70 vs 70-79 vs ⩾80 yo, p 0.6493). At multivariate analysis, outcome was

affected by performance status (p<0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p<0.0001 for both PFS and OS), but not by age.

Conclusions: In our series, ICIs appeared safe and effective irrespective from age. Notably, with the limitation of the low number of cases, no toxicity concerns emerged even in pts aged >80. If these data were confirmed, IO should be considered as a valid treatment option for elderly pts with NSCLC, provided an adequate performance status.

SOLUBLE PROGRAMMED DEATH LIGAND-1 (SPD-L1) IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH IMMUNO-CHECKPOINT INHIBITORS

Mazzaschi G.¹, Ferri V.², Bersanelli M.¹, Cavazzoni A.², Goldoni M.², Bordi P.³, Squadrilli A.³, Buti S.³, Cosenza A.³, Ferri L.³, Rapacchi E.³, Petronini P.G.², Tiseo M.¹, Minari R.³

¹Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma; U. O. Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma; ²Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma; ³U.O. di Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma

Background: Immuno-checkpoint inhibitors (ICIs) anti-PD1/PDL-1 have demonstrated to improve patient outcome in advanced NSCLC but predict treatment benefit still remain an unsolved problem. PD-L1 tissue testing is recommended for all patients with newly diagnosed advanced NSCLC, but sometimes is not feasible and, however, still represents a snapshot not a dynamic portrait. Therefore, here, we investigate the role of soluble PD-L1 (sPD-L1) in predicting clinical outcomes of advanced NSCLC patients (pts) treated with ICIs.

Material and Methods: Levels of sPD-L1 were tested in advanced NSCLC pts treated with ICIs. Serum sample was collected at baseline and analyzed with Human/Cynomolgus Monkey PD-L1/B7-H1 Immunoassay (R&D Systems) following the manufacturer’s instruction. sPD-L1 levels were correlated with patients’ characteristics and principle outcome measures.

Results: From March 2017 to February 2019, 80 advanced NSCLC pts treated with ICIs were consecutively enrolled. Median age was 72 years (range 41-85), 65% were males, 30% never smoker and principal histology was non-squamous (65%). Lines of therapy were first (13.8%), second (66.3%), third (8.7) and above (11.2%). ICIs were nivolumab in 70% of pts, pembrolizumab in 17.5%, atezolizumab in 10% and ipilimumab-nivolumab in 2.5%. Median progression-free survival (PFS) and time to treatment failure (TTF) were both 2.4 months, while overall survival (OS) was 4.9 months. Median value of sPD-L1 was 62.8 pg/ml (range 14.8-189.8 pg/ml). No statistically significant correlation was observed between levels of sPD-L1 and disease control rate. Cox regression analysis, corrected for therapy line, shown a statistically significant inverse correlation between sPD-L1 level and OS and TTF (for both p 0.049). According to PFS and considering two opposite groups (PFS < 6 vs. > 12 months), patients with worse outcome showed higher levels of sPD-L1 (p 0.009).

Conclusions: From our preliminary results, higher level of sPD-L1 seems to be a negative prognostic factor. These results need to be investigated in a better stratified cohort for line of treatment, type of ICIs and with an adequate follow-up. In fact, survival outcome analysis were mature for PFS/TTF analysis but not for OS analysis. Despite this, sPD-L1 constitute as a promising circulating biomarker to explore.

USING PLASMA MICRORNAS AS BIOMARKERS OF RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS IN PD-L1 ⩾50% ADVANCED NSCLC

Proto C.¹, Prelaj A.¹, Verri C.¹, Signorelli D.¹, Lo Russo G.¹, Ferrara R.¹, Galli G.¹, Trevisan B.¹, Mavis M.¹, De Braud F.¹, Garassino M.C.¹, Sozzi G.¹, Boeri M.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Background: PD-L1 is the only clinically approved biomarker for cancer immunotherapy. However, a sizable proportion of PD-L1⩾50% NSCLC patients (pts) do not benefit of immune checkpoint inhibitors (ICIs). A plasma microRNA signature classifier (MSC), reflecting the immune cells switch towards an immunosuppressive profile, was able to identify NSCLC pts with worse prognosis after ICIs, irrespective of PD-L1 expression. In this work we prospectively evaluated the MSC role as biomarker of primary or secondary resistance to ICIs in PD-L1⩾50% advanced NSCLC.

Materials and Methods: Plasma samples, demographics data, baseline smoking history and ECOG PS were collected for 50 consecutive PD-L1⩾50% advanced NSCLC pts treated with ICI as first (n = 32) or further line. Using the MSC test we distinguished high (H) vs intermediate/low (I/L) risk level pts. According to RECIST 1.1 criteria, we classified pts as responders (R), pts with stable disease (SD) and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in baseline MSC risk level strata were our endpoints. Additive, not mandatory, plasma samples were collected at the time of revaluations in 26 R or SD pts with extended follow-up. Changes in the probability of progressive disease after two consecutive MSC tests, considering all possible combinations, were evaluated to determine changes in the risk level during follow-up.

Results: Out of 50 pts, 17 (34%) were R, 17 (34%) pts with SD, 11 (22%) P and 5 (10%) not evaluable pts. At baseline 11 (22%) pts showed MSC H. ORR was 0% in MSC H vs 45% in other pts (p = 0.0090). Median PFS was 2.3 vs 10.9 months in MSC H vs other pts (HR = 0.38; 95%CI = 0.17-0.84; p = 0.0174). Median OS was 2.9 vs 22.0 months in MSC H vs other pts (HR = 0.18; 95%CI = 0.07-0.47; p = 0.0004). Significance was maintained after adjusting for age, sex, pack-years and ECOG PS: PFS HR = 0.31 (95%CI = 0.13-0.73; p = 0.0072) and OS HR = 0.13 (95%CI = 0.04-0.39; p = 0.0003). Among 26 pts with longitudinal evaluation of MSC risk level, all the 12 pts progressed during ICIs showed an increase in the risk level (Sign-test p-value = 0.0039). Conversely, 9/14 (64%) pts with SD or response to ICIs at the time of the analysis, showed a decrease in the risk level (Sign-test p-value = 0.1655).

Conclusions: The MSC test may represent a useful biomarker of primary or secondary resistance in PD-L1>/ = 50% advanced NSCLC pts during ICIs. Ongoing trials are validating these results.

SHORT AND MID-TERM OUTCOMES OF MULTIMODAL TREATMENT FOR LOCALLY-ADVANCED NON SMALL CELL LUNG CANCER IN ELDERLY PATIENTS

Mazzoni F.¹, Bongiolatti S.², Di Pierro G.¹, Gonfiotti A.², Brugia M.³, Caliman E.³, Salvicchi A.², Borgianni S.², Ferrari K.⁴, Antonuzzo L.¹, Voltolini L.²

¹Medical Oncology Unit, Careggi University Hospital, Firenze; ²Thoracic Surgery Unit, Careggi University Hospital, Firenze; ³Medica Oncology Unit, Careggi University Hospital, Firenze; ⁴Pneumology Unit, Careggi University Hospital, Firenze

Background: Multimodality treatments are effective for locally advanced non-small cell lung cancer (LA-NSCLC) and have demonstrated clinical benefits in terms of overall survival (OS) and disease-free survival (DFS). Nevertheless elderly patients are often excluded to these treatment options because of fears of fatal complications.

