430P Efficacy of CDK4/6 inhibitors in BRCA-mutated HR+/HER2- metastatic breast cancer: Turkish Oncology Group (TOG) study

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.