Abstract 1019: HRD status and biallelic loss of BRCA1/2 in breast cancer patients with germline BRCA1/2 mutation assessed by whole genome sequencing

Background: Beyond the properties of hereditary cancers with BRCA1 and BRCA2 mutations, the concept of BRCAness is used to predict hypersensitivity to PARP inhibitors by synthetic lethality. In addition to detecting deleterious mutation in homologous recombination (HR) - related genes and genomic instability score (GIS), the application of a mutational signature has been tried using whole genome sequencing (WGS). Although a BRCA-associated cancer arose in the heterozygous carrier with germline likely pathogenic/ likely pathogenic variant (PGVs) in BRCA1/2 (gBRCA1/2 mutant) had generally been considered as be in HRD status, some BRCA-associated cancer with gBRCA1/2 mutation were classified into homologous recombination proficient (HRP) status by HRD assays. In this study, we tried to investigate the discordance in aspects of assay tools and bi-allelicity. Methods: We collected WGS data from prospectively enrolled clinical database (N=18) and public database (TCGA, N=37) of gBRCA1/2 mutant breast cancer patients. We compared the HRD status analyzed using HRDetect, CHORD, and HRD score (calculated by GIS) method, and investigated the association with biallelic or monoallelic alteration. Results: Of all the 55 WGS data from the clinical and public database, 39 (71 %), 39 (71 %), 44 (80 %) were predicted to be HRD by HRD score, CHORD, and HRDetect, respectively. HRDetect showed 94.9 % positive percent agreement (PPA) and 56.3 % negative percent agreement (NPA) to CHORD, and HRDscore showed 86.4 % PPA and 90.9 % NPA to HRDetect. Most biallelic losses of BRCA1/2 were identified in the tumor with germline mutation and LOH of wild type allele (40 of 43, 93.0%). For the HRD assay using HRDetect, 43 tumors with biallelic loss in BRCA1/2 showed significant correlation with HRD compared to those with monoallelic loss in BRCA1/2 (p value < 0.0001). Conclusions: Even among the gBRCA1/2 mutant breast cancers, HRD status showed some discordance according to the prediction tools and biallelic loss in BRCA1/2 genes. Clinical utility of HRD tumors with biallelic loss in BRCA1/2 need to be further investigated. Citation Format: Ji Soo Park, Jeongsoo Won, Tae Yong Kweon, Sangwoo Kim, Hyung Seok Park. HRD status and biallelic loss of BRCA1/2 in breast cancer patients with germline BRCA1/2 mutation assessed by whole genome sequencing [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 1019.