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

Background: While basal-like markers (BMs), particularly cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR), are traditionally associated with triple-negative breast cancer, their expression in HR+/HER2- tumors defines a clinically distinct subgroup with unique therapeutic vulnerabilities. We comprehensively characterized the clinicopathological features, immune microenvironment, and neoadjuvant immunotherapy response of BM-positive HR+/HER2- breast cancer. Methods: We analyzed 150 basal marker-positive (BM+) and 180 BM-negative HR+/HER2- breast cancer patients. Clinicopathological data and survival outcomes were assessed using Kaplan–Meier and Cox regression analyses. The immune microenvironment was characterized by stromal tumor-infiltrating lymphocytes (sTILs) and immunohistochemistry for immune markers (CD3, CD8, FOXP3, CXCL13, CD68, PD-1, PD-L1). An independent cohort of 53 BM+ patients receiving neoadjuvant chemotherapy with anti-PD-1/PD-L1 immunotherapy was evaluated for pathological complete response (pCR). Results: BM+ patients exhibited significantly more aggressive features: younger age at diagnosis, higher histological grade, increased necrosis, and lower hormone receptor expression. BM+ status independently predicted worse disease-free survival (HR = 1.96, p = 0.034) and overall survival (HR = 2.93, p = 0.037), with CK5/6 expression emerging as an independent prognostic factor for both endpoints. These tumors displayed an activated immune microenvironment with significantly higher sTILs, enhanced cytotoxic T-cell infiltration, and elevated PD-L1 expression. Remarkably, the neoadjuvant immunotherapy cohort achieved a pCR rate of 49.1%, comparable to triple-negative breast cancer rates and substantially exceeding historical HR+/HER2- benchmarks. Conclusions: The basal-like phenotype identifies a clinically aggressive subset of HR+/HER2- breast cancer with distinct immune-activated characteristics and remarkable immunotherapy response rates. These findings suggest that the BM status, particularly CK5/6 expression, may serve as a basis for clinicians to decide whether to administer immunotherapy to patients with HR+/HER2-breast cancer.