Can Radiologic Tumor Size Following Neoadjuvant Therapy Reliably Guide Tissue Resection in Breast Conserving Surgery in Patients with Invasive Breast Cancer?

Abstract

Optimum tissue resection volume for patients with invasive breast cancer undergoing breast conserving surgery following neoadjuvant therapy (NAT) is not known. We compared positive margin and in-breast tumor recurrence (IBTR) between 2 groups that were created based on radiologic tumor size (RTS (cm³)) at diagnosis, RTS post-NAT, and volume of tissue resected (VTL): Pre-NAT group, patients with VTL closer to RTS at diagnosis, and post-NAT group, patients with VTL closer to post-NAT RTS. 82 patients with 84 breast cancers treated with NAT between 2007 and 2017 who had pre- and post-NAT imaging were identified from a prospectively maintained database. RTS at diagnosis, RTS post-NAT, and VTL were determined. Clinical and treatment characteristics, IBTR, and disease-free survival (DFS) were compared between pre-NAT (n = 51) and post-NAT (n = 33) groups. Compared to post-NAT patients, pre-NAT patients had smaller RTS at presentation (9.2 vs. 33.5 cm³, P < .001) and post-NAT (1.2 vs. 8.2 cm³, P = .024). At median follow-up of 4 years, there were no differences between groups in pathologic tumor size, positive margin rate, adjuvant therapy, IBTR, or DFS. Resection volumes that matched RTS on post-NAT imaging were not associated with increased positive margins or IBTR. It may be appropriate to use post-NAT imaging to guide lumpectomy volume.

Keywords

invasive breast cancer breast conserving surgery in-breast tumor recurrence

Introduction

Breast-conserving therapy (BCT) has been established as standard treatment for early-stage breast cancer patients with overall survival rates comparable to patients treated with mastectomy.^1-3 BCT is a safe option for young (20- to 39-year-old) women^4,5 and may confer an increased breast cancer-specific survival rate, although these mechanisms are not yet understood.⁶ Benefits of BCT include improved overall quality of life compared to mastectomy, increased sexual activity, body image satisfaction, and physical functioning.^7-9

Landmark trials established equivalence between neoadjuvant and adjuvant systemic therapy in disease-free and overall survival^10,11 with neoadjuvant therapy (NAT) having additional benefits providing information regarding prognosis and response to therapy.^12-14 NAT may also convert patients with inoperable disease to operative candidates and facilitate BCT in patients only eligible for mastectomy at initial diagnosis.^10,15-18

Despite the widespread clinical use of BCT following NAT, there are little data to guide the volume of tissue resection necessary for optimal oncologic outcomes. We hypothesized that the volume of tissue resected (VTL) at lumpectomy after NAT may be safely estimated by post-NAT radiologic tumor size (RTS) without increased rates of positive margins or in-breast tumor recurrence (IBTR).

Methods

Institutional review board approval was obtained. All consecutive patients with stage I-III invasive breast cancer treated with NAT from January 2007 to March 2017 who underwent BCT were identified from a prospectively maintained single institution database. Of these 121 women, 39 did not undergo repeat preoperative imaging following NAT and were excluded. The remaining 82 women who underwent 84 lumpectomies were reviewed. NAT and adjuvant agent selection were determined by the medical oncologists based on the best available data at the time of diagnosis in accordance with the standard of care or clinical trials. Patients with HER2-positive disease received HER2-targeted therapy in addition to chemotherapy. A subset of patients with estrogen- and/or progesterone-positive disease were participants in clinical trials and were treated with neoadjuvant endocrine therapy alone or in combination with chemotherapy.

Clinical tumor size at presentation and upon completion of NAT was evaluated by palpation on physical exam as well as imaging including mammogram, ultrasound, and magnetic resonance imaging (MRI) as read clinically by breast fellowship-trained radiologists, and the largest tumor diameter on any imaging modality was used to calculate the pre-NAT tumor volume with the equation: volume = (4/3) πr³.¹⁹ The total amount of tissue resected at the time of lumpectomy was calculated for each resected segment using: volume = length × width × height (cm, as measured by pathology), and the volumes of the individual segments were added.¹⁹ The 82 patients with 84 breast cancers were divided into 2 groups based on whether the VTL at lumpectomy was closer to RTS at presentation (pre-NAT, n = 51) or RTS following NAT (post-NAT, n = 33), as calculated by subtracting the VTL from the RTS at presentation and following NAT and classifying the tumor into the “pre” or “post” group based on the smallest absolute difference between VTL and RTS. Clinicopathologic factors including positive margin incidence and local and distant recurrence rates were assessed and compared between the two groups using the simple t-test, Mann-Whitney test, and chi-square test for continuous and categorical clinical variables as appropriate. The outcomes of IBTR defined as time from tissue diagnosis to ipsilateral breast recurrence, DFS, defined as the time from tissue diagnosis to any breast or axillary recurrence or death, were compared using Kaplan-Meier estimates with log-rank test comparisons.

