Background: Germline BRCA mutations (gBRCAm) occur in 5-10% of breast cancer patients, with approximately 60% presenting as HR+/HER2-disease.While CDK4/6 inhibitors have demonstrated significant efficacy in unselected HR+/HER2-metastatic breast cancer (MBC), emerging evidence suggests potentially reduced benefit in gBRCAm patients.A recent meta-analysis reported inferior PFS and OS for gBRCAm versus wild-type patients.This study evaluates real-world outcomes of CDK4/6 inhibitor therapy in gBRCAm HR+/HER2-MBC patients.Methods: This retrospective multi-center study included 121 patients with pathogenic gBRCA1/2 mutations and HR+/HER2-MBC who received CDK4/6 inhibitorbased therapy between 2020-2025.The cohort comprised 30 (24.8%) BRCA1, 88 (72.7%)BRCA2, and 3 (2.5%)dual mutations.Primary endpoints were progressionfree survival (PFS) and overall survival (OS).Kaplan-Meier method was used for survival analyses.Univariable and multivariable Cox regression identified independent predictors of survival.Results: Median age was 44 years.CDK4/6 inhibitors were administered as first-line in 66.9%, with ribociclib (69.4%) and palbociclib (29.8%).Median follow-up was 24 months.BRCA1 carriers demonstrated superior PFS (p=0.013) and OS (p=0.016)versus BRCA2.In multivariable analysis, ECOG 1 (adjusted HR 0.54, 95%CI 0.34-0.86,p=0.010) and fulvestrant-based therapy (adjusted HR 0.58, 95%CI 0.34-0.98,p=0.041) independently predicted worse PFS.For OS, fulvestrant was the only independent predictor (adjusted HR 0.42, 95%CI 0.22-0.80,p=0.008), likely reflecting treatment selection in endocrine-resistant disease.Conclusions: BRCA-mutated HR+/HER2-MBC patients treated with CDK4/6 inhibitors demonstrated median PFS of 17.0 months, numerically lower than pivotal trials in unselected populations (24.8-28.2months), consistent with recent meta-analyses.BRCA1 carriers showed superior outcomes versus BRCA2.While CDK4/6 inhibitors provide meaningful benefit, prospective trials are needed to optimize treatment sequencing with PARP inhibitors and identify predictive biomarkers in this molecularly distinct population.
Seyyar et al. (2026) studied this question.