Molecular, transcriptomic, and immune profiles of 214 male breast tumors stratified by HER2 expression (null, ultra-low, low, and positive) using next-generation sequencing and whole-transcriptome sequencing.
HER2-null tumors (30.8%) were the most biologically distinct: enriched in neutrophils and upregulated stemness genes (NANOG, KLF4, POU5F1) and CEACAM1. HER2 ultra-low tumors had higher PIK3CA mutation rates vs. HER2-null (39.2% vs. 22.6%, p ≤ 0.05) and greater B-cell infiltration. HER2-low and ultra-low subgroups were largely similar across most molecular and immune readouts. No significant differences in TMB-high frequency or PD-L1 expression were seen across subgroups.
- Small cohort (n=214) of a rare cancer limits statistical power, especially for the HER2-positive subgroup (n=15). - Immune cell fractions were computationally inferred (Quantiseq deconvolution), not directly measured. - Hypothesis-generating only; no clinical outcomes or treatment response data reported.
HER2-null male breast cancer shows distinct biology from HER2-low/ultra-low disease, suggesting it may warrant separate biomarker strategies. HER2-low and ultra-low male tumors are molecularly similar, which may support parallel ADC eligibility considerations as in female breast cancer — but prospective validation is needed.
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