Abstract PS3-05-28: Landscape of homologous recombination repair-related gene mutation and homologous recombination deficiency in Chinese patients with HER2-low early breast cancer

Abstract Background: Human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+ with fluorescent in situ hybridization [FISH]-negative) early breast cancer (EBC) constitutes a significant proportion of breast malignancies. Genomic instability, particularly defective DNA repair, is a recognized driver of tumorigenesis. Homologous recombination repair (HRR)-related gene mutation leading to homologous recombination deficiency (HRD) increases risks for tumorigenesis and has been proved as a viable therapeutic target in ovarian cancer and triple-negative breast cancer, with therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors and carboplatin. However, current evidence is largely derived from studies in European and American populations. Therefore, clinical research focusing on Chinese patients with HER2-low EBC is warranted. Methods: This prospective, single-center, observational study (NCT05466786) aimed to enroll 255 treatment-naïve patients with operable primary HER2-low (IHC 1+ of IHC 2+/FISH-negative) invasive EBC, who had completed HRR-related gene mutation and HRD assessments using a customized next-generation sequencing panel targeting 520 cancer-related genes. The HRD score was derived from the combined assessment of three genomic scar signatures: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions. HRD positivity was defined as an HRD score ≥42 and/or the presence of a BRCA1/2 mutation. All enrolled patients received standard therapies according to the National Comprehensive Cancer Network guidelines. The primary outcome was to characterize the landscape of HRR-related gene mutations and HRD. Results: From August 2022 to September 2025, 129 of 255 planned patients were enrolled. The median age of the patients was 43 years (range 27-68), and 38 (30%) had family history of malignant tumor. Tumors were predominantly T1-2 (112 [87%]), node-negative (74 [67%]), and stage II-III (95 [74%]); 103 (80%) were hormone receptor (HR)-positive (estrogen receptor ≥10%), and 102 (79%) had Ki67 expression ≥20%. Among HRR-related gene mutations, BRIP1 (17 [13%]), NBN (11 [9%]), PALB2 (8 [6%]), BRCA 2 (8 [6%]), BRCA 1 (6 [5%]), ATM (4 [3%]), and ATR (4 [3%]) were most common. The median HRD score was 20 (Interquartile range 10-35), and 26 (20%) patients were HRD-positive (including 14 had gBRCA1/2 mutation). HRD-positive status was significantly more common in tumors with histological grade-III, HR-negative, or Ki67 expression ≥20%. Among the 520 cancer-related genes, somatic alterations were frequently observed in PIK3CA (58 [45%]), TP53 (48 [37%]), GATA3 (34 [26%]), MYC (22 [17%]), CCND1 (21 [16%]), FGF3 (20 [16%]), FGF4 (20 [16%]), and FGF19 (20 [16%]). Recurrent germline alterations included BRCA2 (8 [6%]), BRCA1 (6 [5%]), PALB2 (5 [4%]), ATM (2 [2%]), BLM (1 [1%]), and MSH3 (1 [16%]). Conclusions: This study delineates the landscape of HRR-related gene mutation and HRD in Chinese patients with HER2-low EBC. HRD-positivity was significantly associated with histological grade III, HR-negative status, and Ki67 expression ≥20%. Further enrollment is warranted to provide a more comprehensive representation of HRR-related genomic alterations and HRD in this patient population. Citation Format: R. Hu, Y. Xia, Q. Lin, W. Zhang, J. Chen, Y. Zhu, Y. Yang, Q. Lin, Y. Quan, H. Liu, C. Gong. Landscape of homologous recombination repair-related gene mutation and homologous recombination deficiency in Chinese patients with HER2-low early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-28.