Abstract
INTRODUCTION: Recent trial-level meta-analyses have established disease-free survival (DFS) as a valid surrogate for overall survival (OS) in human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), irrespective of disease stage, and in early-stage hormone receptor-positive (HR+)/HER2- BC. To advance the understanding of the association between additional DFS endpoints and OS, this study assessed the patient-level correlations between DFS and OS, invasive DFS (IDFS) and OS, and distant DFS (DDFS) and OS in Medicare beneficiaries with early-stage HER2- BC, overall and in subgroups of patients with HR+/HER2- BC and triple-negative BC (TNBC). METHODS: Patients with stages I-III HER2- BC aged ≥ 66 years were identified from SEER-Medicare data (2010-2019). DFS, IDFS, DDFS, and OS were assessed using Kaplan-Meier analyses. Normal scores rank correlation was estimated between each DFS endpoint and OS, overall and separately in patients with HR+/HER2- BC and TNBC. RESULTS: Of 28,655 patients, 90.4% had HR+/HER2- BC and 9.6% had TNBC (median follow-up 4 years). Median DFS, IDFS, and DDFS were 4.5, 5.9, and 6.3 years, respectively, in HR+/HER2- BC and 3.0, 3.8, and 4.4 years, respectively, in TNBC. Median OS was not reached (5-year OS, HR+/HER2- BC 83.7%; TNBC 67.7%). A significant positive correlation was observed between each DFS endpoint and OS across cohorts, with the strongest correlation observed between DDFS and OS in HR+/HER2- BC (correlation coefficient 0.60; 95% confidence interval 0.57-0.62; p < 0.001) and in TNBC (0.69; 0.65-0.71; p < 0.001). CONCLUSION: We observed significant positive patient-level correlations between DFS and OS, IDFS and OS, and DDFS and OS in early-stage HER2- BC. Our IDFS and DDFS findings advance the understanding of the role of these DFS endpoints as predictors of OS, and their potential utility as surrogate endpoints in clinical trials of early-stage HER2- BC, given additional validation in trial-level meta-analyses.