Methods: The objectives of this single institution retrospective study were: to investigate mortality, morbidity, short and mid-term oncological outcomes of pulmonary resection after induction chemotherapy (IT) for NSCLC in elderly patients treated from June 2014 to December 2018. We divided the study population into two groups based on age at time of the treatment: patients <70 years (group A) and patients >70 years (group B). Inclusion criteria was patients who received IT (+/- radiation therapy) and subsequent pulmonary resection. The multimodal treatment was established by a multidisciplinary team. To be identify factors associated with overall morbidity, including a set of variables chosen according to clinical relevance, a multivariable logistic regression was used.

Results: 77 patients underwent pulmonary resection after IT; among these, 27 were aged >70 years. The majority of patients were classified as clinical stage IIIA in both groups. Platinum-based chemotherapy was administered to 73 patients and chemo-radiation was used more frequently in group A (24% vs 3.7%; p = 0.02). Surgical procedures were similar in both groups, although chest wall resections were more frequent in group A (20% vs 11%, p = 0.52). Pathological stage didn’t differ between the two groups and we had a total of 10 complete responses after IT.

In-hospital mortality (2% vs 0%) was similar, while the percentage of patients with complication (38% vs 48.1%, p = 0.47) and the complication rate (50% vs 77%, p = 0.01) were higher in group B, in particular we observed a significant higher incidence of atrial fibrillation (4% vs 25.9%; p<0.01) but the severity of complications was comparable between the two groups. The multivariable analysis demonstrated the absence of any significant factors associated with overall morbidity. At the median follow-up of 22 months, OS at 3 years and DFS at 2 years were not different between the two groups (61% vs 48.5% and 61.7% vs 44%).

Conclusions: Lung resection for LA-NSCLC after IT can be performed safely in appropriately selected elderly patients with favorable post-operative and mid-term oncological results.

A RANDOMISED PHASE 3 STUDY OF CARBOPLATIN + NAB-PACLITAXEL WITH OR WITHOUT ATEZOLIZUMAB AS FIRST-LINE THERAPY IN ADVANCED NON-SQUAMOUS NSCLC: IMPOWER130

Morabito A.¹, McCleod M.², Hussein M.³, Rittmeyer A.⁴, Conter H.⁵, Kopp H.⁶, Daniel D.⁷, McCune S.⁸, Mekhail T.⁹, Zer A.¹⁰, Reinmuth N.¹¹, Sadiq A.¹², Archer V.¹³, Ochi Lohmann T.¹⁴, Wang L.¹⁵, Kowanetz M.¹⁶, Lin W.¹⁷, Sandler A.¹⁷, West H.¹⁸, Cappuzzo F.¹⁹

¹Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Napoli, Italy; ²Sarah Cannon Research Institute, Florida Cancer Specialists, Fort Myers; ³Sarah Cannon Research Institute, Florida Cancer Specialists, Leesburg; ⁴Department of Thoracic Oncology, Lungenfachklinik Immenhausen, Immenhausen; ⁵Department of Medicine, William Osler Health System, Ontario; ⁶Robert Bosch Centrum für Tumorerkrankungen (RBCT), Klinik Schillerhöhe, Stuttgart; ⁷Tennessee Oncology, Chattanooga; ⁸Northwest Georgia Oncology Centers, Marietta; ⁹AdventHealth Cancer Institute, Orlando; ¹⁰Thoracic Oncology Unit, Rabin Medical Center, Tel Aviv University, Israel; ¹¹Thoracic Oncology, Asklepios Clinics Munich-Gauting, Gauting; ¹²Fort Wayne Medical Oncology and Hematology, Fort Wayne; ¹³Roche Products Limited, Welwyn Garden City; ¹⁴PD Oncology, F. Hoffmann-La Roche Ltd, Basel; ¹⁵Biostatistics, Genentech, Inc., South San Francisco; ¹⁶Oncology Biomarker Development, Genentech, Inc., South San Francisco; ¹⁷Clinical Science, Genentech, Inc., South San Francisco; ¹⁸Thoracic Oncology Program. Swedish Cancer Institute, Seattle; ¹⁹Dipartimento di Oncologia Medica, Azienda Unità Sanitaria Locale della Romagna, Ravenna

Background: Atezolizumab, a humanised anti-PD-L1 antibody, improved overall survival (OS) vs docetaxel, regardless of PD-L1 status, when administered as monotherapy in 2nd/3rd line NSCLC patients in the OAK clinical trial. IMpower130 (NCT02367781) evaluated atezolizumab + Carboplatin/nabPaclitaxel (CnP) vs CnP as first line therapy (1L) in patients (pts) with measurable (RECIST v1.1) stage IV non-squamous NSCLC.

Methods: Patients (randomised 2:1) received atezolizumab (1200 mg IV q3w) + CnP (carboplatin: AUC 6 q3w; nab-paclitaxel: 100 mg/m² IV qw) (Arm A) or CnP (Arm B), for 4 or 6 21-day cycles and maintenance (Arm A: atezolizumab until loss of clinical benefit; Arm B: best supportive care or pemetrexed q3w until disease progression [PD]). Crossover to atezolizumab at PD was initially permitted for Arm B pts. Co-primary endpoints: investigator-assessed PFS and OS (ITT-WT population: EGFR-WT/ALK-negative). Secondary endpoints: OS and PFS (ITT population and by PD-L1 expression), response rate and safety. ITT population could be formally tested for OS/PFS if ITT-WT OS was positive.

Results: Overall, 723 ITT pts (679 ITT-WT) were enrolled. A statistically significant improvement in OS was observed both in ITT-WT (18.6 mo in Arm A vs 13.9 mo in Arm B; HR: 0.79) and in ITT population (18.1 mo in Arm A vs 13.9 mo in Arm B; HR: 0.80). Furthermore, study showed statistically significant improvements in PFS, both in ITT (7.0 mo in Arm A vs 5.6 mo in Arm B; HR: 0.65) and ITT-WT (7.0 mo in Arm A vs 5.5 mo in Arm B; HR: 0.64). PFS and OS benefit was observed in all PD-L1 subgroups (OS was 17.4 mo in Arm A vs 16.9 mo in Arm B with HR 0.84 in PD-L1 high; 23.7 mo in Arm A vs 15.9 mo in Arm B with HR 0.70 in PD-L1 low; 15.2 mo in Arm A vs 12.0 mo in Arm B with HR 0.81 in PD-L1 negative) and consistently across all subgroups, except in pts with liver metastases and EGFR/ALK genomic alterations. In treated pts, 73.2% (Arm A) vs 60.3% (Arm B) had grade 3–4 treatment-related adverse events.

Conclusions: IMpower130 showed statistically significant and clinically meaningful improvements in OS and PFS with atezo + CnP vs CnP, in 1L, stage IV non-squamous NSCLC, in this predominantly ITT-WT population. No new safety signals were identified.

CLINICAL IMPLICATIONS OF RET REARRANGEMENTS IN NON-SQUAMOUS NSCLC PATIENTS: AN ITALIAN SINGLE-INSTITUTION STUDY

Marra A.¹, Belli C.², Passaro A.³, Spitaleri G.³, Guerini-Rocco E.⁴, Barberis M.⁴, Curigliano G.¹, De Marinis F.³

¹Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Department of Oncology and Haematology, University of Milan, Milano; ²Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milano; ³Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milano; ⁴Unit of Histopathology and Molecular Diagnostics, Division of Pathology, European Institute of Oncology IRCCS, Milano

Background: REarranged during Transfection (RET) gene rearrangements are described in <2% of non-small cell lung cancers (NSCLCs). The identification of RET as driver alterations in NSCLC increased its relevance as druggable target, with a growing interest to understand the implications on clinical course of NSCLC patients (pts). The aim of this study is to determine the clinical-pathological characteristics of NSCLC pts harboring RET rearrangements.