Results

The characteristics of the tumors, disease stages, and treatments received are summarized in Table 1. The median patient age was 57 (SD 13.9, range 28-85) years. The 51 patients in pre-NAT had a palpable tumor size at diagnosis of 3.0 cm (interquartile range, IQR: 2.0; 4.0), RTS at presentation of 9.2 cm³ (IQR: 4.8; 22.4), RTS following NAT of 1.2 cm³ (IQR: .0; 4.8), and VTL of 37.8 cm³ (IQR: 21.4; 68.0). The 33 patients in post-NAT had a palpable tumor size at presentation of 3.5 cm (IQR: 2.5; 4.0), RTS at presentation of 33.4 cm³ (IQR: 22.4; 82.4), RTS following NAT of 8.2 cm³ (IQR: .0; 22.4), and VTL of 23.3 cm³ (IQR: 13.1; 90.9). Patients in pre-NAT had a significantly smaller RTS at presentation (P < .001) and post-NAT (P = .024) than patients in post-NAT.

Table 1.

Tumor and Treatment Characteristics.

	All (n = 84)	Pre-NAT (n = 51)a	Post-NAT (n = 33)b	P-value of Pre-NAT vs. Post-NAT comparison
Presenting palpable tumor diameter (cm) [IQR]	3.0 [2.0; 4.0]	3.0 [2.0; 4.0]	3.5 [2.5; 4.0]	.140
Presenting tumor volume on imaging (cm³) [IQR]	18.0 [7.2; 36.8]	9.2 [4.8; 22.4]	33.5 [22.4; 82.4]	<.001c
Clinical T stage				.200
T1 (%)	13 (15.5)	10 (19.6)	3 (9.0)
T2 (%)	56 (66.7)	35 (68.6)	21 (63.6)
T3 (%)	13 (15.5)	5 (9.8)	8 (24.2)
T4 (%)	2 (2.3)	2 (3.9)	0 (0)
Clinical N Stage				.061
0 (%)	46 (54.8)	32 (62.7)	14 (42.4)
1-3 (%)	38 (45.3)	19 (37.2)	19 (57.6)
Tumor histology				.644
Ductal (%)	79 (94.0)	47 (92.2)	32 (97.0)
Lobular (%)	5 (5.9)	4 (7.8)	1 (3.0)
Clinical response to NAT on physical exam				.504
Yes (%)	10 (11.9)	5 (9.8)	5 (15.2)
No (%)	74 (88.1)	46 (90.2)	28 (84.8)
Post-NAT tumor volume on imaging (cm³) [IQR]	2.1 [.0; 8.2]	1.2 [.0; 4.8]	8.2 [.0; 22.4]	.024c
Post-NAT pCR on imaging				.730
Yes (%)	26 (31.0)	17 (33.3)	9 (27.3)
No (%)	58 (69.0)	34 (66.7)	24 (72.3)
Volume of tissue excised (cm³) [IQR]	34.5 [18.4; 73.3]	37.8 [21.4; 68.0]	23.3 [13.1; 90.9]	.258
Tumor volume at excision (cm³) [IQR]	3.1 [.0; 65.4]	3.1 [.0; 26.5]	3.1 [.0; 113.0]	.817
Residual invasive tumor max diameter (cm) [IQR]	.9 [.0; 2.5]	.9 [.0; 1.9]	.9 [.0; 3.0]	.811
Residual DCIS max diameter (cm) [IQR]	.0 [.0; 0.8]	.0 [.0; 0.5]	.0 [.0; 2.0]	.833
Pathologic pCR				.482
Yes (%)	33 (39.3)	18 (35.3)	15 (45.5)
No (%)	50 (60.7)	33 (64.7)	18 (54.5)
Margin status				.699
No invasive disease or DCIS (%)	68 (81.1)	40 (78.4)	28 (84.8)
Invasive disease or DCIS at margin (%)	16 (18.9)	11 (21.6)	5 (15.2)
Adjuvant therapy received
Radiation (%)	77 (93.9)	48 (96.0)	29 (90.6)	.374
Chemotherapy (%)	9 (11.0)	6 (12.2)	3 (9.1)	.734
Endocrine therapy (%)	48 (59.3)	28 (57.1)	20 (62.5)	.804

