This phase 3 randomized clinical trial assesses the role of neoadjuvant systemic therapy in conversion from ineligibility to eligibility for breast-conserving therapy and to assess the association of response to therapy, germline BRCA status, and region of treatment with surgical choice in women with triple-negative breast cancer.
Key Points
Question
How often does neoadjuvant systemic therapy facilitate breast conservation in women with triple-negative breast cancer?
Findings
This prespecified secondary analysis of a randomized clinical trial of 604 women with stages II to III triple-negative breast cancer demonstrates that neoadjuvant systemic therapy made breast conservation possible in 53.2% of patients who would have otherwise required mastectomy, increasing the percentage of those eligible for breast conservation from 76.5% at diagnosis to 83.8%. Rates of pathologic complete response were similar between patients deemed eligible for breast conservation before and those who converted to eligibility after neoadjuvant systemic therapy.
Meaning
Based on these findings, women with triple-negative breast cancer who are not candidates for breast conservation at presentation should be counselled that there is a 50% likelihood they will become candidates after neoadjuvant systemic therapy.
Abstract
Importance
Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer.
Objectives
To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC).
Design, Setting, and Participants
This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019.
Interventions
Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide.
Main Outcomes and Measures
Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed.
Results
Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38).
Conclusions and Relevance
This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation.
Trial Registration
ClinicalTrials.gov identifier: NCT02032277
Introduction
Neoadjuvant systemic therapy (NST) has traditionally been used to convert patients with unresectable, locally advanced breast cancer to candidates for surgery. More recently, the role of NST has expanded to facilitate breast-conserving therapy (BCT) in patients with large, operable breast cancer who would otherwise require mastectomy.1,2,3,4,5 A meta-analysis of 10 studies including 4756 women reported an increase in BCT from 49% to 65% in patients randomized to neoadjuvant as opposed to adjuvant chemotherapy.6 However, few prospective clinical trials to date have incorporated standardized patient assessments to estimate the success of NST in converting BCT-ineligible patients to BCT eligibility. In addition, little prospective data assess how preoperative genetic testing influences a patient’s decision to undergo BCT vs mastectomy and whether preoperative assessment of BCT eligibility correlates with pathologic complete response (pCR).
Triple-negative breast cancer (TNBC) is characterized by the absence or minimal expression of estrogen receptor, progesterone receptor, and ERBB2 (formerly human epidermal growth factor receptor 2 [HER2]), with no amplification of the ERBB2 gene (OMIM 164870). At least one-third of patients with stages II and III TNBC achieve a pCR after anthracycline- and taxane-based NST regimens.7,8,9 Triple-negative breast cancer also has increased sensitivity to DNA-damaging agents, such as alkylating agents and platinum analogues such as carboplatin, with cytotoxicity that may be enhanced by administration of agents that interfere with DNA repair, such as poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitors.10,11,12,13 Patients with TNBC who obtain a pCR have markedly superior event-free and overall survival compared with patients with residual invasive disease after the same treatment; thus, achievement of pCR is often used as a surrogate end point in clinical trials.14 As such, at the recent St Gallen consensus conference, NST was deemed the preferred treatment option for patients with TNBC irrespective of tumor diameter and axillary nodal involvement.15
BrighTNess was a multinational phase 3 randomized clinical study of NST in TNBC whose primary end point, pCR, and safety analysis have been previously reported.16 Planned secondary analyses included the rate of conversion from BCT ineligible to BCT eligible in women treated with NST, the results of which are reported herein along with evaluation of the association of germline BRCA (gBRCA) testing results and region of treatment (North America, Europe, or Asia) with surgical decision-making.
