Abstract PS3-07-13: High genomic risk by multigene assay in germline BRCA1/2 mutated tumors among patients with ER-positive/HER2-negative early breast cancer

Abstract Introduction Indication of BRCA testing is expanding with growing evidence on optimal surveillance and treatments for BRCA-associated breast cancer (BC). As BRCA-associated hormone receptor(HR) positive, HER2 negative metastatic BC has shown to display worse outcome from previous studies, we aim to investigate the genomic risk profile and subsequent outcome in early HRpos/HER2neg BRCA-associate BC compared to BRCA non-associated BC. Methods A retrospective review of 5,081 early HRposHER2neg BC cases between Jan 2011 ∼ Dec 2023 in three institutes was done. Among the 1,401 BRCA-tested patients, 102 (7.3%) was found to have germline BRCA pathogenic variant (PV) and 1,299 (92.1%) with BRCA wild type (WT)/VUS. To minimize the effect of potential BRCA-carrier effect we excluded cases with BRCA testing indicated yet not tested (n=339). Total 3,518 cases were analyzed including 3,320 patients not- indicated for BRCA testing as control. We compared genomic risk using Oncotype recurrence score (RS) (cut-off 26) and Mammaprint (MMP) high vs low risk. Disease free survival and cumulative incidence of contralateral breast cancer was analyzed. Results Among the 3,518 cases analyzed, BRCA-pathogenic variant (PV) displayed high genomic risk compared to control group (high vs low, 50.0% vs 26.7%, p0.001). Mean Oncotype RS was higher in BRCA-PV group (18 ± 9 vs 25 ± 12, p0.001) and 89.5% (17/19) of BRCA-PV group was MMP-high while 43.2% (286/680) in control group. BRCA-PV group showed younger age at diagnosis (46y±11 vs 51y±6, p0.001), and BRCA-PV BC was independently associated with high genomic risk, high grade and high Ki67 compared to control group (all p0.005).Median f/u was 49.0 months (IQR 30.9-63.6). The BRCA-PV group displayed worse disease-free survival (89.3% vs 96.0% at 5years, 70.8% vs 90.0% at 10years, p0.01). While BRCA mutation did not affect overall survival, 5-yr and 10yr-cumulative CBC incidence was higher in BRCA-PV group than in control group (OS: 98.1% vs 99.3% at 5years, p=0.78; CBC: 3.1% (3/102) vs 0.9% (26/4,617) at 5years, 11% (5/102) vs 2.7% (35/4,617) at 10years, p0.05). BRCA-mutation and multigene-assay genomic high risk was both independently associated with high risk of recurrence (HR 2.13, 95%CI 1.05-4.33 and HR 1.51, 95%CI 1.00-2.28, respectively).In subgroup analysis, BRCA-PV patients in both high and low genomic risk group showed worse outcome than control group. Further analysis incorporating actual treatment data is planned. Conclusion BRCA-associated BC displayed high genomic risk and subsequent worse outcome. Worse outcome was observed in both high and low genomic risk group, suggesting the necessity in identifying optimal treatment strategy for this BRCA-associated BC population. Also, risk reducing mastectomy should be considered for younger age BRCA-PV BC patients. Citation Format: E. Kim, S. Baek, S. Bae, J. Jeong, S. Ahn, T. Yoo, S. Lee, I. Chung, H. Kim, B. Ko, J. Lee, B. Son, J. Kim. High genomic risk by multigene assay in germline BRCA1/2 mutated tumors among patients with ER-positive/HER2-negative 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 PS3-07-13.