Male breast cancer (MBC) is an uncommon disease accounting for only 1% of all breast cancers. Despite its rarity, the mortality associated with MBC and the increase in its incidence in recent years, has led to a progressive interest on this subject. Retrospective studies have already demonstrated important differences between MBC and female breast cancer (FBC) but the knowledge about its biological behaviour remains insufficient to define a personalised treatment strategy to MBC patients.

The aim of the present work was to study MBC prognosis based on: the definition of better intrinsic subgroups based on immunoexpression, the analysis of recurrence and of factors that could predict response to adjuvant endocrine therapy.

From clinical records of 111 MBC patients treated in a tertiary cancer center (with a median follow-up of 5.5 years), information was selectively analysed to answer specific research questions. Central pathology revision was performed with additional immunohistochemical (IHC) analysis of the cases in which tumour blocks were available. Blood samples were collected from patients who were in active treatment or surveillance in the center for genetic analysis.

The independent prognostic factors associated with poor outcome were: tumour size larger than 2cm (HR: 1.8, 95% CI: 1.0-3.4 years, p = 0.049), the absence of expression of estrogen receptor (HR: 4.9, 95% CI: 1.7-14.3 years, p = 0.004) and stage IV disease (HR: 5.3, 95% CI: 2.2-3.1 years, p < 0.001). The presence of lymph node metastasis seems to be related with poor outcome in univariate analysis (HR: 1.8, 95% CI: 0.9-3.2 years, p=0.05). The two classifications used to define FBC subgroups (based on three and four IHC markers), could not be linearly translated to MBC patients as some groups are rarely represented among these patients (triple negative: 2.7%-3.2% and HER2 enriched non luminal ≤ 1%), and they lost their prognostic discriminatory capacity when analysed only the most frequent groups (luminals). Cluster analysis based on a six-IHC panel, identified two important prognostic subgroups with extreme outcomes: one with better prognosis, composed by patients with tumours that express estrogen and progesterone receptor without expression of androgen receptor and HER2 and low ki67/p53, and another with the worst survival, associated with patients that had tumours who did not express progesterone receptor.

Recurrence was specifically analysed to evaluate its impact in survival outcome, using two gender cohorts that were matched for age at diagnosis, histological grade, stage, type of tumour and adjuvant treatments performed. MBC patients relapse more often to lung (p = 0.003) and presented poorer survival than FBC and this result remains across all of the five groups defined by relapse pattern. The difference in outcome seems to be related with the absence of systemic palliative treatment in recurrence time that is more commonly registered in MBC patients (21.1% vs 4.4%, p = 0.018). Patients treated with adjuvant tamoxifen categorized as poor tamoxifen metabolizers based on CYP2D6*4 polymorphism had also a higher risk of recurrence (p = 0.0034) and this effect was still observed when controlled important prognostic factors like: size > 2cm (p = 0.001), nodal status (N0 vs N+, p = 0.004), and advanced disease (stage III versus others, p < 0.001). These patients were associated with worse survival when tumours were larger than 2cm.

In conclusion, MBC patients have poorer outcome than FBC patients, even when stratified by important prognostic factors. Clinicians must look with major concerns for MBC patients that present with tumours with more than 2cm, or have lymph nodes involved or do not express ER or PR or present with distant metastasis at diagnosis (stage IV). Poor tamoxifen metabolizers based on CYP2D6*4 polymorphism have higher risk for relapse and probably need a more aggressive adjuvant approach. Considering recurrence time, palliative systemic treatment had a favourable impact in MBC patients' survival.