Genomic landscape, immune microenvironment and survival in male versus female breast cancer

Background: Male breast cancer (MaBC) represents ∼1% of breast malignancies and may have significant differences to female BC (FeBC) that impact prognosis and treatment response. In this work, we sought to characterize the molecular and immune landscape of MaBC. Materials and methods: We analyzed whole-transcriptome (WTS) and whole exome sequencing from 19 697 deidentified tumor samples provided to Caris Life Sciences. Results: Our study found significant sex-based differences in the molecular and immunological landscape within each tumor subtype between MaBC and FeBC, including increased M2 Mϕ, and decreased dendritic cells and immune-related gene expression. Genetic amplifications and mutation frequency differences between MaBC and FeBC across molecular subtypes included significant differences in TP53 and ESR1 mutation [2.4% versus 31.2%; 5.8% versus 13.3%, hormone receptor (HR)-positive/HER2-negative], and BRCA2 and CDH1 mutation [6.7% versus 2.1%, HER2-positive; 16.7% versus 5.6%, triple-negative breast cancer (TNBC)]. Immunologically, MaBC exhibited increased tumor-promoting M2 Mϕ (5.8% versus 3.0%, TNBC), decreased dendritic cell infiltration (2.2% versus 2.6%, HR-positive/HER2-negative) and decreased PDCD1 and LAG3 immune checkpoint gene expression (0.3% versus 0.4%; 2.3% versus 2.9%, HR-positive/HER2-negative) against FeBC. Conclusions: Our findings suggest a unique genomic and immunologic landscape in MaBC requiring a sex-informed approach and provide candidate therapeutic targets and mechanisms of resistance.