Real-World Outcomes of CDK4/6 Inhibitors in Germline BRCA-Mutated Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Turkish Oncology Group (TOG) Study

Background Germline BRCA1/2-mutated (gBRCAm) hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer (MBC) represents a biologically distinct subset in which the efficacy of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors remains incompletely characterized. Given the interplay between DNA damage repair deficiency and cell-cycle regulation, BRCA-associated tumors may demonstrate differential therapeutic sensitivity. We evaluated real-world outcomes, safety, and prognostic factors in a multicenter cohort. Methods This multicenter retrospective cohort study included patients with pathogenic germline BRCA1 and/or BRCA2 mutations treated with a CDK4/6 inhibitor plus endocrine therapy for HR+/HER2 − MBC (June 2020–September 2025) at participating centers in Turkey. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared by log-rank testing. Cox proportional hazards models were used for univariable and multivariable analyses. Results Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) BRCA2, and 3 (2.5%) dual BRCA1 + BRCA2 mutations; 66.9% received CDK4/6 inhibitors as first-line therapy. Ribociclib was used in 69.4% and palbociclib in 29.8%. Objective response rate was 69.4% and clinical benefit rate 82.6%. Median PFS was 17.0 months and median OS was 47.0 months. PFS differed significantly by BRCA subtype (25.0 months for BRCA1, 14.0 months for BRCA2, and 6.0 months for BRCA1 + 2; log-rank p = 0.013). Median OS also differed (57.0, 49.0, and 11.0 months, respectively; log-rank p = 0.016). PFS did not differ between ribociclib and palbociclib (p = 0.192); OS favored ribociclib at a borderline level (p = 0.050), not confirmed in Cox regression. In multivariable analysis, ECOG ≥ 1 (HR 1.846; p = 0.010) and fulvestrant-based therapy (HR 1.735; p = 0.041) predicted shorter PFS; fulvestrant predicted worse OS (HR 2.389; p = 0.008). Dose reductions occurred in 16.5% and discontinuation in 2.5%. Conclusions CDK4/6 inhibitor–based therapy demonstrates clinically meaningful activity in gBRCAm HR+/HER2 − MBC; however, survival outcomes differ by BRCA subtype, suggesting underlying biological heterogeneity. These findings support further investigation of BRCA subtype–specific tumor biology and its implications for therapeutic sequencing in this molecularly defined population.