Divergent Prognostic Impact of Germline BRCA1 and BRCA2 Variants in Non-Metastatic Breast Cancer: A Real-World Cohort Study

Abstract

Background: Germline pathogenic variants in BRCA1 and BRCA2 are established contributors to hereditary breast cancer, yet their separate prognostic effects in non-metastatic disease remain uncertain because they are frequently analyzed as a single group. Methods: We retrospectively evaluated 360 patients with stage I–III invasive breast cancer who underwent germline genetic testing. Patients were categorized as BRCA-negative (n = 281), BRCA1-positive (n = 43), or BRCA2-positive (n = 36). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan–Meier methods and Cox proportional hazards models with adjustment for molecular subtype and clinicopathological variables. Results: During follow-up, 76 DFS events and 27 deaths were observed. BRCA2 positivity was independently associated with worse DFS (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.14–3.98; p = 0.017), whereas BRCA1 positivity showed an association with improved OS (HR 0.08, 95% CI 0.01–0.51; p = 0.007). The OS finding should be interpreted cautiously because of the limited number of death events and the risk of model instability. Conclusions: Germline BRCA1 and BRCA2 variants may have divergent prognostic implications in non-metastatic breast cancer and should not be treated as a single homogeneous prognostic entity. Separate evaluation of these variants may improve risk stratification and support more individualized patient management, although validation in larger cohorts is warranted.