Methods
Study Design and Participants
The BrighTNess trial is a 3-arm, multicenter, phase 3, double-blind, placebo-controlled randomized clinical trial that enrolled women with operable, clinical stages II and III (T2-T4 N0-N2 or T1 N1-N2) TNBC at 145 centers in 15 countries. The following cooperative groups participated: German Breast Group, the Alliance for Clinical Trials in Oncology, National Surgical Adjuvant Breast and Bowel Project, Spanish Breast Cancer Group, Austrian Breast & Colorectal Cancer Study Group, and US Oncology. Patients 18 years or older with biopsy-confirmed disease were eligible, with TNBC defined on core needle biopsy results as estrogen receptor and progesterone receptor expression of less than 1% and ERBB2 negativity by immunohistochemical staining of 0 to 1+ or, if immunohistochemical staining was 2+ or not performed, a fluorescence in situ hybridization ratio of less than 2.0. This study was approved by the institutional review board at each study site. Each participant signed an institutional review board–approved, protocol-specific informed consent in accordance with national and institutional guidelines. The trial protocol is available in Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
All patients were intended to receive 12 weeks of weekly paclitaxel followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide. Patients were randomized in a 2:1:1 ratio to 1 of 3 treatment arms: paclitaxel with carboplatin and the oral PARP inhibitor veliparib; paclitaxel with carboplatin and an oral placebo; or paclitaxel with intravenous and oral placebos. Details of the treatment regimens and the study design have been previously reported.16 Stratification factors included gBRCA mutation status, clinical lymph node status, and schedule of adjuvant chemotherapy administration (every 2 or every 3 weeks).
Procedures
Baseline breast imaging, including mammography and magnetic resonance imaging, was mandated for all patients. Ultrasonography was strongly encouraged but not mandatory. All patients underwent clinical axillary lymph node examination and pre-NST axillary staging with ultrasonography and fine-needle aspiration or core biopsy with placement of a clip in sampled nodes with suspicious features, when feasible. Pretreatment sentinel node biopsy was not allowed. Germline BRCA mutation testing was mandated for study stratification, with results available to patients and physicians before initiating NST. The treating breast surgeons assessed eligibility for BCT by clinical examination and imaging results before treatment initiation and again at a preoperative visit after completion of NST. Baseline magnetic resonance imaging scans were performed no more than 28 days before initiation of therapy and repeated after 12 weeks of therapy, when they were evaluated for tumor morphology, relative enhancement, and tumor extent during initial and late enhancement. The decision to attempt BCT or to perform unilateral or bilateral mastectomy was at the discretion of the treating surgeon and patient. Multiple excisions in the setting of multicentric disease were permitted for those desiring BCT. Sentinel node biopsy and/or axillary lymph node dissection was required at the time of definitive local therapy. Patients with clinically node-negative findings before NST could undergo sentinel node biopsy or axillary lymph node dissection. In those with node-positive findings before NST, axillary lymph node dissection was recommended, although sentinel node biopsy could be considered in the setting of clinical complete nodal response (ycN0). Surgery was to occur 4 to 8 weeks after the patient’s last dose of chemotherapy.
Outcomes
The primary outcome measure for the study was pCR, defined as no residual invasive disease (with or without ductal carcinoma in situ) in the breast and lymph nodes (ypT0/isN0), the results of which have been previously reported along with details on BCT eligibility by neoadjuvant treatment arm.17 Secondary outcome measures reported herein include the rate of eligibility for breast conservation before and after completion of NST, the final surgical procedure performed, and pCR rates in strata defined by BCT eligibility and choice of surgery.
Statistical Analysis
Data were analyzed from January 5, 2018, to October 28, 2019. For this analysis, data from all study arms were combined and analyzed jointly. Eligibility for BCT was scored as yes or no and based on the opinion of the patient’s breast surgeon. The rate of conversion to BCT candidacy was calculated as the number of patients whose BCT eligibility assessment changed from ineligible before NST to eligible after NST, divided by the number of patients who were ineligible before NST. We also sought to determine the BCT rate in patients deemed BCT eligible at baseline and after completion of NST, those considered BCT ineligible at baseline who converted to BCT eligibility after NST, and those who were persistently BCT ineligible after NST by gBRCA mutation status and by region of treatment (North America vs Europe and Asia). Multivariate logistic regression was used to determine whether region was significantly associated with BCT after adjusting for a set of clinically significant baseline characteristics. The adjusted odds ratio and 95% CIs were estimated from the model, and significance was determined by the Wald χ2 value. Proportions and their respective 95% CIs (based on a normal approximation) were calculated, and proportional differences between groups were compared using the Pearson χ2 test. The data cutoff for this report was December 8, 2016. Analyses were performed using SAS, version 9.2 (SAS Institute, Inc). Two-sided P < .05 indicated significance.
