AI-driven risk stratification for distant recurrence in node-positive HR+/HER2− early breast cancer: Independent validation in the NSABP B-28 trial.

558 Background: Accurate prediction of risk of distant recurrence (DR) in HR+, HER2-negative early-stage breast cancer (EBC) is important for optimizing adjuvant therapy decisions, including treatment escalation with CDK4/6 inhibitors (CDK4/6i). Current guidelines recommend consideration of CDK4/6i for node-positive, clinically high-risk EBC, including N1 patients. However, it is not known which patients will benefit, and guideline recommendations suggest that the risks may outweigh benefits for patients with low risk of distant recurrence. Identification of these patients will help prevent over-treatment. RlapsRisk BC (RR) is an AI pathology-based test that integrates features from H&E-stained whole-slide images with clinicopathologic data (age, tumor size, nodal status) to assess risk of distant recurrence in HR+, HER2-negative EBC. The RR model was previously developed and validated using 7 retrospective cohorts totaling 6,039 patients. Here we report validation of RR in the NSABP B-28 cohort of HR+ HER2-negative N+ patients who received post-operative chemoendocrine therapy. Methods: This blinded independent validation study of the pre-specified RR included a subset of NSABP B-28 patients with HR+ and HER2-negative EBC (n=731) and digitized whole slide images from primary tumors. The primary endpoint was distant recurrence-free interval (DRFI). The objective was to validate the prognostic utility of RR score for DR. Univariable and multivariable Cox models were performed. Results: The evaluable cohort had a median follow-up of 11.1 years and included 504 (69%) patients with N1 disease, 87% grade 2/3 tumors, and a median tumor size of 21mm. Across the entire cohort, RR classified 58% of patients as low-risk and 42% as high-risk. RR (high vs low) was significantly associated with DRFI: HR=3.1 (95% CI: 2.3-4.3; p < .001). Estimated 10-year DR-free was 87.5% (95% CI: 83.9-90.4%) for low-risk vs. 65.0% (95% CI: 59.1-70.2%) for high-risk patients. In a multivariable Cox model, the histology-only score remained significant after adjusting for clinicopathologic data: HR=1.6 (95% CI: 1.4-1.9; p < .001). In the N1 subgroup, RR identified 65.7% of patients as low-risk with an estimated 10-year DR-free of 90.6% (95% CI: 86.9-93.4%), compared to 69.8% (95% CI: 62.2-76.2%) for high-risk. Conclusions: RR demonstrates robust prognostic performance in clinically high-risk N+, HR+, HER2-negative EBC patients from the NSABP-28 trial, in which the majority of patients had N1 disease. Our results demonstrate that approximately two-thirds of N1 patients, identified as low-risk by RR, exhibited favorable long-term outcomes with standard chemoendocrine therapies alone. As the clinical landscape shifts toward broader CDK4/6i use, RR could be used to identify N1 patients for whom the benefit of treatment intensification may be minimal.