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<p>Identifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epigenomic, transcriptomic, and proteomic profiling to characterize HER2-low TNBC. We generated genome-wide DNA methylation profiles from a multi-institutional cohort and integrated our data with three independent cohorts (TCGA, SCAN-B, I-SPY2). TNBC cases were categorized as HER2-zero (IHC 0) or HER2-low TNBC (IHC 1+/2+, ISH non-amplified). Among 506 patients (HER2-low, <i>n</i> = 288; HER2-zero, <i>n</i> = 218), HER2-low TNBC exhibited significantly lower tumor mutational burden (<i>P</i> = 0.02). Epigenetic analysis identified 5287 differentially methylated sites, with consistent hypermethylation of <i>HLA</i> genes in HER2-low tumors. Transcriptomic analyses revealed significant downregulation of genes enriched in immune response pathways (e.g., leukocyte activation, T-cell signaling) in HER2-low TNBC (adjusted <i>P</i> &lt; 0.001). Immune cell deconvolution showed reduced immune cell infiltration in the HER2-low tumor microenvironment (<i>P</i> = 0.002). Higher expression of five immune-related genes, downregulated in HER2-low, correlated with improved relapse-free (HR = 0.52; <i>P</i> &lt; 0.001) and overall survival (HR = 0.36; <i>P</i> &lt; 0.001). HER2-low TNBC tumors display distinct molecular features compared to HER2-zero, imparting an immune-evasive phenotype. These findings provide critical insights into the unique biology of HER2-low TNBC, warranting further clinical investigation.</p>

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Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月16日

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  • Andrés F. Bedoya-López,
  • Sookyung Ahn,
  • Miquel Ensenyat-Mendez,
  • Javier I. J. Orozco,
  • Sandra Iñiguez-Muñoz,
  • Pere Llinàs-Arias,
  • Samantha M. Thomas,
  • Jennifer L. Baker,
  • Peggy S. Sullivan,
  • Jitin Makker,
  • Julie B. Steele,
  • Sunil M. Kurian,
  • Diego M. Marzese,
  • Maggie L. DiNome

摘要

Identifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epigenomic, transcriptomic, and proteomic profiling to characterize HER2-low TNBC. We generated genome-wide DNA methylation profiles from a multi-institutional cohort and integrated our data with three independent cohorts (TCGA, SCAN-B, I-SPY2). TNBC cases were categorized as HER2-zero (IHC 0) or HER2-low TNBC (IHC 1+/2+, ISH non-amplified). Among 506 patients (HER2-low, n = 288; HER2-zero, n = 218), HER2-low TNBC exhibited significantly lower tumor mutational burden (P = 0.02). Epigenetic analysis identified 5287 differentially methylated sites, with consistent hypermethylation of HLA genes in HER2-low tumors. Transcriptomic analyses revealed significant downregulation of genes enriched in immune response pathways (e.g., leukocyte activation, T-cell signaling) in HER2-low TNBC (adjusted P < 0.001). Immune cell deconvolution showed reduced immune cell infiltration in the HER2-low tumor microenvironment (P = 0.002). Higher expression of five immune-related genes, downregulated in HER2-low, correlated with improved relapse-free (HR = 0.52; P < 0.001) and overall survival (HR = 0.36; P < 0.001). HER2-low TNBC tumors display distinct molecular features compared to HER2-zero, imparting an immune-evasive phenotype. These findings provide critical insights into the unique biology of HER2-low TNBC, warranting further clinical investigation.