Abstract 530: Genomic landscape of homologous recombination repair defects in Asian breast cancer.

Abstract Patients with BRCA1/2-mutated breast cancer generally respond well to PARP inhibitors. However, only about 5% of breast cancer patients carry germline BRCA mutations. Therefore, many studies have investigated whether a subset of non-BRCA-mutated tumors may also benefit from PARP inhibition. In Asian women, the median age at breast cancer diagnosis is younger than in Western populations, suggesting a contribution of genetic and genomic factors. Nevertheless, large-scale investigations on somatic genomic alterations and homologous recombination (HR) DNA repair status in Asian breast cancer remain limited. Thus, we aimed to characterize somatic HR gene mutations and HR deficiency (HRD) in an Asian breast cancer cohort. We enrolled 300 patients, including 198 estrogen receptor (ER)-positive and 102 triple-negative breast cancers (TNBC). Whole-exome sequencing was conducted. Among the ER-positive tumors, somatic mutations in HR-related genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCG, FANCL, MRE11, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) were detected in 67 patients: 40 had one mutation, 13 had two, and 14 carried at least three. Among the TNBC tumors, 25 patients carried somatic HR gene mutations, including 24 with a single mutation and 1 with two mutations. In total, 92 patients in the cohort had somatic HR gene alterations. Mutations in BRCA1, BRCA2, CHEK2, or PALB2 were significantly associated with higher HRD scores calculated using scarHRD software. Forty-four patients had at least one of these four gene mutations, and their mean HRD score was significantly higher than that of patients without these mutations (41.1 vs. 33.0, p = 0.024). In addition, 17 patients with non-BRCA HR gene mutations exhibited HRD scores > 42, indicating HR deficiency. We also identified five patients with SMARCA4 mutations, which have been reported to impair DNA repair and may sensitize tumors to DNA-damaging therapies such as PARP inhibitors. Altogether, 22 patients without BRCA mutations but with HR gene alterations and high HRD scores could potentially benefit from PARP inhibitor therapy. In conclusion, 30.6% of Asian breast cancer patients in our cohort had somatic HR gene mutations. Beyond BRCA-mutated tumors, PARP inhibition may also be beneficial for patients with non-BRCA HR gene or SMARCA4 mutations accompanied by high HRD scores. Citation Format: Po-Han Lin, Li-Wei Tsai, Chiao Lo, Chun-Yu Liu, Tzu-Chun Yen, Sung-Hsin Kuo, Chiun-Sheng Huang. Genomic landscape of homologous recombination repair defects in Asian breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 530.