Results
From April 1, 2014, through March 30, 2016, BrighTNess randomized 634 patients to its 3 treatment arms (Figure 1). Patient and tumor characteristics are displayed in Table 1 and by region in Table 2. Among these, 501 patients (79.0%) had clinical stage II disease and 108 (17.0%) had clinical stage III disease. The median age of patients enrolled was 51 (range, 22-78) years. Findings in 85 patients (13.4%) were positive for gBRCA mutation.
Figure 1. CONSORT Flow Diagram.
BCT indicates breast-conserving therapy; NST, neoadjuvant systemic therapy.
Table 1. Baseline Cohort Characteristics.
| Characteristic | No. (%) of Patients (n = 604)a |
|---|---|
| Age at TNBC diagnosis, y | |
| ≤50 | 297 (49.2) |
| >50 | 307 (50.8) |
| Race/ethnicity | |
| White | 461 (76.3) |
| African American | 54 (8.9) |
| Asian | 86 (14.2) |
| Other/unknown | 3 (0.5) |
| Smoking status | |
| Current | 83 (13.7) |
| Former | 106 (17.5) |
| Never | 397 (65.7) |
| Unknown | 18 (3.0) |
| gBRCA status | |
| Deleterious mutation | 85 (14.1) |
| No mutation | 519 (85.9) |
| Clinical T category | |
| cT1 | 69 (11.4) |
| cT2 | 432 (71.5) |
| cT3/T4a | 103 (17.1) |
| Nodal status | |
| N0 | 354 (58.6) |
| N1-N2 | 250 (41.4) |
| Histologic grade | |
| High | 362 (59.9) |
| Intermediate | 124 (20.5) |
| Low | 35 (5.8) |
| Unknown | 83 (13.7) |
| Planned schedule of adjuvant chemotherapyb | |
| Every 2 wk | 340 (56.3) |
| Every 3 wk | 264 (43.7) |
| ECOG performance statusc | |
| 0 | 537 (88.9) |
| >0 | 67 (11.1) |
Abbreviations: ECOG, European Cooperative Oncology Group; gBRCA, germline BRCA mutation; TNBC, triple-negative breast cancer.
Percentages have been rounded and may not total 100.
Consists of doxorubicin hydrochloride and cyclophosphamide.
Scores higher than 0 range from restrictions to death.
Table 2. Comparison of Geographical Cohorts in North America and in Europe and Asia.
