Tumor suppressor heterozygosity and homologous recombination deficiency mediate resistance to front-line therapy in breast cancer

Abstract

Germline and somatic variants that drive breast tumorigenesis and therapeutic sensitivity are widely prevalent. The clinical and biologic significance of co-occurring disease-defining germline and somatic events have yet to be defined and exploited. Using multiple, independent clinical cohorts comprising over 4500 patients, we identify that pathogenicRB1variants are enriched in gBRCA2-associated cancers, and manifest poor outcomes on standard-of-care front-line CDK4/6i plus antiestrogen combinations. We demonstrate gBRCA2-associated cancers commonly give rise to allelic configurations manifestingRB1heterozygosity and readily lose the second copy throughgBRCA2loss-mediated homologous recombination deficiency (HRD) under the therapeutic pressure of CDK4/6i. The findings unveil a novel therapeutic strategy of targeting the underlying HRD through PARPiprior toCDK4/6i to intercept the deleteriousRB1-loss trajectory. The work reveals how germline-somatic driven genomic configurations can shape treatment responses and be exploited in biomarker-directed clinical strategies.