Abstract PS3-08-24: Association of Oncotype DX Recurrence Score with Germline Mutations in Cancer Susceptibility Genes Including BRCA1/2 in HR+/HER2− Early Breast Cancer

Abstract Background: In early-stage estrogen receptor-positive (ER+), HER2-negative (HER2−) breast cancer, the Oncotype DX® Recurrence Score (RS) is a clinically validated 21-gene assay that informs prognosis and predicts the benefit of adding chemotherapy to endocrine therapy. While germline pathogenic variants (PVs) in cancer susceptibility genes may influence tumor biology, treatment response and surgical management, their relationship with RS remains insufficiently explored and has been primarily limited to BRCA1/2 genes. This study investigates the association between Oncotype DX RS and the presence of germline PVs across a broader spectrum of breast cancer predisposition genes. Methods: We retrospectively analyzed data from a Greek cohort of early-stage ER+, HER2- breast cancer pts who underwent both germline testing using a 52-gene panel and Oncotype DX testing between 2015 and 2025. Pts were stratified by Oncotype DX Recurrence Score (RS) into low (RS 0-10), intermediate (RS 11-25), and high-risk (RS >25) genomic groups. Germline testing results were categorized into three groups: (a) pathogenic/likely pathogenic (P/LP) variants identified, (b) variants of uncertain significance (VUS), and (c) no variants detected. The P/LP group was further subdivided based on the presence of variants in (a) BRCA1/2, (b) other high-risk genes, (c) moderate-risk genes, and (d) incidental findings in additional genes. Results: A total of 1,465 pts were analyzed. The distribution of Oncotype DX RS across the various germline testing groups is detailed in the table below. Conclusion: The distribution of RS varied notably across genetic variant groups. Pts with BRCA1/2 and other high-risk gene variants exhibited statistically significant higher median RS values (p<0.0001) and higher percentage of pts with RS>25 (p<0.0001) compared to all other subgroups (moderate risk variants, incidental findings, VUS and cases without detected variants). These patterns suggest that pts with germline mutations in high-risk susceptibility genes are more likely to have an unfavorable prognosis for distant recurrence and a greater likelihood of receiving chemotherapy, as indicated by their elevated RS values Citation Format: V. Venizelos, K. Papazisis, C. Markopoulos, G. Xepapadakis, R. Iosifidou, G. Kapetsis, S. Giannoulakis, N. Tsoulos, A. Meintani, D. Bouzarelou, G. Tsaousis, D. Grosomanidis, N. Bredakis, F. Zagouri, C. Christodoulou, K. Anastasakou, M. Paraskeva, D. Mavroudis, N. Michalopoulos, D. Tryfonopoulos, S. Papadopoulos, A. Adamidis, D. Dimas, E. Angelidou, E. Papadopoulou, G. Nasioulas. Association of Oncotype DX Recurrence Score with Germline Mutations in Cancer Susceptibility Genes Including BRCA1/2 in HR+/HER2− 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 PS3-08-24.