| Characteristic | Regiona | P Value | |
|---|---|---|---|
| North America (n = 281) | Europe and Asia (n = 323) | ||
| Age at TNBC diagnosis, mean (SD), y | 51.7 (11.79) | 49.1 (11.12) | .005 |
| Race/ethnicity | |||
| White | 219 (77.9) | 242 (74.9) | .39 |
| African American | 52 (18.5) | 2 (0.6) | |
| Asian | 7 (2.5) | 79 (24.5) | |
| Other/unknown | 3 (1.1) | 0 | |
| Smoking status | |||
| Current | 36 (12.8) | 47 (14.6) | <.001 |
| Former | 72 (25.6) | 34 (10.5) | |
| Never | 169 (60.1) | 228 (70.6) | |
| Unknown | 4 (1.4) | 14 (4.3) | |
| gBRCA status | |||
| Deleterious mutation | 35 (12.5) | 50 (15.5) | .29 |
| No mutation | 246 (87.5) | 273 (84.5) | |
| Clinical T category | |||
| cT1 | 37 (13.2) | 32 (9.9) | .78 |
| cT2 | 197 (70.1) | 235 (72.8) | |
| cT3/T4a | 47 (16.7) | 56 (17.3) | |
| Nodal status | |||
| N0 | 163 (58.0) | 191 (59.1) | .78 |
| N1-N2 | 118 (42.0) | 132 (40.9) | |
| Surgical management | |||
| BCT | 131 (46.6) | 215 (66.6) | <.001 |
| Unilateral mastectomy | 47 (16.7) | 83 (25.7) | |
| Bilateral mastectomy | 101 (35.9) | 20 (6.2) | |
| Mastectomy NOS | 2 (0.7) | 5 (1.5) | |
Abbreviations: BCT, breast-conserving therapy; gBRCA, germline BRCA mutation; NOS, not otherwise specified; TNBC, triple-negative breast cancer.
Unless otherwise indicated, data are expressed as number (percentage) of patients. Percentages have been rounded and may not total 100.
Complete surgical data are available for 604 patients. Overall, 346 patients (57.3%) underwent BCT, and 258 (42.7%) underwent mastectomy. Data from surgical assessments of BCT candidacy were available for 599 patients before NST and for 604 patients after NST. Before NST, 458 patients (76.5%) were considered eligible for BCT and 141 (23.5%) were deemed ineligible for BCT on the basis of tumor size (92 [65.2%]), tumor location (33 [23.4%]), and multicentric disease (14 [9.9%]). For 2 patients (1.4%), the reason for BCT ineligibility was not available. Of patients considered BCT eligible at baseline, 425 (92.8%) remained eligible after NST, of whom 300 (70.6%) underwent BCT (Figure 2). Of patients considered BCT ineligible at baseline, 75 (53.2%) were converted to BCT eligibility after treatment, of whom 42 (56.0%) underwent BCT. Administration of NST therefore increased the absolute number of BCT-eligible patients from 458 (76.5%) to 502 (83.8%), of whom 342 (68.1%) underwent BCT.
Figure 2. Candidacy for Breast-Conserving Therapy (BCT) Before and After Completion of Neoadjuvant Systemic Therapy (NST).
pCR indicates pathologic complete response.
In the 141 patients initially deemed ineligible for BCT, no specific treatment arm was associated with improved BCT eligibility after NST; 15 of 34 patients in the paclitaxel alone arm (44.1%) became eligible after NST, compared with 15 of 34 (44.1%) in the paclitaxel with carboplatin arm and 45 of 73 (61.6%) in the paclitaxel with carboplatin and veliparib arm (P = .11). In the 460 patients deemed eligible for BCT at baseline, there was a significant difference in progression to non-BCT status across treatment arms; 12.8% of patients receiving paclitaxel alone progressed to BCT ineligibility, compared with only 5.0% of patients in the paclitaxel with carboplatin arm and 4.8% of patients in the paclitaxel with carboplatin and veliparib arm (P = .01).
Among 519 patients without a deleterious gBRCA mutation, 436 (84.0%) were judged eligible for BCT after NST, of whom 326 (62.8%) opted for the procedure. In the 193 women who underwent mastectomy, 83 (43.0%) underwent bilateral mastectomies. However, these percentages varied significantly depending on where the patient received treatment. Two hundred fourteen (79.6%) of eligible patients in Europe and Asia chose BCT, compared with 131 (55.0%) in North America. The BCT rate in patients without a pathogenic BRCA mutation who were considered BCT eligible after NST treated in North America was 61.0% (n = 209), whereas the BCT rate in this subgroup of patients treated in Europe and Asia was 86.1% (n = 230; P < .001). Among patients undergoing mastectomy, 57 of 81 (70.4%) of those treated in North America underwent bilateral mastectomies, compared with 6 of 30 (20.0%) of those treated in Europe or Asia (P < .001). Table 3 shows eligibility and receipt of BCT according to germline mutation status and geographic region of treatment.
