Abstract Background: Germline BRCA mutations (gBRCA) are well-established predictors of therapeutic sensitivity in triple-negative breast cancer; however, their clinical implications in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC) treated with CDK4/6 inhibitors (CDK4/6i) remain poorly defined. We evaluated the association of gBRCA status with treatment patterns and clinical outcomes in a large real-world cohort of patients receiving CDK4/6i-based therapy. Methods: This retrospective cohort study included 3,000 patients with HR+/HER2- mBC treated with CDK4/6i between January 2015 to December 2024. Patients were stratified into three groups: gBRCA-mutated (n = 86), BRCA wild-type (n = 913), and those without germline testing (n = 2001). Demographics, tumor characteristics, treatment exposures, and outcomes were compared. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from the initiation of CDK4/6i therapy. Kaplan-Meier analyses and univariate Cox proportional hazards models were used to assess survival outcomes by BRCA status. Results: Compared to BRCA wild-type patients, those with gBRCA mutations were younger at diagnosis (median age 44 vs. 52 years), more likely to have received platinum agents (24% vs. 9%) and PARP inhibitors (52% vs. 2%) in any treatment setting. No significant differences in ER or PR expression, HER2 IHC distribution, or site of progression were observed between groups. Median PFS was 11.3 months (95% CI: 7.4-15.6) in gBRCA patients, versus 20.7 months (95% CI: 17.6-23.1) in BRCA wild-type (WT) and 19.8 months (95% CI: 18.2-21.7) in untested patients (P.001). Median OS from CDK4/6 initiation was significantly shorter in gBRCA- patients (33.7 months 95% CI: 28.9-64.9) compared to BRCA WT (58.8 months 95% CI: 53.2-65.6) and those without testing (45.7 months 95% CI: 43.8-48.9) (P.001). In univariate Cox models, gBRCA was independently associated with inferior PFS (HR = 1.71, 95% CI: 1.34-2.17, P.0001) and OS (HR = 1.73, 95% CI: 1.27-2.35, P = .001). Additional factors associated with worse OS included platinum exposure (HR = 2.03), visceral progression (HR = 1.41), and receiving palbociclib compared to ribociclib (HR = 1.89). Conclusions: In this large real-world cohort, gBRCA mutations were associated with significantly worse OS and PFS among patients with HR+/HER2- mBC treated with CDK4/6i. These findings suggest that gBRCA mutation status may have prognostic implications even in luminal disease and should be considered in treatment sequencing decisions. Prospective validation and exploration of optimal therapeutic combinations, including early use of PARP inhibitors or ADCs in this population, are warranted. Citation Format: A. Raghavendra, W. Qiao, A. Gutierrez, S. Damodaran, R. Layman, B. Arun. Prognostic Impact of BRCA Mutation Status on Outcomes with CDK4/6 Inhibitor Therapy in HR+/HER2- Metastatic Breast Cancer: A Real-World Cohort Study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-15.
Raghavendra et al. (2026) studied this question.