Subtype-Specific Genetic Drivers of Immune Evasion in Breast Cancer

Menyhárt, Otília and Győrffy, Balázs (2025) Subtype-Specific Genetic Drivers of Immune Evasion in Breast Cancer. IMMUNO-ONCOLOGY TECHNOLOGY, 28. No. 101075. ISSN 2590-0188

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Abstract

ABSTRACT Introduction Immune evasion is a hallmark of cancer and a driver of therapeutic resistance. Although immunotherapy is effective in highly immunogenic cancers, its efficacy in breast cancer (BC) remains limited. We aimed to determine the prognostic relevance of immune-related gene signatures across distinct BC subtypes. Methods We used transcriptomic and clinical data from three independent cohorts (GEO, TCGA, GSE96058). We analyzed 106 genes associated with the evasion of immune destruction (EID) and 182 genes involved in the evasion of cytotoxic T lymphocyte-mediated killing (ECTL). Expression of signatures was stratified by BC subtypes. Cox regression and Kaplan–Meier curves were used to assess survival, with FDR correction ensuring statistical robustness. Results High expression of the ECTL signature was significantly associated with improved overall survival (OS) in basal BC patients (HR = 0.25, 95% CI = 0.16–0.4, p = 8.6e−10, FDR < 1%), and similar trends appeared in HER2-positive BC. For EID genes, high expression also correlated with favorable OS in basal BC (HR = 0.3, 95% CI = 0.18–0.49, p = 3.4e−7). Gene-level analyses revealed CXCL10, CXCL9, CXCR4, and JAK3 as robust predictors of OS in basal BC, validated across independent datasets. This four-gene signature demonstrated strong predictive power for response to immune checkpoint inhibitors (AUC = 0.722, p = 1.3E-07). In HER2-positive BC, a three-gene signature (IL2RG, CD3E, CD3G) was consistently prognostic (HR = 0.41, 95% CI = 0.24–0.71, p = 0.0011, GEO) across independent datasets. Conclusions We identified subtype-specific signatures that predict survival and immunotherapy response, providing clinically actionable biomarkers.

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