Abstract
Introduction:
Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) occurs in ≤20% of HR+/HER2− breast cancers; whether this differs among BRCA mutation carriers is uncertain. We compared pCR among BRCA1/2 mutation carriers and matched sporadic controls.
Methods:
From 11/2013–01/2022, we identified 522 consecutive women with clinical stage I-III HR+/HER2− breast cancer treated with NAC and surgery. BRCA1/2 mutation carriers were matched 1:2 to non-carriers on age, clinical tumor (cT) and nodal (cN) stages, and differentiation. Two-sample non-parametric tests compared baseline characteristics. Multivariable logistic regression assessed pCR (i.e., ypT0/ispN0) by BRCA1/2 mutational status.
Results:
59/522 women had BRCA1/2 mutations (median age 50y). 78% were clinically node positive; 97% received anthracycline-based NAC. More BRCA1/2 mutation carriers were younger, had cT1 tumors, and poorly differentiated disease. After matching, 58 BRCA1/2 mutation carriers were similar to 116 non-carriers in age(p=0.6), cT(p=0.9) and cN(p=0.7) stage, and tumor differentiation(p>0.9). pCR occurred in 15.5% of BRCA1/2 mutation carriers(8/21 [38%] BRCA1; 1/37 [2.7%] BRCA2) versus 7.8%(9/116) of non-carriers(p<0.001). 5/12 BRCA1 mutation carriers converted to pN0 after NAC(41.7%), versus 10/27 (37%) of BRCA2 mutation carriers, and 19/91 (20.9%) of non-carriers (p=0.3). In multivariable analysis, BRCA1 mutation status was associated with higher odds of pCR versus non-carrier status (OR 6.31; 95% CI 1.95–20.5; p=0.002), while BRCA2 mutation status was not (OR 0.45, 95% CI 0.02–2.67, p=0.5).
Conclusions:
BRCA1 mutation carriers with HR+/HER2− breast cancers have higher rate of pCR than sporadic cancers and may derive greater benefit from chemotherapy. The use of NAC to downstage these patients should be considered.
Keywords: BRCA, breast cancer, pathologic complete response, neoadjuvant chemotherapy
INTRODUCTION
Germline mutations in BRCA1 and BRCA2 are responsible for most hereditary breast cancers.1 Compared to sporadic breast cancers, BRCA1 mutation carriers more frequently have higher grade, poorly differentiated, and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) negative tumors.2-4 BRCA2 mutation carriers develop breast cancers with HR profiles that are similar to non-carriers but less frequently express HER2.5 These differences may contribute to variability in response to chemotherapy based on BRCA1/2 mutational status.6,7
Prior work examining the benefits of neoadjuvant chemotherapy (NAC) and pathologic complete response (pCR) rates in BRCA1/2 mutation carriers has primarily focused on patients with HER2+ or triple negative breast cancer (TNBC), with studies demonstrating higher rates of pCR in BRCA1 mutation carriers.8–11 Few studies have concentrated on HR+/HER2− tumors alone, and many are limited by small sample size.9 BRCA1/2 carriers more often have high- and intermediate-risk HR+/HER2− disease suggesting a less favorable biology as demonstrated by studies showing higher recurrence scores (Oncotype DX 21-gene expression assay, Exact Sciences, Madison, WI) compared to non-carriers.9 Although Oncotype score is used to predict the benefit of adjuvant chemotherapy in HR+/HER2− breast cancer, whether this translates into differences in pCR rates for BRCA1/2 mutation carriers is unknown. In particular, for HR+/HER2− cancers, which have low pCR rates (i.e., < 20%),12 identifying whether BRCA1/2 mutation carrier status is associated with higher pCR rates would impact decisions regarding NAC or upfront surgery. To further our understanding of this, we evaluated pCR rates among BRCA1/2 mutation carriers compared to matched sporadic controls.
