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Although a substantial proportion of male breast cancers (MBCs) are hereditary, the molecular pathways that are activated are unknown. We therefore examined the frequency and clinicopathological associations of the PIK3CA/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways and their regulatory genes in familial MBC.    Methods  High resolution melting analysis and confirmatory sequencing was used to determine the presence of somatic mutations in  PIK3CA  (exon 9 and 20),  AKT1  (exon 4),  KRAS  (exon 2) and  BRAF  (exon 15) genes in 57 familial MBCs. Further analysis of the PIK3CA/mTOR pathway was performed using immunohistochemistry for the pAKT1, pS6 and p4EBP1 biomarkers.    Results   PIK3CA  somatic mutations were identified in 10.5% (6 of 57) of cases; there were no  AKT1 ,  KRAS  or  BRAF  somatic mutations.  PIK3CA  mutations were significantly more frequent in cancers from BRCAX patients (17.2%, 5/29) than  BRCA2  (0%, 0/25) carriers ( P  = 0.030). Two BRCAX patients had an E547K mutation which has only been reported in one female breast cancer previously.  PIK3CA  mutation was significantly correlated with positive pS6 (83.3% vs. 32.0%,  P  = 0.024) and negative p4EBP1 (100% vs. 38.0%,  P  = 0.006) expression, but not pAKT expression. Expression of nuclear p4EBP1 correlated with BRCA2 mutation carrier status (68.0% vs. 38.7%,  P  = 0.035).    Conclusions  Somatic  PIK3CA  mutation is present in familial male breast cancer but absent in  BRCA2  carriers. The presence of two of the extremely rare E547K  PIK3CA  mutations in our cohort may have specific relevance in MBCs. Further study of  PIK3CA  in MBCs, and in particular BRCAX patients, may contribute to further establishing the relevance of specific  PIK3CA  mutations in MBC aetiology and in the identification of particular patient groups most likely to benefit from therapeutic targeting with the novel  PIK3CA  inhibitors that are currently in development.

PIK3CA mutations are frequently observed in BRCAX but not BRCA2-associated male breast cancer