Supplementary Material for: Proliferation-Guided Risk Stratification in HER2-Low vs. HER2-Positive Hormone Receptor-Positive Breast Cancer: A Multicenter Retrospective Analysis

Background: HER2-low breast cancer is a newly characterized subgroup with unclear prognostic implications. This study investigates the prognostic role of Ki67 in hormone receptor-positive (HR+) HER2-low and HER2-positive breast cancer. Methods: We retrospectively analyzed 224 HR+ breast cancer patients from four tertiary centers (96 HER2-low, 128 HER2-positive). Patients were stratified into Stage I–III (n=156) and Stage IV (n=68). Survival outcomes were assessed according to HER2 and Ki67 status using Kaplan–Meier analysis and Cox regression. Results: HER2-low patients were older (≥65 years: 65% vs. 28%, p<0.001). In Stage I–III patients, disease-free survival (DFS) was significantly longer in the HER2-low subgroup (median: 86 vs. 59 months; p<0.001) and in those with Ki67 <20% (median: 74 vs. 34 months; p<0.001). Multivariable analysis confirmed high Ki67 (HR: 1.664; 95% CI: 1.564–2.048; p<0.001), hormone receptor negativity (HR: 1.967; 95% CI: 1.614–2.433; p=0.020), larger tumor size, and axillary nodal involvement as independent predictors of poor DFS. Among Stage IV patients, overall survival (OS) did not differ significantly by HER2 status (34 vs. 28 months; p=0.427) but was significantly shorter in those with Ki67 ≥20% (18 vs. 29 months; p<0.001). In multivariable analysis, high Ki67 (HR: 2.174; 95% CI: 1.994–2.256; p<0.001), hormone receptor negativity (HR: 1.649; 95% CI: 1.184–2.143; p<0.001), and presence of brain metastasis (HR: 1.564; 95% CI: 1.379–1.994; p<0.001) were independent predictors of poor OS. Conclusion: Ki67 appears to be an important prognostic biomarker in HR+ breast cancer across both HER2-low and HER2-positive subgroups. Dual stratification by HER2 and Ki67 status may improve risk assessment and help identify high-risk subgroups who could benefit from treatment approaches beyond endocrine therapy alone. These findings warrant confirmation in prospective studies.