Material and Methods: We performed a retrospective, single-institution study on EGFR, ALK and ROS1 wild type, non-squamous NSCLC pts, evaluated and treated at our Institution (IEO, Milan). All pts were tested for RET by next generation sequencing (using the Oncomine™ Comprehensive Assay, Thermo Fisher Scientific) with confirmatory in situ hybridization. Data on clinical-pathological features and progression-free survival (PFS) under first line (1L) treatment were retrieved from clinical records. Demographic and clinical-pathological features [age, sex, histology, PD-L1 expression (evaluated by tumor proportion score (TPS) immunohistochemistry), stage at presentation, metastatic sites, type of treatment] were analyzed using descriptive statistics. PFS was calculated using the Kaplan–Meier method. Differences between variables were assessed by the log-rank test.

Results: Of 578 NSCLC pts screened, RET rearrangements were detected in 21 cases (3.6%). Median age was 57 years (range 37-80, IQR 18), with >80% of pts younger than 65 years. Of 21 pts, 13 (61.9%) were females and 16 (76.2%) never smokers. 17/21 (81%) of pts presented with de novo stage IV NSCLC, including 4 pts with brain metastases at diagnosis. PD-L1 expression ⩾50%, was detected in 8/21 (38.1%) pts; all these patients received 1L pembrolizumab (IO). Conversely, pts with PD-L1<50% received standard 1L chemotherapy (76.9% platinum+pemetrexed, 15.4% platinum+gemcitabine, and 7.7% gemcitabine monotherapy). PFS after therapy in the 1L setting was significantly longer for RET-rearranged NSCLC pts receiving chemotherapy compared to IO (18.5 vs 2.9 month; log-rank p<.001). No significant differences in PFS were detected in the subgroup analysis.

Conclusions: In our cohort, RET-rearranged NSCLCs were more frequent in female, younger, and non-smoker pts, confirming the current available data. In addition, our results suggest that RET-rearranged NSCLCs seem to be poorly responsive to IO. These results need to be validated in a larger prospective cohort of NSCLC pts.

DEMO SCORE: A PROSPECTIVE EVALUATION OF A PROGNOSTIC CLINICO-MOLECULAR COMPOSITE SCORE IN PATIENT WITH ADVANCED NSCLC TREATED WITH IMMUNOTHERAPY

Prelaj A.¹, Proto C.², Lo Russo G.², Signorelli D.², Ferrara R.², Galli G.², De Toma A.², Randon G.², Pagani F.², Travisan B.², Ganzinelli M.², Zilembo N.², De Braud F.², Mensah M.³, Torri V.⁴, Garassino M.C.¹, Sozzi G.³, Boeri M.³

¹Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Milano; ²Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Milano; ³Unit of Tumor Genomics, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Milano; ⁴Pharmacological Research Institute IRCSS Mario Negri, Via La Masa 19, 20156 Milano, Italy, Milano

Background: The DiMaio (D), EPSILoN (E) and plasma microRNA signature classifier (MSC), are 3 different clinico-biochemical and molecular scores able to independently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immunotherapy (IO). By assessing the ability of each test a combined score called DEMo was developed. The study aims to prospectively evaluate the prognostic value of DEMo in aNSCLC pts treated with IO.

Methods: We included in the analyses 166 aNSCLC pts treated in first (n = 47) and further-lines (n = 119) with IO at Istituto Nazionale Tumori of Milan. For all pts we obtained complete necessary data for both clinical scores: D-clinic (sex, histology, ECOG-PS stage, uses of platinum-based therapy at first-line and response to first-line) and E-biochemical (ECOG-PS, Smoke, Liver, LDH, NL-ratio). MSC (molecular score) was prospectively evaluated in plasma samples collected at baseline IO and the risk level was assessed. Endpoints were median overall survival (mOS), progression-free survival (mPFS) and overall response rate (ORR). Kaplan-Meier was used to generate survival curves and also Cox hazard model to perform multivariate analyses.

Results: In multivariate analysis adjusted accroding age, sex, smoke and ECOG-PS each score (D-E-MSC) remain independently significant for both mPFS (D: HR = 1.99, CI95% 1.21–3.03, p = 0.007; E: HR = 1.87 CI95% 1.12 – 3.10, p = 0.016; MSC: HR = 1.56, CI95% 1.03–2.37, p = 0.0370) and mOS (D: HR = 3.12, CI95% 1.80–5.41, p = 0.0001; E: HR = 2.21, CI95% 1.28–3.79, p = 0.0041; MSC: HR = 2.03, CI95% 1.30–3.17, p = 0.0019). DEMo was able to separated patients in 4 different-risk groups (grs) based on the presence of 3–2–1–0 poor prognostic scores. Strata had 0%–7%–20%–46% 18-months (mo) PFS (p<0.0001) and 0%–23%–44%–78% 18-mo OS (p<0.0001). We further combined DEMo grs 3/2 and 0/1 to perform a multivariate analysis: mPFS and mOS for grs 3/2 vs 0/1 were 2.1 vs 6.4 mo (HR = 2.06, CI95% 1.26–3.36, p = 0.0038) and 4.1 vs 20.3 mo (HR 3.17, CI95% 1.91–5.24, p<0.0001). The ORR was 2.9 (CI95% 1.4–6.0) fold lower for gr 3/2 compare to 1/0 (p = 0.0034).

Conclusions: In conclusion, we created a composite clinic- biochemical-molecular combined biomarker classifier able to better predict prognosis compared to each single score. In particular, DEMo where capable to select those patients who are less likely benefit from IO and thus could be a useful tool to guide choices in aNSCLC.

PROGNOSTIC ROLE OF CD73 IN METASTATIC NON-SMALL CELL LUNG CANCER ACCORDING TO THE PRESENCE OF DRIVER ALTERATIONS

Ferrara R.¹, Galli G.¹, Pagani F.¹, De Toma A.¹, Lo Russo G.¹, Signorelli D.¹, Prelaj A.¹, Zilembo N.¹, Ganzinelli M.¹, Brich S.¹, Fabbri A.¹, Sangaletti S.¹, Pruneri G.¹, Colombo M.P.¹, De Braud F.¹, Garassino M.C.¹, Proto C.¹

¹Fondazione IRCCS Istituto Nazionale Tumori, Milano

Background: The enzyme CD73 is responsible of the conversion of extracellular Adenosine Monophosphate (AMP) into adenosine (Ad). Ad has an inhibitory function on T lymphocytes and can thus be implicated in tumor immune escape. Few data exist about the CD73 role in Non-Small Cell Lung Cancer (NSCLC), particularly in presence of genetic drivers.

Material and Methods: All cases of metastatic NSCLC with available tumor tissue sample treated according to clinical practice at Istituto Tumori, Milan, between 2010 and 2018 were reviewed and classified according to the presence or not of a genetic driver. CD73 expression was determined by immunohistochemistry (Ab133582 ABCAM). Semiquantitative H score (HS) was calculated multiplying the membrane intensity score (0-3) by the % of stained cells to yield a value of 0–300. Median value of HS was chosen as a cutoff. A gene expression profiling was performed on NSCLC datasets from Tumor Cancer Genome Atlas (TCGA, n = 488), and cases were divided according to CD73 median level. A Cibersort analysis was performed in these series to profile the immune infiltrate.

