Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer.

Abstract

Germline BRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naïve tumors diagnosed before age 50 (92.6% ≤40): gBRCA1 86(63.2%); gBRCA2 50(36.8%) 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 signatures (SBS). gBRCA1(93%) and gBRCA2(96%) breast cancers had high rates of asLOH, but differed significantly in average HRD scores (57.4 ± 1.3 vs 43.7 ± 1.5, P < 0.0001) and median SBS composition (%): SBS1 (aging-associated) 12.9 vs 7.3, P = 0.013; SBS18 (reactive oxygen species [ROS]-associated) 1.4 vs 0, P = 0.007; and SBS3 (HRD-associated) 27.3 vs 42.6, P = 0.002. Compared to gBRCA2 tumors, gBRCA1 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 gBRCA1/2 carriers compared to noncarriers, we found significant enrichment of RB1 (OR:6.3;95%CI:2.8-15.4;padj = 0.001), TP53 (OR:4.6;95%CI:1.9-12.1;padj = 0.017), FAT1 (OR:3.9;95%CI:1.84-8.7;padj = 0.013), and MYC (OR:4.0;95%CI:1.8-9.1;padj = 0.017) SNV/indels/CNVs, associated with CDK4/6i resistance. Together, these findings demonstrate significant differences between gBRCA1 and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms supporting prospective trials with individualized therapy for gBRCA1 vs gBRCA2 carriers, and comparing PARPi to CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.