Dana Pueschl

Carriers of germline BRCA1/2 pathogenic variants (g BRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset g BRCA -associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with g BRCA2 tumors, g BRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from g BRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1 , TP53 , FAT1 , and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between g BRCA1 - and g BRCA2 -associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for g BRCA1 versus g BRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive g BRCA1/2 -associated breast cancer.