Background: Distinct pathological characteristics and mutational signatures in BRCA-associated breast cancers may result in differential response to chemotherapy but understanding of treatment response after neoadjuvant chemotherapy (NAC) is limited. We describe a single-institutional experience to compare rates of pathologic complete response (pCR) after NAC in BRCA carriers (gBRCA1/2) and noncarriers. Methods: From 11/2013 to 01/2022, 1426 consecutive women with clinical stage I-III breast cancer were treated with NAC followed by surgery. Baseline disease characteristics were compared between gBRCA1/2 and noncarriers using two-sample non-parametric tests. Conditional logistic regression was used to evaluate the association between BRCA status and pCR (i.e., ypT0/is pN0) adjusting for variables selected using backward elimination. Results: 92 (6.5%) and 73 (5.1%) had deleterious mutations in BRCA1 and BRCA2, respectively. Compared to noncarriers, gBRCA1/2 were younger (p<0.001) with clinical T1 (p=0.002) and triple negative disease (TN) (57% vs 25% noncarriers, p<0.001). Almost all patients received doxorubicin/cyclophosphamide/paclitaxel therapy (93%) with gBRCA1/2 more likely to receive carboplatin (p<0.001). pCR rate was 42% of gBRCA1, 21% of gBRCA2, and 26% of noncarriers (p=0.001). Among clinically node positive (cN+) patients, nodal pCR was higher in gBRCA1/2 compared to noncarriers (53/96 (55%) vs 371/856 (43%), p=0.012). This difference was seen in ER+/HER2- (36% gBRCA1/2 vs 20% noncarriers; p=0.027) and TN subtypes (79% gBRCA1/2 vs 45% noncarriers; p<0.001). Poorly differentiated tumors (p<0.001), cN+ (p=0.010), lower cT stage (p=0.028), ductal histology (p<0.001), TN and HER2+ receptor status (p<0.001), absence of lymphovascular invasion (p<0.001), carboplatin receipt (p=0.041), and BRCA1 status (p=0.001) were also associated with pCR on univariate analysis. After adjusting for differentiation and molecular subtype, BRCA1 status remained independently associated with pCR. Conclusions: gBRCA1 undergoing NAC have higher pCR rates relative to gBRCA2 and patients with sporadic disease. Across breast cancer subtypes, gBRCA1/2 more frequently converted to pN0. Defining biological mechanism for these findings would allow customization of treatment based on germline genetics.

Abbreviations: CI= confidence interval; IQR= interquartile range; HR= hormone receptor; HER2= human epidermal growth factor 2.

* Relative to noncarrier. † Relative to poorly differentiated. § Relative to HR+ HER2-.