METHODS
After obtaining institutional review board approval, 1426 consecutive patients with clinical stage I-III breast cancer who underwent NAC followed by surgery at Memorial Sloan Kettering Cancer Center (New York, NY, USA) between November 2013 and January 2022 were identified for this retrospective study. Per our institutional guidelines, patients who met National Comprehensive Cancer Network (NCCN) criteria13 for genetic testing were referred to our genetic counseling service for consultation. All patients who underwent genetic testing outside of Memorial Sloan Kettering Cancer Center had results reviewed and verified by their breast surgical oncologist. 522 patients had tumors that were HR+, defined as having ≥ 1% of tumor cells stain positive for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemistry, and absence of HER2 overexpression by either immunohistochemistry or fluorescence in situ hybridization. Patients were excluded if their genetic testing revealed BRCA variants of uncertain significance, had non-BRCA germline mutations (e.g., PALB2, TP53, etc.), or if the pathologic data from their surgical specimen were unknown/missing. Clinical characteristics that might confound the association between BRCA status and pCR were considered a priori and factored into development of the matched study cohort. BRCA1/BRCA2 mutation carriers were matched 1:2 to non-carriers on the basis of age, clinical tumor (cT) and nodal (cN) stages, and differentiation. One patient with a BRCA2 mutation was unable to be matched and therefore excluded from the final analytic cohort.
Percent of ER and PR staining from biopsy specimens was documented and classified as HR low expression if ER/PR < 20%, or as HR high if ER/PR ≥ 20%.14–16 Demographic data, tumor characteristics, initial clinical stage, NAC regimen, surgery type, and pathologic stage were abstracted. The definition of pCR was the absence of residual invasive tumor in the breast and ipsilateral axillary lymph nodes (ypT0/is ypN0).
Two-sample non-parametric tests compared demographic and clinical characteristics between patients with BRCA1/2 mutations and non-carriers. Logistic regression analysis was conducted on a subset of patients that was matched (1:2) based on age, clinical T stage, clinical N stage, and differentiation, between mutation carriers and non-carriers, using an optimal pair matching algorithm. The outcome variable was pCR defined as ypT0/is ypN0, and the explanatory variables were race, BRCA status, and level of HR positivity. Since race was not significant on univariate analysis, only BRCA status and HR positivity were retained in the final multivariable model. The type I error rate was set to 0.05 (α), and all analyses were performed using R 4.2 (R Foundation for Statistical Computing, Vienna, Austria). The Match.it package17 was used for carrying out the matching algorithm.
RESULTS
Of 522 HR+/HER2− patients treated with NAC, 21 and 38 patients were found to have BRCA1 and BRCA2 mutations, respectively. Demographic and disease characteristics for the entire cohort are presented in Table 1. Almost all patients received anthracycline-based chemotherapy. Prior to matching, a higher proportion of BRCA1/2 mutation carriers were younger, had smaller tumors, and had poorly differentiated disease. As there were no differences in age (p = 0.156), cT (p = 0.193), cN (p = 0.120), or tumor differentiation (p = 0.399) between BRCA1 and BRCA2 mutation carriers, non-carriers were matched to the combined cohort of BRCA1/2 mutation carriers rather than separately to BRCA1 and BRCA2 mutation carriers.
TABLE 1.
Patient, tumor, and treatment characteristics of the study cohort by BRCA1/2 mutation status. Study cohort prior to matching includes women with clinical stage I-III HR+/HER2− breast cancer treated with neoadjuvant chemotherapy followed by surgery between 11/2013 and 01/2022.