Results: We identified 54 EGFR Mutated (EM) cases, 28 ALK Rearranged (AR) cases and 40 Wild Type (WT) cases. Median HS of these 3 subpopulations was 0, 100 and 0, respectively. Main clinical and pathological variables were well balanced between the subgroups. Although no significant differences in outcome were observed, EM cases with high HS had a trend towards a worse OS (23.4 vs 39.5 months, p.2237), while AR and WT cases with high HS had a trend towards a superior OS (53.3 vs 25.1 months, p.1263, and 59.6 vs 18.7 months, p.5063, respectively). Cibersort analysis highlighted some differences in immune cells infiltration among the CD73 high subgroups of TCGA cases: WT ones were enriched in Treg and resting Dendritic Cells (DCs), AR had abundance of M1 macrophages, EM had a reduction in activated NK cells along with an increase in activated DCs.

Conclusions: CD73expression seems to play a different prognostic role in EM, AR and WT metastatic NSCLC. Notably, the trend towards a better outcome in AR cases with high HS may find a biological rationale in the specific inflammatory infiltrate evidenced in the analysis on TCGA. Gene expression profile using nanostring platform is ongoing on our cases to confirm these findings.

INCIDENCE OF T790M IN NSCLC PATIENTS PROGRESSED TO GEFITINIB, ERLOTINIB AND AFATINIB: A STUDY ON CIRCULATING TUMOR DNA

Del Re M.¹, Petrini I.², Mazzoni F.³, Valleggi S.¹, Gianfilippo G.², Pozzessere D.⁴, Crucitta S.², Restante G.², Chella A.¹, Miccoli M.¹, Garassino M.C.⁵, Danesi R.²

¹Azienda Ospedaliero Universitaria di Pisa, Pisa; ²Università di Pisa, Pisa; ³Azienda Ospedaliero Universitaria di Firenze - Careggi, Firenze; ⁴Ospedale di Prato, Prato; ⁵Istituto Nazionale per la Cura dei Tumori, Milano

Background: Insights into the mechanism of resistance to first generation EGFR-TKIs may provide important information for further patient management, including the choice of second-line treatments. T790M is a gatekeeper mutation of the ATP binding pocket of the EGFR kinase domain and is the most common mechanism of resistance to first-generation EGFR-TKIs. Owing to its biologic relevance in the response of NSCLC to the selective pressure of treatments, the present study investigated in circulating cell-free DNA (cfDNA) if the occurrence of T790M at progression differed among gefitinib, afatinib, and erlotinib.

Methods: This study included patients with NSCLC bearing EGFR activating mutation, and given gefitinib (G), erlotinib (E) or afatinib (A) as first-line treatment. Plasma samples for the analysis of cfDNA were taken at disease progression (PD) and analyzed by a ddPCR using the ddPCR EGFR Mutation Assay. In selected cases, a rebiopsy was performed to confirm the absence of the T790M in negative plasma.

Results: A total of 83 patients were enrolled; 42 patients received G/E and 41 received A. Patients’ characteristics were comparable across the two groups. Median time to progression (TTP) was 14.4 in G/E vs 10.2 months in A group (p = 0.09). Forty-seven out of 83 patients (56.6%) were positive for the T790M in plasma. There was a higher incidence of the T790M in patients who progressed to G/E than in patients treated with A: 33 (79%) vs 14 (34%), respectively (p<0.0001, OR: 7.1, 95% CI: 2.7-18.5). To confirm the absence of the T790M, a rebiopsy was feasible in 7 patients of the G/E group and in 23 of the A group. The analysis of the cytological sample confirmed the absence of the T790M, and PI3K mutation was found in both groups in 1 patient (2%). Three patients (7%) had MET amplification in the A group. Afatinib dosage was reduced in 15 patients to 30 mg; T790M was not correlated with the dose reduction, being detectable in 6 patients who needed the reduction and in 8 who received the full standard dose (p = 0.54).

Conclusions: In conclusion, even though gefitinib, erlotinib, and afatinib belong to the same class of EGFR-TKIs,differences in the appearance of resistance mutation are demonstrated in the present study and this finding may have implications in the choice of 2nd-line treatment.

HYPERPROGRESSIVE DISEASE IN ADVANCED NON–SMALL CELL LUNG CANCER PATIENTS TREATED WITH IMMUNOTHERAPY

Lo Russo G.¹, Signorelli D.¹, Proto C.¹, Galli G.¹, Prelaj A.¹, Ferrara R.¹, Sommariva M.¹, Moro M.¹, Cancila V.², Ganzinelli M.¹, Brich S.¹, Sangaletti S.¹, Boeri M.¹, Pruneri G.¹, Tripodo C.², Colombo M.P.¹, Rivoltini L.¹, Balsari A.¹, Sozzi G.¹, Garassino M.C.¹

¹Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; ²Università di Palermo, Palermo

Background: Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).

Methods: We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 02/2019. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). All ICIs administered for ⩾2 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.

Results: We reviewed 309 cases and 268 were evaluable for response. On the basis of the clinical/radiological best response obtained, we identified four categories: responders (R, 59 cases, 22.0%), patients with stable disease (SD, 74 cases, 27.6%), progressors (P, 79 cases, 29.5%), and patients with HPD (56 cases, 20.9%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,6 vs 2,2 vs 1,5 months (p < 0.0001) and 38,9 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.551, 95% CI 2.247-2.950, p<0.0001) and OS (HR 2.525, 95%CI 2.132-2.985, p < 0.0001) confirmed the worse outcome of HPD group.

Conclusions: Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients.The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.

THE ROLE OF OPIOIDS IN PATIENTS WITH NSCLC TREATED WITH IMMUNOTHERAPY

Rinaldi S.¹, Marcantognini G.¹, Fiordoliva I.¹, Di Pietro Paolo M.¹, Morgese F.¹, Torniai M.¹, Carloni A.L.¹, Burattini M.¹, Lucarelli A.¹, Ricci G.¹, Burattini L.¹, Mazzanti P.¹, Berardi R.¹

¹Clinica di Oncologia, Università Politecnica delle Marche, Ancona

Background: Opioids seem to interfere with innate and adaptive immune response. The aim of our study is to analyse a real-world sample of advanced non-small cell lung cancer (NSCLC) patients treated with immunotherapy, focusing on the prognostic and predictive impact of opioids’ treatment.

Patients and Methods: we retrospectively analyzed data about consecutive patients treated with immunotherapy at our Institution for advanced NSCLC, between August 2015 and December 2018. Tumour response was assessed using the Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST). Progression-Free Survival (PFS) and Overall Survival (OS) were estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses.

Results: sixty-six patients were enrolled, 50 males (75,8%) and 16 females (24,2%). Median age was 72 years (range 25-88) and the majority had a good Performance Status (PS) recorded at the start of immunotherapy according to the Eastern Cooperative Oncology Group (ECOG) system (ECOG-PS <2 = 84.4%). Thirty-one patients (47%) received opioids at the beginning and/or during immunotherapy.

