A novel immune subtype classification of ER-positive, PR-negative and HER2-negative breast cancer based on the genomic and transcriptomic landscape.

BACKGROUND The diversity and plasticity behind ER+/PR-/HER2- breast cancer have not been widely explored. It is essential to identify heterogeneous microenvironment phenotypes and investigate specific genomic events driving the formation of these phenotypes. METHODS Based on the immune-related gene expression profiles of 411 ER+/PR-/HER2- breast cancers in the METABRIC cohort, we used consensus clustering to identify heterogeneous immune subtypes and assessed their reproducibility in an independent meta-cohort including 135 patients collected from GEO database. We further analyzed the differences of cellular and molecular characteristics, and potential immune escape mechanism among immune subtypes. In addition, we constructed a transcriptional trajectory to visualize the distribution of individual patient. RESULTS Our analysis identified and validated five reproducible immune subtypes with distinct cellular and molecular characteristics, potential immune escape mechanisms, genomic drivers, as well as clinical outcomes. An immune-cold subtype, with the least amount of lymphocyte infiltration, had a poorer prognosis. By contrast, an immune-hot subtype, which demonstrated the highest infiltration of CD8+ T cells, DCs and NK cells, and elevated IFN-γ response, had a comparatively favorable prognosis. Other subtypes showed more diverse gene expression and immune infiltration patterns with distinct clinical outcomes. Finally, our analysis revealed a complex immune landscape consisting of both discrete cluster and continuous spectrum. CONCLUSION Overall, this study revealed five heterogeneous immune subtypes among ER+/PR-/HER2- breast cancer, also provided important implications for clinical translations.