Table 3. Surgical Therapy by Eligibility for BCT, Stratified by gBRCA Mutation Status and Geographic Region of Treatmenta.
| Patient Group | BCT Eligibility After NST | |||||||
|---|---|---|---|---|---|---|---|---|
| Eligible (n = 507) | Ineligible (n = 97) | |||||||
| No. of Patients | BCT | Mastectomy | CPMb | No. of Patients | BCT | Mastectomy | CPMc | |
| All | 507 | 345 (68.0) | 162 (32.0) | 94 (59.1) | 97 | 1 (0.1) | 96 (99.0) | 27 (29.3) |
| North America | 238 | 131 (55.0) | 107 (45.0) | 80 (75.5) | 43 | 0 | 43 (100) | 21 (50.0) |
| Europe and Asia | 269 | 214 (79.6) | 55 (20.4) | 14 (26.4) | 54 | 1 (1.9) | 53 (98.1) | 6 (12.0) |
| gBRCA negative status | 436 | 322 (73.9) | 114 (26.2) | 63 (56.8) | 80 | 1 (1.3) | 79 (98.8) | 20 (26.7) |
| North America | 209 | 127 (60.8) | 82 (39.2) | 57 (70.4) | 37 | 0 | 37 (100) | 16 (44.4) |
| Europe and Asia | 230 | 198 (86.1) | 32 (13.9) | 6 (20.0) | 43 | 1 (2.3) | 42 (97.7) | 4 (10.3) |
| gBRCA positive status | 68 | 20 (29.4) | 48 (70.6) | 31 (64.6) | 17 | 0 | 17 (100) | 7 (41.2) |
| North America | 29 | 4 (13.8) | 25 (86.2) | 23 (92.0) | 6 | 0 | 6 (100) | 5 (83.3) |
| Europe and Asia | 37 | 16 (41.0) | 23 (58.9) | 8 (34.8) | 11 | 0 | 11 (100) | 2 (18.2) |
Abbreviations: BCT, breast-conserving therapy; CPM, contralateral prophylactic mastectomy; gBRCA, germline BRCA mutation; NST, neoadjuvant systemic therapy.
Unless otherwise indicated, data are expressed as number (percentage) of patients. Percentages are based on row totals.
Laterality unknown in 3 BCT-eligible cases with gBRCA-negative status. Based on number undergoing mastectomy.
Laterality unknown in 4 BCT-ineligible cases with gBRCA-negative status. Based on number undergoing mastectomy.
Among 85 patients with a documented deleterious gBRCA mutation, 68 (80.0%) were eligible for BCT after NST, of whom 20 (23.5%) opted for BCT. Sixty-five patients (76.5%) chose mastectomy, of whom 38 (58.5%) underwent bilateral mastectomies. One hundred fourteen patients with findings negative for a gBRCA mutation underwent mastectomy. These results also differed significantly by region of treatment. In North America, 4 of 29 patients with gBRCA (13.8%) who were BCT eligible after NST underwent BCT, and 23 of 25 (92.0%) opting for mastectomy underwent bilateral mastectomies. In contrast, 16 of 37 post-NST BCT eligible patients (41.0%) with gBRCA mutation treated in Europe or Asia underwent BCT, with 8 of 23 (34.8%) of those opting for mastectomy undergoing bilateral mastectomies. In an adjusted analysis controlling for clinically significant baseline factors including age, gBRCA status, tumor size, and smoking history, world region remained significantly associated with BCT, with women in Europe and Asia 2.7-fold more likely to receive conservative surgery relative to those in North America (odds ratio, 2.66; 95% CI, 1.84-3.84; P < .001).