Patients receiving opioids had a poorer prognosis (mOS 5.37 months vs not reached, p = 0,0009; mPFS 3.83 months vs not reached, HR: 4.15, CI 95% 2.22−10.66, p = 0,0001). Elevated neutrophil-lymphocytes ratio (cut off 9,53) resulted as a negative prognostic factor (mOS 2.97 months vs not reached; p = 0.0049). Patient with ECOG-PS ⩾ 2 had a lower survival (mOS 3.23 months vs not reached, p = 0.0059; mPFS of 1.7 months vs 3.8 months, p = 0,0089). Sex, age (cut-off 70 years), smoking history, histology, lymphopenia and PD-L1 expression did not result as prognostic and predictive factors. At multivariate analysis treatment with opioids was confirmed as independent negative prognostic and predictive factor, while ECOG-PS ⩾2 as an independent negative predictive factor. Patients requiring higher opioids’ doses or opioids switch for uncontrolled pain during immunotherapy had a lower survival (mOS 4.9 vs 16.5 months; p = 0,0030). A trend of worse prognosis was observed in patients receiving morphine (mOS 4.1 vs 8.6 months, p = 0.059) and fentanyl (mOS 4.17 vs 8.63 months).

Conclusions: this study showed that opioid treatment and its escalation at the beginning and during immunotherapy are negative prognostic factors in advanced NSCLC. Need for concomitant opioid treatment could be considered for treatment choice in NSCLC patients.

NSCLC MOLECULAR PROFILE ACCORDING TO STEPWISE ALGORITHM IN MONOCENTRIC EXPERIENCE IN NORTHERN ITALY

Filippini D. M.¹, Dall’Olio F.G.¹, Conci N.¹, Fiorentino M.², Altimari A.¹, Gruppioni E.¹, Gelsomino F.¹, Casolari L.¹, Melega M.G.², Abbati F.², Massucci M.², Sperandi F.¹, Melotti B.¹, Ardizzoni A.²

¹Policlinico di Sant’Orsola, Bologna; ²Università di Bologna, Bologna

Objective: Characterizing the type and frequency of main genetic alterations in non-squamous NSCLC patients whose specimens were analyzed in our institution according to a stepwise, pragmatic algorithm that included a first screening with KRAS and EGFR mutation analysis. EGFR and KRAS wild type sample were subsequently analyzed for ALK translocations, ALK wild type tumors were analyzed for ROS 1 and, in case of “quadruple wildtype” tumors, BRAF, MET, HER2 and RET were analyzed singularly or within an NGS panel.

Materials and methods: This is a monocentric retrospective cohort study conducted at the Sant’Orsola-Malpighi University Hospital. All consecutive patients whose histological specimen were analyzed in our institution between January 2014 and November 2017 were retrospectively enrolled, and data were extracted from their clinical records.

Results: 642 patients’ specimen were included. 100% of specimen eligible according to our algorithm were analyzed for EGFR, 90.3% for KRAS, 78.5% for ALK, 58.3% for ROS1 and 19-26% for rarer molecular alterations. The analysis lead to the finding of 110 patients (17.1%) with EGFR mutations (54% exon 19, 35% exon 21), 202 (31.5%) with KRAS mutation (44.6% G12C, 19% G12V, and G12D, 16.6%), 18 (7.7%) for ALK, 7 (5.6%) for ROS1. Of the 48 specimens analyzed for rare mutations, 16 alterations were found. The number of eligible specimens excluded from subsequent analysis increased at each step of the algorithm, probably due to sample material exhaustion or clinical deterioration of patients.

Conclusions: Our study showed a prevalence of more common alteration (EGFR, KRAS and ALK) similar to those previously reported in Caucasian populations, while the stepwise algorithm lead to an higher rate of discovery of rarer ones, but also to an increasingly higher risk of dropout and, of course, to the lack of recognition of co-mutations. Upfront NGS sample analysis and data collection is ongoing.

OPEN IN VIEWER

		EGFR	KRAS	ALK	ROS1	MET ampl	MET mut	RET	BRAF	HER2
Patients eligible according to stepwise algorithm		642	642	298	216	119	119	119	119	119
Patients tested (% of eligible)		714 (100%)	580 (90.3%)	234 (78.5%)	126 (58.3%)	32 (26.7%)	28 (23.3%)	30 (25%)	27 (22.5%)	23 (19.2%)
Mutated or rearranged (% of tested)		110 (17.1%)	202 (31.5%)	18 (7.7%)	7 (5.6%)	9 (28.1%)	2 (7.1%)	3 (10%)	1 (3.7%)	1 (4.3%)
Not assessed		0 (0%)	63 (9.8%)	77 (24.4%)	83 (38.4%)	81 (68%)
Mean age (range)		66,8 years (37-90)	66,9 years (37-89)	61,7 years (40-87)	68.8 years (67-72)	63.5 years (46-79)
Sex	M	43 (32%)	126 (60%)	8 (44%)	4	5	1	1	1	1
	F	90 (68%)	85 (40%)	10 (56%)	3	4	1	2	0	0

IMMUNE-ONCOLOGY GENE EXPRESSION PROFILES ALLOW LUNG CANCER PATIENTS’ STRATIFICATION AND IDENTIFICATION OF RESPONDERS TO IMMUNOTHERAPY

Tabbò F.¹, Annaratone L.², Nocifora A.², Vignale C.², Carnio S.³, Metovic J.², Scodes S.⁴, Russo A.⁵, Franchina T.⁵, Sini C.⁶, Coco S.⁷, Garlatti P.⁸, Scotti V.⁸, Adamo V.⁵, Boccardo S.⁷, Grossi F.⁹, Cappuzzo F.⁴, Papotti M.², Righi L.¹⁰, Passiglia F.¹⁰, Novello S.¹⁰

¹Università degli Studi di Torino - Dipartimento di Oncologia, Orbassano (TO); ²Università degli Studi di Torino, Torino; ³AOU San Luigi Gonzaga, Orbassano (TO); ⁴Dipartimento Oncologia ed Ematologia, Ravenna; ⁵Università degli Studi di Messina, Messina; ⁶Ospedale di Olbia, Olbia; ⁷IRCCS Ospedale Policlinico San Martino, Genova; ⁸Ospedale universitario Careggi, Firenze; ⁹IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano; ¹⁰Università degli Studi di Torino, Orbassano (TO)

Background: Immune-checkpoint inhibitors (ICI) represent a new standard of care for Non-Small Cell Lung Cancer (NSCLC) patients. Beyond tumor PD-L1 protein expression, other biological parameters are emerging as potential predictive biomarkers. We evaluated high-throughput immune-related Gene Expression Profiles (GEP) in tumor tissue from ICI-treated patients, correlating immune activation data with clinical response to immunotherapy.

Methods: RNA was isolated from tumor tissues of 44 metastatic NSCLC patients treated with Nivolumab (as 2^nd or 3^rd line therapy) and collected from different Italian centers. The nCounter® PanCancer IO360™ Panel was applied on NanoString platform to analyze 770 genes involved in key immuno-oncology pathways. Clinical-pathological data, as well as best response to ICI treatment, have been collected.

Results: Patients were dichotomized as responders (7 Partial Response and 19 Stable Disease) and non-responders (18 Progressive Disease). A pre-identified T-cell inflamed signature was evaluated at single gene level and the expression of CCL5, CD27, CD276, CMKLR1, CXCL9, CXCR6, LAG3, NKG7, PDCD1LG2, PSMB10, TIGIT was higher in the responder group, although not reaching statistical significance. Moreover, higher STING, CGAS and IRF3 genes expression level appeared to be more commonly associated with non-responder patients.

