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

Silvestri, V; Valentini, V; Bucalo, A; Porzio, V; Scafetta, G; Cerbelli, B; Zanna, I; Bianchi, S; Tibiletti, MG; Carnevali, I; Calistri, D; Arcangeli, V; Zampiga, V; Gasparini, E; Cortesi, L; Giannini, G; Capalbo, C; Fox, SB; Masala, G; Mezi, S; d&#39;Amati, G; Ottini, L

Author(s): Silvestri, V; Valentini, V; Bucalo, A; Porzio, V; Scafetta, G; Cerbelli, B; Zanna, I; Bianchi, S; Tibiletti, MG; Carnevali, I; Calistri, D; Arcangeli, V; Zampiga, V; Gasparini, E; Cortesi, L; Giannini, G; Capalbo, C; Fox, SB; Masala, G; Mezi, S; d'Amati, G; Ottini, L;
Details: Publication Year 2026-04-07,Volume 28,Issue #1,Page 90
Journal Title: Breast Cancer Research
Publication Type: Research article
Abstract: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-026-02236-5.
Publisher: BioMed Central
Keywords: Brca1/brca2; Germline mutations; Immune cell infiltration; Immunotherapy; Male breast cancer; Molecular biomarkers; Molecular subtypes; Pd-1/pd-l1; Precision oncology; Transcriptomics
Department(s): Pathology
Publisher's Version: https://doi.org/10.1186/s13058-026-02236-5
Open Access at Publisher's Site: https://doi.org/10.1186/s13058-026-02236-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-05-05 06:05:43

Last Modified: 2026-06-04 04:32:20