Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers.

Piera Rizzolo,Anna Sara Navazio,Veronica Zelli,Giovanna Masala,Laura Ottini,Valentina Silvestri,Marco Scarnò,Domenico Palli,Simonetta Bianchi,Virginia Valentini,Stefania Tommasi,Ines Zanna

doi:10.18632/oncotarget.12272

Abstract

Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer.We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes.Pathogenic mutations of PIK3CA were detected in 2% of MBCs. No pathogenic mutations were identified in ESR1 and EGFR. Gene copy number variations (CNVs) analysis showed amplification of PIK3CA in 8.1%, EGFR in 6.8% and CCND1 in 16% of MBCs, whereas deletion of ESR1 was detected in 15% of MBCs. Somatic mutations and gene amplification were found only in BRCA1/2 mutation negative MBCs.Significant associations emerged between EGFR amplification and large tumor size (T4), ER-negative and HER2-positive status, between CCND1 amplification and HER2-positive and MIB1-positive status, and between ESR1 deletion and ER-negative status.Our results show that amplification of targetable oncogenes is frequent in BRCA1/2 mutation negative MBCs and may identify MBC subsets characterized by aggressive phenotype that may benefit from potential targeted therapeutic approaches.

Highlights

We examined 103 Male breast cancer (MBC) cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, epidermal growth factor receptor (EGFR), ESR1 and CCND1 genes
We focused on somatic mutations and copy number variations (CNVs) of PIK3CA, EGFR, ESR1 and CCND1 genes by examining a large series of MBCs screened for BRCA1/2 germ-line mutations
PIK3CA mutations were identified in 2 out of 102 (2%) primary MBCs examined. Both these MBCs were from BRCA1/2 mutation negative patients with no family history of breast cancers (BCs), were invasive ductal carcinomas, and presented with high grade (G3), estrogen receptor (ER)-positive, HER2negative and lymph node positive status

Summary

INTRODUCTION

Male breast cancer (MBC) is a rare disease, representing less than 1% of all breast cancers (BCs) and less than 1% of all cancers in men [1]. As MBC is an estrogen-driven disease and is most frequently ER-positive, the investigation of CCND1 alterations might be relevant in male breast tumors [8]. Recurrent activating mutations of ESR1, the gene encoding the estrogen receptor alpha (ERα), have been identified in hormone therapy-refractory ER-positive metastatic FBC [42,43,44]. Knowledge on somatic landscape of MBC is increasing, comprehension on the role of somatic alterations of specific genes with potential prognostic and therapeutic significance need to be further investigated in MBCs characterized for BRCA1/2 mutations. We focused on somatic mutations and CNVs of PIK3CA, EGFR, ESR1 and CCND1 genes by examining a large series of MBCs screened for BRCA1/2 germ-line mutations

RESULTS

DISCUSSION

MATERIALS AND METHODS