Background: Male breast cancer (MaBC) accounts for <1% of all breast cancers and its genomic landscape has yet to be characterized. The majority of MaBCs are ER-positive invasive ductal carcinomas of no special type and, unlike female breast cancers (FBC), rarely display HER2 gene amplification or a triple-negative phenotype. Given the relative rarity of MaBCs, treatment decisions for MaBC patients are often extrapolated from trials carried out with FBC patients. Here we employed targeted capture massively parallel sequencing to define the repertoire of somatic mutations and gene copy number alterations (CNAs) in MaBCs.
Methods: Subtyping of the 64 MaBCs included in this study was performed by means of immunohistochemistry using the definitions described in the latest St. Gallen’s consensus report. DNA extracted from microdissected tumor and adjacent normal tissue were subjected to massively parallel targeting sequencing of all exons of 273 genes most frequently mutated in FBCs or directly related to DNA repair. Somatic mutations were defined using a combination of MuTect, SomaticSniper, MutationSeq and Haplotype Caller. Selected mutations were validated with Sequenom MassARRAY. CNAs were identified using Varscan2 and GISTIC2.0. Pathway and network analysis of mutations/CNAs was performed using Ingenuity Pathway Analysis and HOTNET. The genomic landscape of MaBCs was compared with that of FBCs of the same subtype analyzed as part of The Cancer Genome Atlas project.
Results: All MaBCs were ER-positive and HER2-negative. Using the St. Gallen’s criteria, 37.5% and 62.5% were classified as luminal A-like or luminal B-like, respectively. The genes most frequently mutated in MaBCs were PIK3CA, GATA3, FLG and PLEC, with PIK3CA being the only significantly mutated gene as defined by MutSigCV (q=0.003). CNA analysis revealed recurrent gains of 1q and 8q and loss of 16q. GISTIC2.0 identified significantly recurrent high-level amplifications in 1q25.3, 8p11 (FGFR1, ZNF703), 8q24.3 (DEPTOR), 17q23 (PPM1D) and 15q26 (IGF1R) and deletions in 11q22 (ATM) and 21q22.12 (RUNX1). HOTNET analysis of the genes mutated and/or targeted by gene amplifications in MaBCs revealed significantly altered subnetworks involving genes related to DNA repair, PI3K and FGF signaling pathways. The most frequently mutated genes in luminal A-like MaBCs were PIK3CA and MLL3, while those of luminal B-like MaBCs were PIK3CA and GATA3. MLL3 and GATA3 mutations were only found in luminal A-like MaBCs (p=0.039) and luminal B-like MaBCs (p=0.048), respectively. Although the mutational landscapes of MaBCs and luminal FBCs were qualitatively similar, PIK3CA and TP53 were less frequently mutated in MaBCs (p<0.001), whereas genes found to be recurrently mutated in FBCs, such as MAP2K4 and NCOR1, were not mutated in MaBCs.
Conclusions: MaBCs are preferentially of luminal subtype and are characterized by recurrent mutations in PIK3CA, GATA3, FLG and PLEC. Genetic alterations in MaBCs often target DNA repair and FGF signaling pathways. The known drivers of luminal FBCs appear to be less frequently altered in MaBCs. Given these important differences between MaBCs and FBCs, caution should be exercised in the extrapolation of biologic and clinical implications from studies in FBCs to the management of MaBCs.
Citation Format: Salvatore Piscuoglio, Melissa Murray, Charlotte KY Ng, Elena Guerini Rocco, Luciano G Martelotto, Francois-Clement Bidard, Carey A Eberle, Nicola Fusco, Rita A Sakr, Leticia De Mattos-Arruda, Raymond Lim, Timour Baslan, James Hicks, Tari A King, Edi Brogi, Larry Norton, Britta Weigelt, Clifford A Hudis, Jorge S Reis-Filho. The genomic landscape of male breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-06.