| Characteristic | Overall n = 522 | BRCA mutation carrier n = 59 | Non-carrier n = 463 | p-value* |
|---|---|---|---|---|
| Age at surgery, median, years (IQR) | 50 (42, 59) | 40 (35, 47) | 51 (44, 61) | < 0.001 |
| Race, n (%) | 0.800 | |||
| Black | 65 (13) | 9 (16) | 56 (13) | |
| Asian-American/ Native-American/Other | 87 (18) | 11 (19) | 76 (18) | |
| White | 333 (69) | 37 (65) | 296 (69) | |
| Unknown | 37 | 2 | 35 | |
| Clinical T stage, n (%) | < 0.001 | |||
| T0/Tis/T1 | 96 (18) | 23 (39) | 73 (16) | |
| T2 | 255 (49) | 24 (41) | 231 (50) | |
| T3 | 113 (22) | 10 (17) | 103 (22) | |
| T4 | 58 (11) | 2 (3.4) | 56 (12) | |
| Clinical N, n (%) | 0.200 | |||
| N0 | 110 (21) | 17 (29) | 93 (20) | |
| N1 | 368 (70) | 39 (66) | 329 (71) | |
| N2/3 | 44 (8.4) | 3 (5.1) | 41 (8.9) | |
| Differentiation, n (%) | 0.046 | |||
| Poorly differentiated | 258 (50) | 36 (62) | 222 (48) | |
| Well/moderately differentiated | 261 (50) | 22 (38) | 239 (52) | |
| Unknown | 3 | 1 | 2 | |
| Histology | 0.120 | |||
| Ductal | 447 (87) | 55 (93) | 392 (86) | |
| Lobular/mixed | 68 (13) | 4 (6.8) | 64 (14) | |
| Unknown | 7 | 0 | 7 | |
| Pathologic T stage, n (%) | < 0.001 | |||
| pT0 | 58 (11) | 13 (22) | 45 (10) | |
| pT1 | 274 (53) | 39 (66) | 235 (51) | |
| pT2–4 | 186 (36) | 7 (12) | 179 (39) | |
| Unknown | 4 | 0 | 4 | |
| Pathologic N stage, n (%) | 0.009 | |||
| pN0 | 186 (36) | 31 (53) | 155 (33) | |
| pN1 | 192 (37) | 19 (32) | 173 (37) | |
| pN2/3 | 144 (28) | 9 (15) | 135 (29) | |
| Neoadjuvant regimen, n (%) | 0.700 | |||
| ACT | 505 (97) | 59 (100) | 446 (96) | |
| CMF | 7 (1.3) | 0 (0) | 7 (1.5) | |
| Taxane | 10 (1.9) | 0 (0) | 10 (2.2) | |
| Breast surgery, n (%) | < 0.001 | |||
| Breast conservation | 174 (34) | 2 (3.4) | 172 (37) | |
| Unilateral mastectomy | 169 (33) | 2 (3.4) | 167 (36) | |
| Bilateral mastectomy | 175 (34) | 55 (93) | 120 (26) | |
| Unknown | 4 | 0 | 4 | |
| Axillary surgery, n (%) | 0.002 | |||
| SLNB alone | 187 (36) | 32 (54) | 155 (33) | |
| ALND | 335 (64) | 27 (46) | 308 (67) | |
| pCR, n (%)# | 40 (7.7) | 10 (17) | 30 (6.5) | 0.009 |
Statistical significance analyzed by Wilcoxon rank sum, Pearson’s Chi-squared, or Fisher’s exact tests
Pathologic complete response (pCR) defined as no residual invasive carcinoma in either breast or axilla (ypT0/is ypN0)
Abbreviations: IQR interquartile range, ACT Adriamycin, Cytoxan, Taxol, CMF cyclophosphamide, methotrexate, 5-fluorouracil, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, pCR pathologic complete response
After matching, 58 BRCA1/2 mutation carriers were similar to 116 non-carriers in age, cT/N stage, tumor differentiation, and degree of HR expression (Table 2). The majority of BRCA1/2 mutation carriers (54/58 [93%]) underwent bilateral mastectomy compared to 39/116 (34%) of non-carriers (p < 0.001). 30/58 (52%) of BRCA1/2 mutation carriers underwent SLNB compared to 47/116 (41%) of non-carriers (p = 0.2). Overall pCR rates were 16% in BRCA1/2 mutation carriers (8/21 [38%] BRCA1; 1/37 [2.7%] BRCA2) versus 9/116 (7.8%) in non-carriers (p < 0.001). 5 of 12 (42%) BRCA1 mutation carriers with biopsy-proven cN positive disease converted to pN0 after NAC, compared with 10/27 (37%) of BRCA2 mutation carriers, and 19/91 (21%) of non-carriers (p=0.3).
