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Purpose Male breast cancer (MaBC) is rare and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of MaBC patients is extrapolated from results in females with the disease (FBC). We sought to define whether MaBCs harbor somatic genetic alterations in genes frequently altered in FBCs. Experimental Design All MaBCs were estrogen receptor-positive and all but two were HER2 negative. 59 MaBCs were subtyped by immunohistochemistry and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in FBCs or DNA-repair related. The repertoires of somatic mutations and copy number alterations of MaBCs were compared to that of subtype-matched FBCs. Results 29% and 71% of MaBCs were immunohistochemically classified as luminal A-like or luminal B-like, respectively. MaBCs displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative FBCs, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative MaBCs, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative FBCs. In addition, MaBCs were found to be significantly enriched for mutations affecting DNA repair-related genes. Conclusion MaBCs less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative FBCs, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of MaBCs are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biological and therapeutic findings from studies of FBCs to MaBCs.

Aims Somatic mutations in exon 2 of the MED12 gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumors (PTs) would harbor MED12 somatic mutations in a way akin to FAs. Methods and results A collection of 73 fibroepithelial tumors (including 26 FAs, 25 benign PTs, 9 borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from FFPE blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumor and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs significantly less frequently harbored MED12 exon 2 somatic mutations than FAs, benign and borderline PTs. Conclusions Although MED12 exon 2 somatic mutations likely constitute the driver genetic event of most FAs, benign and borderline PTs, our results suggest that the majority of malignant PTs may be driven by other genetic/epigenetic alterations.