Male versus female breast cancer: a comparative study of 523 matched cases reveals differences behind similarity

Retrospective studies on male breast cancer (MBC) have suffered from small numbers of cases available from any one centre; thus a significant problem in effectively studying this disease is accruing sufficiently large numbers to allow comparative analysis of biomarkers associated with response. Using a coordinated multicentre approach, we present the first large-scale study to address the relevance of the expression of hormone receptors in MBC and female breast cancer (FBC) using immunohistochemistry combined with a novel bioinformatics approach. Following ethical approval, 523 archival blocks (260 MBCs and 263 matched FBCs) were obtained retrospectively. Tissue microarrays were constructed and sections stained for ERα, ERβ1, ERβ2, ERβ5, total PR, PRA, PRB and AR and typed using CK5/6, CK14, CK18 and CK19 by immunohistochemistry. Following scoring, a range of ordination techniques were conducted on the datasets including hierarchical clustering and principal component analysis (PCA) to determine the differential nature of influences and interactions between MBC and FBC. Luminal A subgroup (ERα⁺ and/or PR⁺, HER2^-) was the most common phenotype in both sexes. Luminal B (ERα⁺ and/or PR⁺, HER2⁺) was not seen in males, while basal-like tumours (ERα^-, PR^-, HER2^-, CK5/6⁺) were infrequent in both. Hierarchical clustering revealed common clusters between MBC and FBC including total PR-PRA-PRB and ERβ1/2 clusters. ERα occurred on distinct clusters between males and females. AR, ERβ1, ERβ2 and ERβ5 all existed on the same cluster but with a different substructure, particularly around the positioning of AR. ERα associated with this cluster in the male but not the female group. PCA confirmed that in both groups strong influences came from PR-PRA-PRB. In MBC strong influences additionally came from AR and ERβ1, ERβ2 and ERβ5, whereas in FBC strong influences came from ERα alone. Our data support the hypothesis that breast cancer is biologically different in male and females, which could have implications for therapy.