TABLE 2.
Patient, tumor, and treatment characteristics of matched cohort by BRCA mutation status. BRCA1/2 mutation carriers were matched to non-carriers on the basis of age, clinical T and N stages, and tumor differentiation.
| Characteristic | BRCA1/2 mutation carrier n=58 | Non-carrier n=116 | p-value* |
|---|---|---|---|
| Age at surgery, median, years (IQR) | 40 (35, 48) | 40 (36, 49) | 0.6 |
| Race, n(%) | 0.8 | ||
| Black | 9 (16%) | 15 (15%) | |
| Asian American/Other | 11 (20%) | 25 (24%) | |
| White | 36 (64%) | 63 (61%) | |
| Unknown | 2 | 13 | |
| cT, n (%) | 0.9 | ||
| T0/Tis/T1 | 23 (40%) | 40 (34%) | |
| T2 | 23 (40%) | 49 (42%) | |
| T3 | 10 (17%) | 20 (17%) | |
| T4 | 2 (3.4%) | 7 (6%) | |
| cN, n(%) | 0.7 | ||
| N0 | 16 (28%) | 25 (22%) | |
| N1 | 39 (67%) | 83 (72%) | |
| N2/3 | 3 (5.2%) | 8 (6.9%) | |
| Differentiation, n(%) | >0.9 | ||
| Poorly differentiated | 36 (62%) | 72 (62%) | |
| Well/moderately differentiated | 22 (38%) | 44 (38%) | |
| Hormone-receptor (HR) expression | 0.825 | ||
| HR < 20% | 8 (14%) | 19 (17%) | |
| HR ≥ 20% | 49 (86%) | 96 (83%) | |
| Unknown | 1 | 1 | |
| Final surgery, n(%) | <0.001 | ||
| BCT | 2 (3.4%) | 47 (42%) | |
| Unilateral mastectomy | 2 (3.4%) | 27 (24%) | |
| Bilateral mastectomy | 54 (93%) | 38 (34%) | |
| Unknown | 0 | 4 | |
| Axillary surgery, n (%) | 0.2 | ||
| ALND | 28 (48%) | 69 (59%) | |
| SLNB alone | 30 (52%) | 47 (41%) |
Statistical significance analyzed by Wilcoxon rank sum, Pearson’s Chi-squared, or Fisher’s exact tests
Pathologic complete response (pCR) defined as no residual invasive carcinoma in either breast or axilla (ypT0/is ypN0)
Abbreviations: IQR interquartile range, HR hormone receptor, BCT breast-conserving therapy, ALND axillary lymph node dissection, SLNB sentinel lymph node biopsy, pCR pathologic complete response
On univariate analysis, compared to White patients, there was no significant difference in pCR among Blacks and Asians (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.10–2.65, p = 0.6, and OR 0.66, 95% CI 0.14–2.23, p = 0.5, respectively). HR-high expression was negatively associated with pCR (OR 0.18, 95% CI 0.06–0.51, p = 0.001)) on univariate analysis (Table 3). An exploratory review of patients revealed that compared to non-carriers, a higher proportion of BRCA1 mutation carriers had HR-low tumors (7/21 [33%] BRCA1 versus 19 /116 [16%] non-carriers). 4/14 (29%) BRCA1 mutation carriers with HR-high tumors had pCR compared to 5/96 (5%) non-carriers with HR-high tumors who had pCR (Fig. 1). BRCA2 mutation carriers were not included in this analysis given the small sample size and lack of statistical difference in pCR relative to non-carriers.
TABLE 3.
