Basal-like HR + /HER2- breast cancers show higher tumor-infiltrating lymphocytes and immune signatures with potential therapeutic implications

Hormone receptor-positive (HR + )/HER2-negative (HER2 - ) early breast cancers (BCs) are typically considered immunologically cold. However, combining immune checkpoint inhibitors (ICIs) with chemotherapy has shown to improve pathological complete response (pCR) in high-risk patients. Understanding the relationship between immune activation and tumor biology may help identify HR + /HER2 - BC patients most likely to benefit from such combinations. Baseline gene expression data from two neoadjuvant trials (GIADA and LETLOB) including HR + /HER2 - BC patients were analyzed. PAM50 intrinsic subtyping and relevant immune-related gene signatures were calculated. Tumor-infiltrating lymphocytes (TILs) were assessed on baseline samples. Among 109 tumors, PAM50 classified 44% as Luminal-B (LumB), 33% Luminal-A (LumA), 18% Basal-like, and 5% HER2-enriched. TIL levels (available for N = 101) were generally low (median 2; range 0-100), with higher levels in Basal-like BCs (p = 0.008). Basal-like BCs exhibited significantly higher levels of immune-related signatures (CD8 T-cells, Cytotoxic cells, IFN-γ, response to ICI + CT in GeparNuevo) and of PD-1, PD-L1, and PD-L2 genes. No differences were found between LumA and LumB subtypes. TILs and immune signatures showed a significant weak-to-moderate positive correlation with the basal-like signature. HR + /HER2- BCs that display both features of biological aggressiveness and enhanced immunogenicity may represent ideal candidates for the combination of ICI and chemotherapy.