Transcriptomic deconvolution reveals prognostic immune signatures and immunotherapy-responsive subtypes in male breast cancer.

BACKGROUND

Male breast cancer (MBC) is a rare malignancy with distinct biological and clinical features compared to its female counterpart. Emerging evidence suggests that a subset of MBCs may exhibit an immunogenic tumor microenvironment; however, the lack of sex-specific data on immune biomarkers has limited the inclusion of male patients in immunotherapy trials.

METHODS

We performed transcriptomic profiling of 123 MBCs, including 41 with germline pathogenic variants (PVs) in BRCA2 (n = 26), BRCA1 (n = 12), and PALB2 (n = 3). Immune characterization included PD-1 and PD-L1 expression, immune scores, and immune cell infiltration using deconvolution tools. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was applied to predict potential response to immune checkpoint inhibitors.

RESULTS

A distinct subset of MBCs showed high PD-L1 expression and high immune scores. Immune deconvolution revealed that CD4 + memory resting T cells (24.5%), M2 macrophages (14.4%), and M0 macrophages (13.8%) were the most abundant infiltrating immune populations within the tumor microenvironment. Notably, 37.4% of tumors were predicted to respond to immunotherapy, primarily within the Luminal B subtype. These tumors demonstrated significantly higher PD-1/PD-L1 expression, higher immune scores, and enriched immune cell infiltration, compared to non-responders. Unsupervised clustering identified two transcriptionally distinct molecular subgroups. Cluster 1 was enriched for immune-related pathways and comprised the majority of predicted responders. Immune infiltration patterns varied significantly according to germline mutation status, intrinsic subtype, histological grade, androgen receptor expression, and Ki-67 proliferation index.

CONCLUSIONS

This study identifies a transcriptionally defined, immunogenic subset of MBCs with potential sensitivity to immune checkpoint inhibitors. These findings highlight the need for sex-specific immune profiling and provide a rationale for incorporating immunotherapy into precision treatment strategies for men with breast cancer.