Abstract PS3-05-14: Clinical significance of pathogenic variants in breast cancer patients at risk for hereditary breast cancer

Abstract Background: Approximately 5-10% of breast cancers (BC) are attributed to inherited germline pathogenic variants, primarily in genes involved in homologous recombination repair (HRR), most notably BRCA1/2. This study aimed to identify clinical risk factors associated with pathogenic variants in patients with a high genetic risk of breast cancer and evaluate the utility of multigene panel testing. Methods: A total of 533 high-risk BC patients underwent next-generation sequencing (NGS)-based germline multigene panel testing covering 61 HRR-related genes. Eligibility was defined by the presence of at least one of the following: triple-negative breast cancer (TNBC), early-onset disease (≤50 years), a family history of malignancy, or multiple primary tumors (including bilateral BC). Targeted capture-based sequencing was performed using DNA extracted from peripheral blood leukocytes. Results: The median age at diagnosis was 40.6 years old. All patients had ductal carcinoma. Pathogenic HRR variants were detected in 120 patients (22.5%), with 123 total variants identified; one patient (HR-positive/HER2-negative) carried two variants and another (TNBC) carried three. Pathogenic BRCA1 and BRCA2 variants were observed in 36 (6.75%) and 37 (6.94%) patients, respectively. Non-BRCA HRR pathogenic variants were present in 47 patients (8.82%), with PALB2 being the most frequently mutated non-BRCA gene (n=19, 3.56%). TNBC patients (43/145, 29.66%; P=0.012) and those with ≥2 clinical risk factors (84/329, 25.53%; P=0.021) had a significantly higher prevalence of pathogenic variants. A trend toward increased mutation frequency was noted in younger age groups (≤30y: 27.54%, 31-40y: 23.61%, 41-50y: 20.96%, ≥51y: 17.19%), although the difference was not statistically significant (P=0.284). Among HR-positive/HER2-negative and HR-negative/HER2-positive patients, pathogenic variant prevalence was 20.65% and 18.75%, respectively. Conclusions: This study highlights the clinical relevance of germline HRR gene testing in high-risk BC patients. Multigene panel testing should be considered routine for patients with TNBC or those presenting with multiple risk factors to guide personalized management and familial risk assessment. Citation Format: X. Kuang, Y. Lin, N. Shao. Clinical significance of pathogenic variants in breast cancer patients at risk for hereditary 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 PS3-05-14.