Considering the disease stage at the time of diagnosis, a different gene panel (CCL5, CD27, CD274, CD8A, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PSMB10, TIGIT) resulted to be more expressed in early and locally advanced (16 from stage I to IIIA) compared to metastatic (28 stage IV) tissue samples.

Conclusions: A trend in differential expression patterns was observed between responders and non-responders NSCLC patients treated with Nivolumab and additional analyses on this cohort could reveal specific pathways able to predict unresponsiveness to ICI treatment. Different disease stage seems also to influence immune-related GEPs.

INFLUENZA VACCINE IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS (ICIS): A SINGLE INSTITUTION EXPERIENCE

De Toma A.¹, Lo Russo G.¹, Proto C.¹, Signorelli D.¹, Ferrara R.¹, Prelaj A.¹, Galli G.¹, Pagani F.¹, Trevisan B.¹, Zilembo N.¹, Ganzinelli M.¹, De Braud F.¹, Garassino M.C.¹

¹Fondazione IRCCS Istituto Nazionale Tumori, Milano

Background: In cancer patients we usually recommend influenza vaccination due to the risk to develop flu-complications. In these recent years immunotherapy has emerged and, right now, there aren’t clear data about recommendation of this vaccine in patients (pts) with NSCLC. Some recently published studies report controversial results about vaccine in pts treated with ICIs and a possible increase of the Immune-related Adverse Events (IRAEs).

Material and Methods: We retrospectively collected data of consecutive NSCLC pts in our institution (Fondazione IRCCS, Istituto Nazionale Tumori of Milan) treated with ICIs and who underwent influenza vaccination between September and December 2018. We selected pts subjected to inactivate influenza vaccine before or within 30 days after ICI start. The aim of our study was to collect the occurred toxicities due to flu-syndrome and IRAEs potentially related to the vaccine.

Results: Of 75 pts treated with ICIs between October 2018 and January 2019, 21 received influenza vaccine. Of those 14 pts (66.6%) were adenocarcinomas, 3 squamous carcinomas (14.3%) and 4 had other histologies (19%). Of the 21 pts, 12 received pembrolizumab (57.1%), 4 atezolizumab (19%), 4 nivolumab (19%) and 1 durvalumab (4.8%). Most were metastatic pts (95.2%); 8 were treated with ICI in 1st line (38.1%), 12 (57.1%) in 2nd or further lines and 1 as maintenance therapy for 3rd stage NSCLC (4.8%). In our cohort 6 pts (28.6%) experienced a toxicity possibly related to influenza vaccine with 1 (4.8%) death due to a pneumonitis. Other toxicities were lung infection in 2 pts (9.5%) and 2 infection of the upper respiratory track (9.5%). Only 1 patient (4.8%) develop flu infection with complete resolution.

Conclusions: In our cohort we report a substantially good safety of using influenza vaccine in pts with NSCLC treated with ICIs. Of the 6 reported toxicities reported, 5 resolved with no further consequences, whilst 1 occurred death possibly related to vaccine assumption. Safety and utility of influenza vaccine in NSCLC during treatment with ICIs remains an unanswered question and further studies with a large sample is needed to correctly assess if this vaccine gives a benefit in this kind of pts or it has even a detrimental effect.

PD-1/PD-L1 IMMUNE CHECKPOINT INHIBITORS FOR PRE-TREATED ADVANCED MALIGNANT MESOTHELIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS

Tagliamento M.¹, Bironzo P.², De Luca E.³, Pignataro D.², Rapetti S.G.², Audisio M.³, Bertaglia V.², Paratore C.², Bungaro M.², Olmetto E.², Artusio E.², Reale M.L.², Zichi C.², Capelletto E.², Carnio S.², Buffoni L.², Passiglia F.², Novello S.², Di Maio M.³

¹Dipartimento di Oncologia, Università degli Studi di Torino, AOU S. Luigi Gonzaga; Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Orbassano (TO); Genova; ²Dipartimento di Oncologia, Università degli Studi di Torino, AOU S. Luigi Gonzaga, Orbassano (TO); ³Dipartimento di Oncologia, Università degli Studi di Torino, AOU Ordine Mauriziano, Torino

Background: Despite recent advances in oncology, advanced malignant mesothelioma (aMM) still lags behind other diseases due to its rarity and modest activity of standard chemotherapy. Recently, immune checkpoint inhibitors (ICIs) directed against PD-1/PD-L1 have been tested in clinical trials in chemotherapy pre-treated aMM patients, but their efficacy is still debatable as randomized trials results are not available and single studies were characterized by small sample size.

Materials and Methods: We searched PubMed and proceedings of major meetings, to perform a systematic review and meta-analysis of clinical trials testing ICIs in this setting, describing activity in terms of Objective Response Rate (ORR) and Disease Control Rate (DCR, defined as stable disease or objective response as best response). To explore the potential predictive role of PD-L1 expression, we also collected the ORR in subgroups of patients selected for PD-L1 expression (based on the highest cut-off used in each study).

Results: 6 studies were selected (4 phase II, 2 phase IB), including 273 patients, most with pleural MM; one registry study was excluded due to inclusion of treatment-naive patients. 220 patients (80.6%) were treated with anti-PD-1 (nivolumab [N] or pembrolizumab [P]), 53 (19.4%) with anti-PD-L1 (avelumab [A]). Overall, ORR was 19.8% (95% CI, 15.5-24.9%) with no significant difference among drugs (N 22.9%, P 21.4%, A 9.4%,p = 0.10); DCR was 60.1% (95% CI, 54.2-65.7%) with no significant difference among drugs (N 57.3%, P 65.2%, A 58.5%; p = 0.48). When restricting the analysis to patients selected for PD-L1 expression (n = 91, based on cut-offs ranging from 1% to 50% in different trials), ORR was 34.1% (95% CI, 25.2-44.3%), ranging from 18.8% to 71.4% in different trials. In unselected patients, median progression-free survival ranged from 2.6 to 6.1 months, and median overall survival ranged from 10.7 to 17.3 months.

Conclusions: To our knowledge, this is the first meta-analysis synthesizing the evidence of activity of PD-1/PD-L1 ICIs in pre-treated aMM. ORR in unselected patients is encouraging compared to historical results with second-line chemotherapy, and DCR is promising. Selection based on PD-L1 expression could increase activity, but trials were heterogeneous for test and cut-off. Results of ongoing randomized trials are needed to drive more robust conclusions on the role of these agents in pre-treated aMM.

SARCOPENIA AND IMMUNOTHERAPY RESPONSE IN PRETREATED ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)

Rossi S.¹, Disconzi L.¹, Toschi L.¹, Finocchiaro G.¹, Giordano L.¹, Lanza E.¹, Lutman R.F.¹, Santoro A.¹

¹Humanitas Cancer Center, Rozzano (MI)

Background: The loss of muscle mass – named sarcopenia – is a common condition in NSCLC. Previous studies evidenced its detrimental effect on survival outcomes of patients treated with chemotherapy. This retrospective study investigates whether sarcopenia has a predictive role in immune checkpoint inhibitors (ICIs) treatment.