Abbreviations: DCIS, ductal carcinoma in-situ; NAT, neoadjuvant therapy; pCR, pathologic complete response.

pathologic tumor volume closer to radiographic tumor volume at presentation.

pathologic tumor volume closer to radiographic tumor volume post-NAT.

significant P-value defined by P ≤ .05.

IBTR and DFS results are summarized in Table 2. Patients were followed up for a median of 46.3 months before death or loss to follow-up. There were no differences between the groups in rate of positive margins, biomarker profile, pathologic tumor size (including invasive carcinoma and ductal carcinoma in-situ [DCIS]), presence of clinical tumor response on physical exam after NAT, clinical pathologic complete response on post-NAT imaging, pathologic complete response, nodal status, receipt of adjuvant chemotherapy, endocrine therapy, HER2-directed therapy, or radiation therapy, IBTR, or DFS. Across the entire cohort, the pathologic tumor maximum diameter (hear rate [HR] 1.4, CI 1.1-1.9, P = .011) was predictive of IBTR on univariable analysis; pathologic tumor maximum diameter (HR 1.2, CI 1.0-1.5, P = .018) and extent of DCIS at resection (HR 1.6, CI 1.0-2.4, P = .047) were predictive of DFS on univariable analysis.

Table 2.

Univariable Analysis Using Cox Proportional Hazards Model Assess Factors Associated with IBTR and DFS.

	IBTR		DFS
	HR [95% CI]	Log P value	HR [95% CI]	Log P value
Presenting palpable tumor diameter (cm)	1.35	.115	1.15 [.89, 1.48]	.292
Presenting tumor volume on imaging (cm³)	1.00 [.99, 1.01]	.605	1.00 [.99, 1.01]	.407
Clinical T stage
T1	Ref		Ref
T2	2.40 ×10⁸ [0, inf]	.999	2.64 ×10⁸ [0, inf]	.998
T3	4.54 ×10⁸ [0, inf]	.999	2.37 ×10⁸ [0, inf]	.998
T4	.99 [0, inf]	1.000	.99 [0, inf]	1.000
Clinical N Stage
0	Ref		Ref
1-3	1.12 ×10⁹ [0, inf]	.998	No events
Clinical response to NAT on physical exam
Yes	.41 [.4, 4.00]	.443	.41 [.11, 1.50]	.176
No	Ref		Ref
Post-NAT tumor volume on imaging (cm³)	1.00 [1.00,1.02	.582	1.00 [.99, 1.01]	.759
Post-NAT pCR on imaging
Yes	.35 [.42, 2.93]	.334	.41 [.9, 1.87]	.248
No	Ref		Ref
Volume of tissue excised (cm³)	1.00 [.99, 1.02]	.477	1.00 [.99, 1.01]	.574
Residual invasive tumor max diameter (cm)	1.43 [1.10, 1.87]	.011a	1.24 [1.04, 1.48]	.018a
Residual DCIS max diameter (cm)	1.49 [.60, 3.74]	.395	1.56 [1.00, 2.43]	.047a
Pathologic pCR
Yes	.00 [.00, Inf]	.99	.13 [.02, 1.02]	.052
No	Ref		Ref
Margin status
No invasive disease or DCIS	Ref		Ref
Invasive disease or DCIS at margin	4.11 [.57,29.51]	.159	.97 [.21, 4.49]	.965
Adjuvant therapy received
Radiation	1.31x10⁷ [.00, Inf]	.999	.28 [.05, 1.00]	.050
Chemotherapy	2.05 [.21, 19.95]	.54	1.39 [.30, 6.39]	.671
Endocrine therapy	1.75 [.18, 16.82]	.628	.61 [.20, 1.89]	.392

Abbreviations: DCIS, ductal carcinoma in-situ; DFS, disease-free survival; HR, heart rate; IBTR, in-breast tumor recurrence; pCR, pathologic complete response.

significant P-value defined by P ≤ .05.

