The impact of ovarian function suppression with adjuvant endocrine therapy on survival outcomes in young germline BRCA mutation carriers with breast cancer: Secondary analysis of an international cohort study.

507 Background: In young women with hormone receptor-positive (HR+) breast cancer (BC), ovarian function suppression (OFS) has been shown to improve outcomes when combined with adjuvant endocrine therapy (ET). However, limited evidence exists on its efficacy in germline BRCA (gBRCA) carriers. Here we investigated the association between OFS plus ET and outcomes in the largest global cohort of young g BRCA carriers with BC. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study of women harboring germline BRCA1/2 pathogenic/likely pathogenic variants, diagnosed between 2000 and 2020 with stage I-III invasive BC at age of ≤ 40 years. The analysis included patients with HR+ BC and available data on ET and OFS. The OFS group included patients treated with luteinizing hormone-releasing hormone agonists (LHRHa) and/or bilateral risk-reducing salpingo-oophorectomy (RRSO) within 1 year of BC diagnosis. Outcome analyses included disease-free survival (DFS), BC-free interval (BCFI) and overall survival (OS). Cox proportional hazard models, stratified for country, year of diagnosis, nodal status, and surgery type and adjusted for RRSO and bilateral risk-reducing mastectomy (time-dependent), were used to explore the association between OFS use (vs non-use) and outcomes. Sensitivity analysis explored OFS as time-dependent covariate. To address immortal time bias, an additional Cox model accounted for left truncation, considering differences in time to BRCA testing. Results: Among 5,660 patients from 109 centers, 1,865 patients with HR+ BC were included, of whom 1,071 (57%) received OFS plus ET ( 35% with an aromatase inhibitor [AI], 65% with tamoxifen [tam])and 794 (43%) received tam alone. Patients receiving OFS were more likely to have node-positive disease (56% vs 47%), receive treatment in recent years (36% vs 17%), undergo mastectomy (70% vs 57%) and be tested for g BRCA at diagnosis (46% vs 30%). With a median follow-up of 7.8 years (IQR 4.6-12.1), OFS combined with ET was associated with significantly improved DFS (adjusted HR [aHR] 0.79, 95% CI 0.66-0.94), BCFI (aHR 0.74, 95% CI 0.61-0.89) and OS (aHR 0.66, 95% CI 0.50-0.88) over tam alone. Sensitivity analysis using OFS as a time-dependent factor yielded consistent results. No significant interactions were observed between OFS use and specific g BRCA mutations or HER2 status. Sub-analyses by type of ET (OFS + AI vs. OFS + tam vs. tam alone) will be presented at the conference. Conclusions: In this global cohort of young BRCA mutation carriers, OFS combined with ET was associated with improved DFS, BCFI and OS versus tam without OFS. These findings support the consideration of OFS as a key component of adjuvant therapy in this population.