Molecular and clinical predictors of NAC response and relapse in HR+/HER2− early breast cancer

Neoadjuvant chemotherapy (NAC) is the standard of care for aggressive early-stage and locally advanced hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer (BC). However, this subtype exhibits a high rate of treatment resistance, necessitating improved predictive tools for response assessment. In this study, we developed predictive models for pathological complete response (pCR) and distant relapse (DR) by integrating clinicopathological features with gene expression data from a retrospective cohort of 44 HR+ /HER2− BC patients treated with anthracycline- and taxane-based NAC. The model combining molecular and clinical variables achieved an AUC of 0.86 in both the discovery and validation cohorts, suggesting promising discriminatory performance for pCR prediction. For DR prediction, seven genes were differentially expressed between relapsed and non-relapsed patients. A combined model incorporating clinical variables and molecular features, including COL2A1 and MAPK8IP1 expression, achieved an AUC of 0.73 in residual disease samples. Notably, COL2A1 overexpression correlated with improved distant relapse-free and overall survival in external datasets. Longitudinal transcriptional analysis of matched primary, residual, and metastatic samples identified immune pathway activation in NAC-resistant tumors, contrasting with cell cycle pathway inhibition. Tumor progression to metastasis was associated with upregulation of TFEB, CD3E, and TNFRSF9, while metastatic samples exhibited increased cell cycle-related signaling and FAK pathway inhibition. Our findings support the potential value of integrating clinical and molecular features to improve response stratification in HR+/HER2− BC patients treated with NAC.