In the 425 patients who were BCT eligible before and after NST, the pCR rate was 55.3% (235 of 425), and the pCR rate was similar between eligible patients who chose BCT vs those who chose mastectomy (55.0% [n = 165] vs 52.8% [n = 66]; P = .72) and not significantly different from the pCR rate in women who converted from BCT ineligible to BCT eligible after NST (49.3% [n = 37]; P = .38). The pCR rate in the 66 patients who remained BCT ineligible after NST was 36.4% (n = 24; P = .12) and was 32.3% (n = 10) even in 31 patients deemed BCT eligible at baseline who were reclassified as BCT ineligible after NST (Figure 2).
Discussion
Surgical results from the BrighTNess trial demonstrate that neoadjuvant chemotherapy makes breast conservation possible in half of patients with stages II to III TNBC who would have otherwise required mastectomy, increasing the overall percentage of those eligible for BCT from 76.5% at diagnosis to 83.8% after NST. However, only two-thirds of those eligible for breast conservation opted for this surgical approach; in BrighTNess, many BCT-eligible women—including 114 (26.0%) of those with negative test results for a deleterious gBRCA mutation—still underwent mastectomy. There was, however, significant geographic variation in this finding, with women in North America eligible for BCT more likely to undergo unilateral or bilateral mastectomy relative to comparable women treated in Europe and Asia. Of interest, the pCR rate was similar between women considered BCT eligible throughout treatment and those ineligible for BCT at baseline who converted to eligible candidates after treatment. In addition, pCR was documented in one-third of the patients deemed BCT ineligible after NST, underscoring the inadequacy of our current methods for assessing pathologic response to therapy.18
Our findings mirror results from the CALGB 40603 trial, a randomized phase 2 study assessing neoadjuvant paclitaxel with or without carboplatin and/or bevacizumab, followed by doxorubicin and cyclophosphamide, for stages II to III TNBC.11 In the prospective surgical substudy embedded within the trial, 42% of BCT-ineligible patients converted to BCT eligible after neoadjuvant treatment, with a resultant increase in the absolute BCT eligibility rate from 54% to 68%.19 Moreover, 93% of patients deemed eligible for breast conservation and opting for this approach were able to successfully undergo BCT with clear margins. Despite the relative success of conversion from needing mastectomy to BCT candidates, only 69% of eligible patients chose conservative surgery, resulting in an overall BCT rate of only 47%.19 Similar rates of breast conservation were reported in the subgroup of patients with TNBC treated in the ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) trial.20
Higher BCT rates after NST have been reported by the German GeparSixto trial,12 which included 315 patients with TNBC who were randomized to neoadjuvant treatment with or without carboplatin added to a control regimen of weekly paclitaxel and low-dose liposomal doxorubicin with bevacizumab. That study showed an increase in pCR from 37% to 53% with the addition of carboplatin and reported a BCT rate of over 73%.
The differences in rates of breast conservation across previously published TNBC studies may be explained by variations in practice patterns across continents as well as variable rates of genetic susceptibility in study populations.21,22 The higher proportion of deleterious gBRCA mutation carriers found in the population with TNBC (15%-20% in unselected populations of patients with TNBC) may alter surgical choices, especially in patients who do not know their genetic status. In BrighTNess, with uniform trial requirements for genetic testing and pretreatment and posttreatment clinical evaluation, we accounted for gBRCA mutation status and demonstrated equivalent BCT eligibility rates across world regions. Despite this, we noted substantial geographic differences in surgical choices in that 79.6% of all eligible European and Asian patients opted for BCT compared with 55.0% of participants in North America. Even among BCT-eligible patients who were not gBRCA mutation carriers, we saw a nearly 25% absolute difference in BCT rates between those in North America and those in Europe and Asia. This finding suggests that although surgical evaluations of BCT candidacy do not differ substantially across regions, results of collaborative decision-making between surgeons and patients vary widely according to geographic region of treatment, irrespective of clinicoradiographic response to NST and negative gBRCA mutation status.
