Genomic profiling of young-onset gBRCA1/2 breast cancer reveals distinct genomic landscapes and therapeutic implications for PARP and CDK4/6 inhibitor selection

Purpose: gBRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. Understanding the distinct genomic landscapes of gBRCA1- and gBRCA2-associated breast cancer, including presence of PARP and CDK4/6 inhibitor (PARPi; CDK4/6i) response-associated alterations, may inform treatment selection for these patients. Patients and methods: We evaluated 136 treatment-naïve primary tumors from POSH study participants diagnosed with breast cancer before age 50 years (92.6% diagnosed ≤40): gBRCA1 86(63.2%), gBRCA2 50(36.8%). We evaluated somatic mutational and copy number variations (CNV), allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution signatures (SBS) from whole exome sequencing. Results: Both gBRCA1 (93%) and gBRCA2 (96%) breast cancers had high rates of asLOH. We found significant differences between gBRCA1 and gBRCA2 tumors in average HRD scores (57.4±1.3 vs 43.7±1.5, p<0.0001) and 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; SBS3 (HRD-associated) 27.3 vs 42.6, p=0.002; and SBS26 (mismatch repair-associated) 5.9 vs 9.4, p=0.049. Compared to gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for gains of chr6q, and alterations in Hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from POSH gBRCA1/2 carriers compared to noncarriers from the TCGA, 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, which are associated with CDK4/6i resistance. Conclusion: Our data suggest that PARPi may be preferable over CDK4/6i to treat ER-positive, HER2-negative breast cancer in young-onset gBRCA1/2-associated breast cancer when both therapies are considered in adjuvant and metastatic settings. Additionally, we identified significant differences between gBRCA1- and gBRCA2-associated tumors, which may inform therapeutic development.