Association between chemotherapy use and clinical outcomes in young BRCA carriers with T1N0 breast cancer: Results from an international cohort study.

541 Background: Systemic treatment decisions for young BRCA carriers with small node-negative breast cancers present unique challenges due to limited evidence on the benefits of chemotherapy in this setting. This study evaluated chemotherapy use and survival outcomes among these patients. Methods: The BRCA BCY collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included carriers of germline pathogenic variants in BRCA1/2 diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. Among patients diagnosed with T1N0 disease, survival outcomes - disease-free survival (DFS) and overall survival (OS) defined from breast cancer diagnosis - were compared between patients who received chemotherapy and those who did not, using multivariate Cox models adjusted for propensity score (including age at diagnosis, histology, grade, country and year of diagnosis) and risk-reducing surgeries (bilateral risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO)), and accounting for the delayed entry at the time of BRCA testing (i.e. left truncation). Subgroup analyses were performed according to tumor subtype (HR+/HER2- vs triple negative breast cancer (TNBC)). Results: Out of 5660 from 109 centers, 1280 patients had T1N0 breast cancer: T1mic (n = 14, 1.1%), T1a (n = 92, 7.2%), T1b (n = 303, 23.7%), T1c (n = 778, 60.8%), and T1 size unknown (n = 93, 7.3%). Most patients received chemotherapy (80%), although use was less frequent over time. Among patients who received chemotherapy, the majority were treated with an anthracycline-containing regimen (83.6%) and in the adjuvant setting (85.7%). Patients who received chemotherapy were younger and more likely to have high grade, TNBC or larger tumors compared to those who did not. The median follow-up was 8.7 years (IQR 5.0-13.4 years), during which 428 had DFS events including second primary breast cancer (n = 174), locoregional (n = 130), distant relapse (n = 65), second primary non breast cancer (n = 53), and 88 had died. Overall, 8-year DFS was 69.4%. In multivariate analysis, no significant differences in DFS or OS were observed between patients who received chemotherapy and those who did not (DFS HR = 0.92, 95% CI 0.65-1.31; OS HR = 0.68, 95% CI 0.37-1.24). No significant difference in 8-year DFS was observed between patients with HR+/HER2- breast cancer (n = 474) treated with or without chemotherapy (HR 0.91: 95% CI 0.59-1.43), or between patients with TNBC (n = 637) treated with or without chemotherapy (HR 0.84: 95% CI 0.46-1.53). Conclusions: In this global study of young BRCA carriers with T1N0 breast cancer, chemotherapy was not associated with better DFS or OS overall. However, these patients remain at high risk of events and warrant investigation of additional risk-reduction strategies.