Univariate and multivariable analyses evaluating association of variables of interest with pathological complete response among matched cohort.
| Univariate | Multivariable | |||||
|---|---|---|---|---|---|---|
| Characteristic | OR | 95% CI | p-value | OR | 95% CI | p-value |
| Race | ||||||
| Black | 0.66 | 0.10, 2.65 | 0.6 | |||
| Asian American | 0.66 | 0.14, 2.23 | 0.5 | |||
| White | -- | -- | -- | |||
| BRCA status | ||||||
| BRCA1 | 7.32 | 2.38, 22.7 | <0.001 | 6.31 | 1.95, 20.5 | 0.002 |
| BRCA2 | 0.33 | 0.02, 1.85 | 0.3 | 0.45 | 0.02, 2.67 | 0.5 |
| Non-carrier | -- | -- | -- | -- | -- | -- |
| HR expression | ||||||
| HR-high | 0.18 | 0.06, 0.51 | 0.001 | 0.24 | 0.08, 0.78 | 0.015 |
| HR-low | -- | -- | -- | -- | -- | -- |
Abbreviations: CI confidence interval, HR hormone receptor
Fig. 1.
Percent of BRCA1/2 mutation carriers and non-carriers by pCR and degree of HR expression among matched cohort. Abbreviations: pCR pathologic complete response, HR hormone receptor
After adjusting for HR-low versus HR-high status, having a BRCA1 mutation was associated with higher odds of pCR compared to non-carrier status (OR 6.31, 95% CI 1.95–20.5, p = 0.002), while having a BRCA2 mutation was not (OR 0.45, 95% CI 0.02–2.67, p = 0.5). In the multivariable model, relative to patients with HR < 20%, those with HR ≥ 20%, had lower odds of achieving pCR (OR 0.24, 95% CI 0.08–0.78, p = 0.015).
DISCUSSION
In this single-institution experience investigating pCR rates after NAC in HR+/HER2− cancer, we show in a well-matched cohort that BRCA1 mutation carriers had a higher overall pCR rate after NAC compared to BRCA2 mutation carriers and non-carriers after controlling for degree of HR expression.
Work from other studies18,19 suggests that even within subtypes as approximated by HR and HER2 status, response to treatment and prognosis may vary for patients with BRCA mutations. In a retrospective study of 80 patients with TNBC who received NAC, 26 of whom were BRCA1/2 mutation carriers, Sivina et al. found that mutation carriers had significantly higher rates of pCR compared to non-carriers (15/26 [57.7%] BRCA1/2 mutation carriers versus 11/54 [20.4%] non-carriers; p = 0.001).10 Similarly, a secondary analysis of patients enrolled in the GeparOcto multicenter prospective randomized clinical trial demonstrated that BRCA1/2 mutation status was associated with higher rate of pCR in TNBC, HER2+, and HR+ breast cancers.20 Our findings add to this literature demonstrating improved response to NAC among BRCA1/2 mutation carriers with HR+/HER2− cancers, which is primarily driven by the BRCA1 mutation carriers.
The degree to which ER and PR are expressed may contribute to differences in pCR rates between BRCA1/2 mutation carriers relative to non-carriers. In their study of 1147 women with breast cancer, 84 (7.3%) of whom had a pathogenic BRCA1 mutation and 47 (4.1%) of whom had a BRCA2 mutation, Guzman-Arocho et al. found that nearly all HR+ breast cancers in the BRCA1 mutation carrier cohort exhibited luminal B phenotype compared to an even distribution of luminal A and B subtypes in the BRCA2 mutation carriers.15 In this study, the BRCA1/2 mutation carriers and non-carriers were matched based on differentiation as a surrogate for luminal A versus B,21 and HR expression was adjusted for in the multivariable analysis. To better understand the possible role of HR expression in pCR, we performed an exploratory subset analysis. We found that a larger proportion of BRCA1 mutation carriers had HR-low tumors compared to non-carriers, which may have contributed to the increased pCR rate in this group. However, within HR-high tumors, BRCA1 mutation carriers still had a higher pCR rate compared to non-carriers. While the small sample size limits our ability to draw conclusions about how degree of HR-expression influences pCR, these exploratory results may indicate that additional factors contribute to pCR in mutation carriers. The possible mechanisms underlying increased pCR rates in BRCA1 mutation carriers, regardless of differentiation or degree of HR expression, warrant further study.
