Basal-like Phenotype Identifies Immunotherapy-Responsive Subset of HR+/HER2- Breast Cancer with Aggressive Clinical Behavior

Abstract

Simple Summary HR+/HER2- breast cancer represents 70% of all breast cancers but has shown limited benefit from immunotherapy, with pathological complete response (pCR) rates of only 24–30% compared to 58–66% in triple-negative breast cancer (TNBC). This resistance has been considered an immutable biological characteristic, leading to exclusion of most HR+/HER2- patients from immunotherapy strategies. However, emerging evidence suggests this subtype is biologically heterogeneous, with approximately 16–20% exhibiting basal-like features despite retaining hormone receptor expression. We present a clinically practical solution using standard immunohistochemistry to identify basal marker-positive (BM+) HR+/HER2- breast cancer. We demonstrate that BM+ tumors exhibit aggressive features and significantly worse survival. Crucially, these tumors display an activated immune microenvironment with higher stromal tumor-infiltrating lymphocytes (TILs), enhanced cytotoxic T-cell infiltration, and elevated PD-L1 expression. In an independent cohort of 53 BM+ patients receiving neoadjuvant immunotherapy, we achieved a remarkable pCR rate of 49.1%, nearly double the historical benchmark for unselected HR+/HER2- patients and approaching TNBC response rates.