The significantly lower BCT rates in North America compared with those in Europe and Asia, along with the fact that bilateral mastectomy procedures are significantly more common in North America, merit further explanation. Mastectomy and even bilateral mastectomy is an appropriate surgical option for some women with TNBC, particularly those with a documented gBRCA mutation or even a strongly positive family history without an identified mutation, yet our study found that three-quarters of patients in North America undergoing bilateral mastectomies did not have a documented gBRCA mutation, consistent with other studies.23,24,25 Although the reasons behind surgical decision-making are an area of ongoing research, we note that in North America, especially in the United States, women who are diagnosed with breast cancer may choose to undergo BCT, unilateral mastectomy, or bilateral mastectomy, with reconstruction that is often fully covered by insurance, even in the absence of a gBRCA mutation.26,27 This stands in sharp contrast to that in Europe and Asia, where contralateral prophylactic mastectomy and subsequent reconstruction are often not covered by insurance in the absence of elevated genetic risk and even with a proven genetic high risk mutation. It may be that the higher out-of-pocket costs of additional surgical procedures for patients in Europe or Asia contribute to our findings.
Patient and surgeon perceptions of perceived risks of residual disease, in-breast recurrence, and development of a secondary primary ipsilateral or contralateral breast cancer are complex and likely play a role in surgical decision-making.28,29 The relative balance between patient autonomy and deference to the opinion of medical specialists may differ between cultures and insurance systems. Among women eligible for BCT, those whose status converted from BCT ineligibility to eligibility were less likely to opt for BCT (56.0%) than those who were BCT eligible at baseline (70.6%), despite similar pCR rates. These findings underscore the importance of the breast cancer care team conveying to patients an accurate assessment of their risk of locoregional recurrence, contralateral breast cancer, and second primary cancers, as well as to discuss surgical risks and cosmetic outcomes associated with the various surgical options so that patients can make informed decisions regarding local management.30 Surgical oncologists working with breast radiologists also need to incorporate appropriate breast imaging, before and after NST, to improve their assessment of treatment response so that suitable patients can be offered and encouraged to attempt BCT.31,32 This incongruity was seen in the 34 patients (35.1%) deemed poor candidates for BCT who were found to have a pCR on final pathologic results.
Limitations
Our study has several limitations. First, we did not collect data on factors that may influence surgeon and patient decision-making, such as the need for additional imaging and biopsies, fear and risk perceptions regarding recurrence of TNBC, insurance coverage for ipsilateral and contralateral mastectomy, and patient or surgeon preferences. We were concerned that attempting to collect more detailed data from the patients and their surgeons regarding reasons why eligible patients might choose not to consider BCT could have affected compliance with collecting the end points of this substudy. Now that we have these baseline data, it is clear how vital it will be to collect these additional data in subsequent studies designed to better understand surgical choices in this setting to ensure that patients are making well-informed decisions. Second, our results report on definitive surgery, with a lack of information on whether BCT was attempted before mastectomy, although such cases are expected to be few.
Conclusions
Despite the stated limitations, this trial, with its enrollment of more than 600 patients, is to our knowledge the largest to date to evaluate NST in TNBC and the first to prospectively address eligibility for breast conservation within a cohort that includes important data on deleterious gBRCA mutations. Our results show that patients with stages II to III TNBC who are not eligible for BCT at presentation have an approximately 50% likelihood of converting to BCT eligible with NST. If 1 purported benefit of NST is to improve BCT rates, then surgeons must appropriately counsel patients with TNBC about the likelihood of successful breast conservation after treatment. The significantly lower rate of BCT and higher rate of bilateral mastectomy seen in those without a documented gBRCA mutation in North America relative to Europe and Asia is concerning, given similar rates of BCT eligibility in these populations. The multidisciplinary nature of NST requires careful patient-centered planning, and future NST trials should include increasing BCT eligibility and overall BCT rates as an end point.
Trial Protocol
Data Sharing Statement
References
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Trial Protocol
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