Patients and methods: We included 110 patients affected by advanced NSCLC treated with ICIs (pembrolizumab or nivolumab) and at least one previous line of chemotherapy. Weight and height were obtained from medical records when immunotherapy was started. Skeletal muscle index (SMI) was measured by the analysis of electronically stored computed tomography images obtained before the start of ICIs; sarcopenia was defined using gender-specific cutoffs by international consensus. Kaplan-Meier method and Log-Rank test were used to determine the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS). Exact Fisher test and Chi-squared test were used to establish the association between the presence of sarcopenia and other variables. Median follow-up time was 20.5 months, with a median OS of 10.1 months and median PFS of 3.7 months.

Results: Ninety-two out of 110 patients were sarcopenic (83.6%): 3 of them were under weight (BMI ⩽18.5), 32 overweight/obese (BMI⩾25), 57 had a normal weight. The median OS was shorter in sarcopenic when compared to non-sarcopenic patients (8.1 vs 16.2 months; p = 0.045). Overweight/obese sarcopenic patients had a trend toward a longer OS when compared to normal-weight sarcopenic patients (11.3 vs 5.6 months; p = 0.071) with an OS rate at 1 year of 49.8% vs 29.6%, respectively. A shorter PFS was found in sarcopenic compared to non-sarcopenic patients, although statistical significance was not reached (p = 0.054; PFS rate at 1 year: 15.6% vs 36.1%); no differences were found between overweight/obese and normal-weight sarcopenic patients (p = 0.214; PFS rate at 1 year: 16.2% vs 16.9%). At univariate analysis, sarcopenia was not associated to histologic subtype, fast progression during first-line chemotherapy or performance status.

Conclusions: Sarcopenia at baseline could be a predictor of worse outcome in patients with advanced NSCLC receiving ICIs.

IMMUNE GENE PROFILING AND BAYESIAN NETWORK ANALYSIS IN ADVANCED NON SMALL CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH IMMUNOTHERAPY

Baglivo S.¹, Bianconi F.², Tofanetti F.R.¹, Pistola L.¹, Siggillino A.¹, Reda M.S.¹, Martini L.¹, Colella R.³, Metro G.¹, Minotti V.¹, Fausto R.¹, Ludovini V.¹

¹Azienda Ospedaliera di Perugia - Medical Oncology, Perugia; ²Independent Researcher, Perugia; ³University of Perugia - Department of Experimental Medicine - Section of Anatomic Pathology and Histology, Perugia

Background: Immune checkpoint inhibitors (ICIs) have revoluzionized the therapeutic paradigm for different types of cancer including NSCLC. Clinical benefit, however, is limited to a minority of patients. The only adopted predictive biomarker, PD-L1 IHC testing, suffers from some limitations. A better understanding of biomarkers associated with response to ICIs is needed. Here, we studied immune gene expression profile and association with clinical response to immunotherapy in advanced NSCLC patients (pts) treated with ICI.

Material and Methods: A total of 37 Formalin-fixed, paraffin-embedded (FFPE) samples from advanced NSCLCs were analyzed by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) (ThermoFisher Scientific) to measure the expression level of 395 genes associated with 36 functional groups including checkpoint pathways, lymphocyte regulation and cytokine interactions, using the Ion Chef and Ion Torrent PGM. Gene level differential expression analysis were performed with the Torrent Suite and Transcriptome Analysis Console (TAC) 4.0 Software. Gene network analysis based on Bayesian algorithm was performed by GeneMANIA database querying with the genes selected through mRNA expression analysis

Results: Among 37 FFPE samples only 18 showed more than 300 OIRRA detectable target genes. In this subgroup, gene expression analysis revealed 7 genes (CCR2, CRTAM, FASLG, SELL, TIGIT, TNFRSF4, and TP63) up-regulated and one gene (CXCL8) down-regulated (p<0.05) in ICI-responders compare to ICI-no responders. Bayesian enrichment computational analysis of the eight gene expression signature showed a more complex network which involves other 10 genes (SIRPG, GZMK, XCL2, CD8A, CD2, IFNG, SIT1, TAGAP, PTPRC and GZMH), correlated with different functional groups. Three main immune-pathways were identified (p<0.01) (T cell activation, leucocyte activation and migration) involving TIGIT, TNFRSF4, CCR2 and CXCL8 genes among the gene expression signature identified

Conclusions: Our results revealed an immune response gene expression signature of 8 genes differentially expressed between ICI and ICI-no responders. Cancer systems biology analysis approach strengthen our findings identifying an immune molecular network and confirm the correlation of the gene expression signature with relevant immune regulatory functions. If validated, our results may have an important role for the development of a robust test to select patients properly and predict immune response to enable precision immunotherapy

LIQUID BIOPSY FOR T790M ANALYSIS IN ADVANCED EGFR-MUTATED NSCLC PATIENTS PROGRESSED TO I-II GENERATION TKI: A MULTICENTER “REAL-LIFE” RETROSPECTIVE STUDY

Minari R.¹, Alberti G.², Bordi P.¹, Altimari A.³, Gruppioni E.³, Andrini E.⁴, Parisi C.⁴, Guaitoli G.⁵, Bettelli S.⁶, Longo L.⁷, Bertolini F.⁵, Pagano M.⁸, Bonelli C.⁸, Tagliavini E.⁹, Nicoli D.¹⁰, Ubiali A.¹¹, Zangrandi A.¹¹, Trubini S.¹¹, Proietto M.¹², Gnetti L.¹³, Tiseo M.¹⁴

¹U. O. Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma; ²Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma; ³Istituto Oncologico “F. Addarii” - Policlinico S.Orsola-Malpighi, Bologna, Bologna; ⁴Alma Mater Studiorum Università di Bologna, Policlinico S.Orsola-Malpighi, Bologna; ⁵Dipartimento Oncologia ed Ematologia, AOU Policlinico Modena, Modena; ⁶S.C. Anatomia Patologica, AOU Policlinico Modena, Modena; ⁷Ospedale Ramazzini Carpi (MO) AUSL Modena, Modena; ⁸S.C. di Oncologia Medica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia; ⁹ Unità di Patologia Clinica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia; ¹⁰Unità di Biologia Molecolare, Oncologia e Tecnologie avanzate, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia; ¹¹U.O. Anatomia Patologica, AUSL Piacenza, Piacenza; ¹²U.O. Oncologia, AUSL Piacenza, Piacenza; ¹³U.O. Anatomia Patologica, Azienda Ospedaliero-Universitaria di Parma, Parma; ¹⁴Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma; U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma

Background: In advanced EGFR-mutated (EGFR+) non-small cell lung cancer (NSCLC) patients (pts), progressed to I-II generation TKI (I-II gen TKI), liquid biopsy (LB) emerged as a valid non-invasive tool to evaluate the presence of EGFR T790M as mechanism of acquired resistance. The diagnostic accuracy of circulating tumor DNA (ctDNA) in NSCLC patients progressed to prior EGFR-TKIs is associated with a wide range of concordance rate with the tumor tissue analysis. The objective of this study was to asses a “real-life” picture of EGFR T790M detection in liquid biopsy.

Material and Methods: Results of LB performed between June 2016 and October 2018 in advanced EGFR+ NSCLC pts, at disease progression (PD) to I-II gen TKIs, were evaluated retrospectively in 5 centers (Piacenza, Parma, Reggio Emilia, Modena and Bologna). All molecular procedures were performed on site, ctDNA was extracted from plasma and tested with different commercial kit (Diatech, Qiagen and Roche), all similar in term of sensibility. Analysis of detection rate and correlation with patients’ characteristics were performed.

