A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences

Abstract

Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ERα, ERβ1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26-0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46-1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07-0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12-0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR-PRA-PRB and ERβ1/2 clusters. A striking feature was the occurrence of ERα on distinct clusters between genders. In female breast cancer, ERα clustered with PR and its isoforms; in male breast cancer, ERα clustered with ERβ isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.

A review of estrogen receptor/androgen receptor genomics in male breast cancer

“…In ERα-positive breast cancer cells, AR has been shown to limit ERα-mediated growth (Cops et al 2008, Peters et al 2009) indicating the propensity to confer better response in patients who are positive for both receptors. This finding is supported in MBC by clinical work in which ERα-positive/AR-positive patients had significantly better outcome compared to ERα-positive/AR-negative patients, and their hormone receptor immunohistochemical profiles illustrated co-clustering based on ER (both ERα and ERβ) and AR expression (Shaaban et al 2012). In FBC on the other hand, ERα clustered with progesterone receptor, whereas AR clustered with ERβ, suggesting an intrinsic difference in hormone receptor biology and hormone receptor dependencies between genders.…”

“…Notably, AR is highly expressed in male breast cancers (Zhou et al 2014) and has been found to be indicative of good outcome in male breast (Shaaban et al 2012) and poor outcome in hormone-refractory prostate cancer (Buhmeida et al 2006). These discordant results may be indicative of inherent differences between breast and prostate cancer or they may highlight the importance of treatment setting in these studies as ERα/AR dual positivity has recently been shown to be associated with improved outcome (Li et al 2016).…”

“…This indicates additional molecular 24:3 features may differentiate between genders, potentially leading to additional or new treatments for male breast cancer. The vast majority of male breast cancers express AR (Murphy et al 2006, Shaaban et al 2012, and the receptor is considered a valid drug target in this setting, as evidenced by recent initiation of multiple clinical trials (Table 1). FBC trials are also listed in this table for reference.…”

“…These two subgroups of MBC, the luminal M1 and luminal M2 subgroups, do not completely overlap with FBC luminal A/B classifications suggesting potential ERα-related differences in MBC, which may be clinically relevant. As gene expression is typically related to protein expression, examination of the differences between MBC and FBC were studied at the HR immunohistochemical level in a large series of 514 matched cases (Shaaban et al 2012). Strikingly, hierarchical clustering revealed in FBC ERα clustered together with PR, whereas in MBC, ERα clustered with AR suggesting a clinically actionable difference between genders in hormone receptor biology.…”

The Management and Outcomes of Male Breast Cancer

“…Although there are similarities between MBC and FBC, there is also mounting evidence that they are quite different biologically. There is little proof that the prognostic features found in FBC are also valid for MBC (11)(12)(13).…”