Discussion

BCT is commonly performed following NAT, but there is little evidence to guide the amount of tissue resection needed in patients who have responded to therapy. The current study found no differences in positive margin rate, IBTR, or DFS in patients undergoing BCT who were divided into groups where VTL was closer to RTS at presentation or where VTL was closer to RTS post-NAT. This implies that post-NAT RTS may be used to guide the volume of tissue resection at the time of lumpectomy surgery in patients who have received and responded to NAT.

Two single-institution studies^20,21 found significantly smaller volumes of tissue removed in patients who underwent NAT than in patients who were treated with surgery first. In a comparison of surgical outcomes between NAT and adjuvant chemotherapy, Komenaka et al²⁰ found that while the 57 patients treated with NAT were significantly younger (67% vs. 45% < 50 years old) and had larger tumors at presentation (4.6 cm vs. 3.3 cm) than the 155 patients treated with adjuvant chemotherapy, the NAT group compared to the adjuvant chemotherapy group had half the rate of close or positive margins (23% vs. 46%; P = .04) and a smaller volume of tissue removed (143.6 cm³ vs. 273.9 cm³; P = .003) without a significant difference in ipsilateral breast tumor recurrence rate. Both groups had greater VTL and a higher rate of positive margins than the patients in our study. Karanlik et al²¹ found that within a group of 251 consecutive patients with stage T2 breast cancer, the 110 patients treated with NAT followed by surgery had a lower incidence of positive margins (5% vs. 16%; P = .02) and smaller excision volumes (132.2 cm³ vs. 158.1 cm³; P = .04) without a difference in 5 year local-regional recurrence rate compared to patients treated with primary surgery followed by chemotherapy, despite the NAT group having significantly larger tumors at presentation. These findings and our study suggest that NAT allows resection of smaller tissue volumes which does not appear to result in higher positive margin rates. Conversely, Tiezzi²² reported larger volumes of tissue resected in 88 patients treated with NAT compared to 191 patients treated with breast conserving surgery initially (108 cm³ vs. 78 cm³; P = .002), despite the NAT group having smaller mean tumor diameters (1.6 cm vs. 1.9 cm; P = .01) at the time of surgery. The NAT group had more advanced disease with larger tumors at presentation, suggesting surgeon-based resection volumes on pre-NAT tumor size not post-NAT residual tumor volume.

One report²³ estimated optimum excision volume using the volume of tumor mass resected with the addition of a 1 cm margin based on prior studies demonstrating that malignant breast cancer cells rarely extend more than 1 cm from the primary tumor.²⁴ The actual volume resected was divided by the optimal volume to calculate a resection ratio representing the excess volume of resected tissue. They compared 191 patients who underwent upfront BCT for early-stage disease (including stage I, IIA, and IIB with tumor ≤ 3 cm) with patients who achieved partial or complete response (no tumor >3 cm) after NAT for locally advanced disease (stage IIa with tumors ≥ 3 cm, IIb excluding T2N1M0 with tumor ≤ 3 cm), and III) and found a significantly greater resection ratio in the locally advanced group with no difference in tumor volume at the time of resection or rate of positive margins. This suggests surgeons tend to resect larger volumes even after downstaging with NAT. Our data suggest that this practice may not be necessary, as we found equivalent rates of positive margins, IBTR, and DFS between groups where VTL resembled the pre-NAT RTS and where VTL resembled the post-NAT RTS. The question regarding safety of resecting reduced tissue volumes is particularly pertinent to patients who have a pathologic complete response (pCR) following NAT, and a clinical trial is underway to investigate the safety of even eliminating surgery completely in these patients.²⁵

Limitations of this study include a sample size of fewer than 100 patients, inherent selection bias in the retrospective study design, and limited follow up for survival calculations. There is also variation in the imaging modalities used to estimate radiographic tumor size and interobserver variability in RTS reporting. Nonspherical tumor volumes may have led to overestimates of tumor size using the spherical volume calculation, and the effects of fixation may have altered the measured lumpectomy specimen dimensions and subsequently calculated volumes. Patients who had a pCR were included with a residual tumor volume of 0 cm in the described calculations; therefore, these patients were included in both groups and not analyzed separately from patients with residual disease. There were a limited number of recurrence events which impacted the IBTR and DFS estimates.

Conclusion

Lumpectomy resection volumes that matched RTS on post-NAT imaging were not associated with an increased incidence of positive margins or increased IBTR, suggesting it is safe and appropriate to use post-NAT imaging to guide the VTL at lumpectomy for patients undergoing BCT after a response to NAT.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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