NAC has been used for surgical downstaging and to facilitate breast-conserving surgery for those who would otherwise require mastectomy. In mutation carriers, clinical decision making behind breast conservation or mastectomy also factors in risk of a second cancer event, and many mutation carriers will elect to undergo bilateral mastectomy for their index cancer.22 Therefore, downstaging of the breast alone may have little impact on the surgical management for BRCA1/2 mutation carriers. However, understanding the rates of axillary downstaging would significantly influence the choice of NAC over upfront surgery. Nearly half of BRCA1 mutation carriers in our study converted from node positive to node negative, compared to one-third of patients with BRCA2 mutations and one-fifth of non-carriers. While these differences were not statistically significant, likely due to small sample size, the high nodal pCR rate among BRCA1 mutation carriers demonstrate the potential of NAC to downstage the axilla and allow sentinel lymph node biopsy, and should be strongly considered. In our study, nodal pCR rate among non-carriers was comparable to that cited in the literature.22 NAC may be recommended for non-carriers in an attempt to de-escalate surgical management of the axilla, especially in premenopausal women who will be receiving chemotherapy in any case, with the understanding that nodal pCR rates are low. BRCA2 mutation carriers, among whom nodal pCR occurs with similar frequency to non-carriers, may benefit from the same multidisciplinary decision making regarding NAC or upfront surgery as non-carriers.23
Our study has several limitations. Its limited sample size may have restricted our ability to observe statistically significant differences in pCR when comparing BRCA2 mutation carriers to non-carriers, and when comparing nodal pCR rates. Changes to NCCN guidelines for genetic testing between 2013 and 2022 contributed to fewer patients undergoing genetic testing in earlier study periods, which may have further restricted sample size. Although the described cohort uniformly received ACT-based NAC, data dose reduction, adherence to, and/or cessation of chemotherapy were unavailable. Our findings regarding degree of HR expression among patients who achieved pCR were exploratory and performed post-hoc and are limited by the number of patients with HR-low disease. Given the recency of this cohort, and the pathophysiology of recurrence and distant disease progression among patients with HR+/HER2− disease, it is unclear whether the differences in pCR observed among these patients translate to survival outcomes. Finally, our study’s single-institution data source limits the generalizability of our findings. However, despite these limitations, we believe that our study findings demonstrate that specific germline genetic mutations are associated with differential response to NAC in HR+/HER2− cancers and will help in clinical decisions regarding NAC or upfront surgery.
Conclusions
HR+/HER2− tumors in BRCA1 mutation carriers have a higher rate of pCR than sporadic counterparts. There was no significant difference in pCR among BRCA2 mutation carriers and non-carriers, although sample size is limited. As BRCA1 mutation carriers with HR+/HER2− breast cancers may derive greater benefit from NAC compared to sporadic breast cancers, its use may be considered for axillary downstaging in these patients.
Synopsis:
Here we compared pCR among BRCA mutation carriers and matched sporadic controls. HR+/HER2− breast cancers associated with BRCA1, but not those associated with BRCA2, have higher rate of pCR than sporadic cancers.
ACKNOWLEDGMENTS
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant No. P30 CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in poster format at the 2023 American Society of Clinical Oncology Annual Meeting, June 2–6, 2023, Chicago, IL. The authors acknowledge the significant contribution of the Memorial Sloan Kettering Cancer Center Department of Surgery research project managers Tiana Le and Paula Garcia to this study. All authors have no conflict of interest disclosures to report.
Disclosures:
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant No. P30 CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in poster format at the 2023 American Society of Clinical Oncology Annual Meeting, June 2–6, 2023, Chicago, IL. All authors have no conflict of interest disclosures to report.
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