Abstract PS5-04-19: 70-gene signature high risk classification provides stronger prognostic value than histologic grade in hr+ her2- early breast cancer

Abstract Background: Pivotal trials of immunotherapy and CDK4/6 inhibitors in early-stage hormone-receptor positive (HR+) HER2 negative (HER2–) breast cancer (BC) relied on histologic grade 3 to define high-risk disease, despite its variability and limited prognostic accuracy. The 70-gene MammaPrint® (MP) signature provides a genomic recurrence risk assessment and guides treatment. Patients (pts) classified as MP High Risk are typically recommended chemotherapy (CT). We evaluated distant relapse-free survival (DRFS) in CT-treated HR+HER2– pts classified as MP High Risk, further stratified into High Risk 1 (H1) and High Risk 2 (H2). We also compared MP risk groups with clinicopathologic factors, especially histologic grade, to assess prognostic value. Methods: This is part of the prospective, observational FLEX Study (NCT03053193), including pts with stage I–III disease who underwent MP testing and consented to transcriptome and clinical data collection. Pts with HR+HER2– genomic High Risk BC who received CT and had follow-up data were included (n=1407). Kaplan–Meier (KM) survival analyses were performed, with median follow-up of 3.2 yrs. DRFS was the primary endpoint per STEEP 2.0. Cox proportional hazards models assessed how grade (G), tumor (T) size, lymph node (LN), and menopausal status compared to MP risk stratification. Results: Of 1407 pts, 74% had H1 and 26% H2 BC. Pts with H2 BC were younger (mean 55 vs 58 yrs, p=0.004), more often G3 (62% vs 24%), and had larger tumors, while LN and menopausal status were similar. KM analyses showed pts with H2 BC had worse DRFS at 5 yrs (86.4, 95% CI 82.4–90.6) vs H1 (93.1, 95% CI 91.1–95.2), a diff of 6.7% (p<0.001). Although MP H2 was associated with poorer prognosis, we did not stratify outcomes by CT regimen; prior data suggest anthracycline-based CT improves outcomes in pts with MP H2 BC. When stratifying G3 pts by High Risk subgroups, H2 remained associated with worse outcomes (8.4% diff at 5 yrs, p=0.0029), showing that MP refines risk beyond histologic grade. Cox analyses confirmed higher recurrence risk for H2 vs H1 (uni: HR 2.37, p<0.001; multi: HR 2.14, p=0.005); T size and LN were also significant, while grade lost significance after adjustment. Conclusions: In this real-world cohort of HR+HER2– BC pts treated with CT, MP H2 was associated with significantly worse DRFS vs H1, even after adjusting for clinicopathologic factors such as grade. Notably, grade lost independent prognostic value when corrected for MP, underscoring the limits of histologic features alone. These findings support MP H2 as a superior prognostic biomarker to grade, offering greater accuracy for tailoring therapy in HR+HER2– BC. In addition, MP H2 tumors were previously shown to have an immune active state, supporting its use as a biomarker to select pts for immunotherapy trials, such as SWOG 2206. Citation Format: E. F. Cobain, L. Pusztai, C. L. Graham, P. D. Beitsch, C. R. C. Osborne, R. L. Rahman, N. M. Johnson, A. Brufsky, R. L. Mahtani, V. K. Gadi, K. Hoskins, H. M. Linden, R. A. Mukhtar, E. A. Brown, L. P. Gold, J. Alberty, S. Benjamin, S. Lee, J. V. Pellicane, H. Ramaswamy, R. Weber, N. Stivers, A. Menicucci, W. Audeh, J. O'Shaughnessy. 70-gene signature high risk classification provides stronger prognostic value than histologic grade 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 PS5-04-19.