Abstract
BackgroundThe 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.MethodsBased 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.ResultsOur 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.ConclusionOverall, this study revealed five heterogeneous immune subtypes among ER+/PR–/HER2− breast cancer, also provided important implications for clinical translations.
Highlights
The diversity and plasticity behind estrogen receptor (ER)+/Progesterone receptor (PR)−/human epidermal growth factor receptor 2 (HER2)− breast cancer have not been widely explored
We focused on two aspects in the gene selection: first, microenvironment cell-specific genes derived from two signatures, TCIA [18] and MCP-counter [19]; second, immune-related genes such as cytokines, cytokine receptors, and genes related to the antigen processing and presentation, downloaded from the ImmPort database [20]
Our analysis revealed that ER+/ PR−/HER2− breast cancer had five heterogeneous phenotypes that could not be fully explained by 3-gene classifier subtype
Summary
The diversity and plasticity behind ER+/PR−/HER2− breast cancer have not been widely explored. Hormone receptor (HR) positive breast cancer, a clinically and biologically heterogenous disease [1], has been categorized into two major groups, known as luminal A and B subtypes [2]. These two molecular entities have significant differences in prognosis and response to therapies [3]. In terms of endocrine sensitivity, clinical data suggest that luminal A and B tumors benefit but. Patients with estrogen receptor (ER) positive and PR-negative (ER+/PR−) tumors experienced higher risk of mortality than tumors with ER+/PR+ status [8, 9], suggesting that ER+/PR− tumors are a more aggressive phenotype and may benefit from more escalated therapies
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