Results: 116 advanced EGFR+ NSCLC pts underwent to LB were consecutively enrolled. Median age was 67 years, 67.2% were females, 62.1% never smoker and principal histology was adenocarcinoma (83%). Distribution of metastatic site was intra-thoracic (16.4%), extra-thoracic (28.4%) and both in 55.2% pts. Median progression-free survival to I-II gen TKI was 12 months (range: 1.1-75.3). Positivity for T790M was observed in 21 pts (18.1%) at fist LB and in 8 pts at subsequent liquid re-biopsies; the overall T790M detection rate on LB was 25%. Fifty-eight out of 87 (66,7%) LB negative pts underwent tissue re-biopsy and 55.2% pts resulted positive for T790M. The overall % of T790M in the study cohort was 50%. LB performed for clinical decision before formal PD according RECIST criteria was negative for T790M in all patients (n = 25; p 0.006). No other significant correlation was observed between distribution of metastatic site and shedding status and no sensitivity measures were possible considering that only 3 pts performed both liquid and tissue re-biopsy.

Conclusions: This retrospective study shows that the detection of T790M positive patients progressed to I-II gen TKI in “real-life” is similar to what expected according to literature data. This result is, however, obtained with an articulated clinical course, repeated liquid biopsies and tissue re-biopsy.

DIAGNOSTIC AND THERAPEUTIC CHALLENGES IN THE MANAGEMENT OF ADVANCED NON-SMALL CELL LUNG CANCER AMONG ITALIAN MEDICAL ONCOLOGISTS: A NATIONAL SURVEY

De Giglio A.¹, Orlando V.², Lamberti G.³, Ricciuti B.¹, Chiari R.⁴

¹Medical Oncology, Santa Maria della Misericordia Hospital, Perugia; ²Medical Oncology, Niguarda Cancer Center, Milano; ³Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna; ⁴Medical Oncology, Ospedali Riuniti Padova Sud, AULSS6 Euganea, Padova

Background: Molecular testing is crucial for the implementation of personalized therapy in patients with lung cancer. Whether routine biomarker testing and access to personalized therapies are limited in some Italian regions is unclear.

Methods: We conducted a national cross-sectional survey between April and May 2019 among Italian oncologists to determine differences in biomarker testing and access to personalized therapies for lung cancer. The anonymous online questionnaire included 23 items across 3 sections: demographics, diagnostics and therapeutics. Institutions with at least 2 of the following criteria were defined as referral center for the purpose of this study: ⩾50 new NSCLC patients treated/year, ⩾10 active clinical trials for NSCLC, ⩾10% patients referred from other regions.

Results: Based on GIMBE report n. 3/2018, 32 respondents (39.5%) were defined as belonging from budget deficit regions (BDRs) while 49 (60.5%) as from balanced/positive budget regions (BPRs). Respondents from thoracic oncology referral centers were 10/31 (32.3%) and 18/47 (38.3%) in the BDRs and BPRs group, respectively. At least 10% of patients were referred to an outside institution according to 28.6% and 62.5% of respondents from BPRs and BDRs respectively. Diagnostic assays for EGFR/ALK/ROS1 and PD-L1 were reported to be available in 43/47 (91.5%) and 22/30 (73.3%) centers from BPRs and BDRs, respectively (P = 0.05). 37/49 (69.4%) and 16/32 (50.0%) respondents from BPRs and BDRs, respectively, reported that molecular assessment was available in <15 days from biopsy. 80/81 (98.8%) oncologists reported that ⩾75% of eligible patients received 1^st line targeted therapies. Reason for not administering 1^st line targeted therapies was defined as clinically-unrelated (molecular testing not available or incomplete, pharmacoeconomic issues) by 28/44 (63.6%) of respondents from BPRs and 25/31 (80.6%) from BDRs (P = 0.13). Among PD-L1 ⩾50% NSCLC patients, ⩾75% were reported to receive 1^st line pembrolizumab by 32/49 (65.3%) and 16/32 (50.0%) of respondents from BPRs and BDRs, respectively (P = 0.24). Reason for not administering 1^st line pembrolizumab was defined as clinically-unrelated by 11/45 (24.4%) of respondents from BPRs and 18/31 (58.1%) from BDRs (P = 0.004).

Conclusions: Disparities in access to diagnostic assay and 1^st line immunotherapy exist between BPRs and BDRs. Implementing timely diagnostic testing and granting access to high-cost treatments represent an urgent need.

HOST METABOLIC FACTORS AND PROGNOSIS IN PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS FOR NON-SMALL CELL LUNG CANCER

Biello F.¹, Genestroni S.¹, Borra G.¹, D’Avanzo F.¹, Audisio M.², Lacidogna G.², Sponghini A.P.¹, Rondonotti D.¹, Forti L.¹, Barone-Adesi F.³, Di Maio M.², Sica A.⁴, Gennari A.⁵, Vignani F.²

¹Division of Medical Oncology, Maggiore Hospital, Novara, Italy, Novara; ²Medical Oncology, Mauriziano Hospital; Department of Oncology, University of Turin, Turin, Italy, Torino; ³Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy, Novara; ⁴Lab of Immuno-Oncology,CAAD, Center of Autoimmune and Allergic Disease, University of Eastern Piedmont, Novara, Italy, Novara; ⁵Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy, Novara

Background: An altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1).

Material and Methods: The relationship between body mass index (BMI) (normal < 25 kg/m2, overweight or obese > = 25 kg/m2) at baseline and outcome was assessed in 93 patients treated with immune checkpoint inhibitors in two cancer centers from January 2016 to May 2019. We also analized the relationship between presence of type 2 diabetes mellitus (T2DM) and outcome in the same population. Progression-free survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimator; multivariable Cox regression was performed according to age, gender and line of treatment.

Results: Median age at diagnosis was 68 years (range 47-81); sixty-nine were males (75%); forty-six (50%) patients had BMI < 25. Median PFS was 23 months in BMI > = 25 vs 12 in BMI < 25(HR 2.16; 95%CI 1.30-3.57); median OS was 39 months in BMI > = 25 vs 15 in BMI < 25(HR 2.11; 95%CI 1.21-3.67). Seventeen patients (18%) were diabetics at baseline. Median PFS was 13 months in non-diabetics vs 23 in diabetics patients (HR 0.50; 95%CI 0.26-0.98); median OS was 20 months in non-diabetics vs 34 in diabetics patients (HR 0.66; 95%CI 0.32-1.33).

Conclusions: The results of our analysis show that in patients with advanced NSCLC treated with immune checkpoint inhibitors, lower BMI is associated with a significantly worse PFS and OS, independently from, age and gender. Moreover, non-diabetics patients have worse PFS and OS.

CYCLOOXYGENASE (COX) INHIBITION IMPACTS THE EFFICACY OF FIRST LINE SINGLE AGENT PD-1/PD-L1 INHIBITORS (ICI) IN ADVANCED NON-SMALL CELL LUNG CANCER (ANSCLC) PATIENTS (pts)

Pagani F.¹, De Toma A.¹, Randon G.¹, Signorelli D.¹, Lo Russo G.¹, Proto C.¹, Prelaj A.¹, Galli G.¹, Zilembo N.¹, Ganzinelli M.¹, Sangaletti S.¹, Colombo M.P.¹, Campochiaro C.², Sica A.³, De Luca G.², Broggini M.³, Trevisan B.¹, De Braud F.¹, Garassino M.C.¹, Ferrara R.¹