Abstract 3294: Subtype-specific genetic drivers of immune evasion in breast cancer

Abstract Introduction: Immune evasion is a hallmark of cancer and a significant driver of therapeutic resistance. While immunotherapy has shown promise in highly immunogenic cancers, its efficacy in breast cancer (BC) remains limited, particularly in less immunogenic subtypes. We aimed to investigate the prognostic relevance of two immune-related gene signatures—106 genes associated with evasion of immune destruction (EID) and 182 genes linked to evasion of killing by cytotoxic T lymphocytes (ECTL)—across distinct BC subtypes. Methods: Transcriptomic and clinical data from three integrated datasets (GEO, n=1, 965; TCGA, n=1, 069; and GSE96058, n=2, 976) were analyzed. Expression of immune evasion-related genes was stratified by BC subtype using PAM50 classification. Survival analysis was conducted using Kaplan-Meier curves and Cox regression models, stratifying gene expression into high- and low-expression groups. A False Discovery Rate (FDR) correction was applied to ensure statistical robustness. Subtype-specific survival associations were further evaluated with individual gene-level analyses. Results: High mean expression of the ECTL signature was significantly associated with improved overall survival (OS) in triple-negative BC (TNBC) patients (HR = 0.25, 95% CI = 0.16-0.4, p = 8.6e−10, FDR < 1%). Similar trends were observed in HER2-enriched BC but were less pronounced after FDR correction. For the 106 EID genes, high mean expression correlated with favorable OS in TNBC (HR = 0.3, 95% CI = 0.18-0.49, p = 3.4e−7). Gene-level analysis identified essential immune evasion genes, including CXCL10, CXCL9, CXCR4, and JAK3, as robust predictors of survival in TNBC, validated across independent datasets. The new, combined four-gene signature showed significant predictive power for response to immune checkpoint inhibitors (ICI), with an AUC of 0.722 (p = 1.3e−7). Conclusions: Immune evasion-related gene signatures exhibit subtype-specific prognostic value, particularly in TNBC and HER2-enriched BC. A signature based on genes within these signatures represent potential biomarkers for predicting survival outcomes and guiding immunotherapy. Citation Format: Otilia Menyhart, Balazs Gyorffy. Subtype-specific genetic drivers of immune evasion in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3294.