Abstract 6596: Tumor molecular landscape and therapy implications in young BRCA1/2 carriers with breast cancer

Women with BRCA1/2 pathogenic variants (PVs) have a high likelihood of developing young onset breast cancer (BC) compared to noncarriers. In women enrolled in the POSH prospective cohort study of young women diagnosed with BC under age 40 or under age 50 if known BRCA1/2 positive, no difference in overall survival was observed in BRCA1/2 carriers vs noncarriers. Treatment options for BC include PARP inhibitors (PARPi) for BRCA1/2 driven tumors and CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy for ER-positive, HER2-negative tumors. In BC from BRCA1/2 carriers unselected for age, up to 10% BRCA1 and 46% BRCA2 carriers do not have loss of heterozygosity (LOH) at the germline variant locus, suggesting non-BRCA1/2 tumorigenesis. It is not known what the tumor molecular landscape, including rates of LOH and homologous recombination deficiency (HRD), is in young BRCA1/2 PV carriers with BC, and whether the tumor molecular features impact disease outcomes or predict therapy response. To elucidate the molecular landscape of breast tumors in young women with BRCA1/2 PVs, we evaluated treatment naïve primary breast tumors from 136 (86 [63.2%] BRCA1; 50 [36.8%] BRCA2) PV carriers in the POSH study. 71 (52.2%) of the tumors were ER-positive. We performed whole exome sequencing and called single nucleotide variants, indels, copy number variants, and BRCA1/2 allele specific LOH in the tumors, calculated HRD scores and tumor mutational burden (TMB), and evaluated single base substitution (SBS) signatures. We found high rates of LOH by gene: BRCA1 (93%) and BRCA2 (96%), and by ER-status: ER-negative (94.4%) and ER-positive (93.8%). Mean HRD scores were significantly higher in tumors with LOH compared to nonLOH tumors in both BRCA1 (57.4 vs 22.6, p<0.0001) and BRCA2 (43.7 vs 23.5, p=0.005) carriers as well as ER-negative (57.6 vs 22.8, p<0.0001) and ER-positive tumors (46.4 vs 22.8, p<0.001). LOH tumors had higher proportional contribution of HRD-associated SBS3 than nonLOH tumors (0.36 vs 0.22, p=0.048). BRCA1 LOH tumors had higher median TMB than BRCA2 LOH tumors (4.8 vs 2.5, p=0.034). Overall survival in women with nonLOH tumors was 100% throughout the follow-up period but was not significantly different from that of women with LOH tumors. Overall survival did not differ by tumor HRD status: analyses were limited by small numbers in the non-LOH and low HRD groups. We found statistically significant enrichment of AURKA (OR:4.2, 95%CI:1.3-16.6, p=0.015) and MYC (OR:2.4, 95%CI:1.0-5.7, p=0.043) amplification which are associated with resistance to CDK4/6i in ER-positive, HER2-negative tumors from POSH cohort PV carriers compared to noncarriers from the TCGA. Given the high levels of LOH and presence of CDK4/6i resistance associated alterations, our data suggest that PARPi may be preferable over CDK4/6i in young BRCA1/2 carriers with ER-positive, HER2-negative BC when both therapies are being considered in the adjuvant setting. Citation Format: Mwangala P. Akamandisa, Mingyi Xia, Wilson Cheah, Bradley Wubbenhorst, Kurt D'Andrea, Mengyao Fan, Jake Shilan, William J. Tapper, Ellen Copson, Ramsey I. Cutress, Diana M. Eccles, Susan M. Domchek, Katherine L. Nathanson. Tumor molecular landscape and therapy implications in young BRCA1/2 carriers with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6596.