BRCA2 Germline Variants and RB1 Loss Drive CDK4/6 Resistance in Breast Cancer

A large clinicogenomic analysis of 5,881 breast cancer patients shows germline BRCA2 mutations predispose tumors to acquire RB1 loss under CDK4/6 inhibitor pressure, aided by baseline RB1 hemizygosity and ongoing homologous recombination deficiency. This RB1 loss drives resistance to frontline CDK4/6 inhibitors, while PARP inhibitors outperform CDK4/6 inhibitors across models and data. The study proposes prioritizing PARP inhibition for gBRCA2 carriers to intercept RB1‑loss trajectories and delay resistance, and provides a predictive framework using pre-treatment germline/somatic context and mutational signatures to forecast resistance trajectories.