Genomic profiling and comparative analysis of male versus female metastatic breast cancer across subtypes

Abstract

Abstract Background Male breast cancer (MaBC) has limited data on genomic alterations. We aimed to comprehensively describe and compare MaBC’s genomics with female breast cancer’s (FBC) across subtypes. Methods Using genomic data from Foundation Medicine, we categorized 253 MaBC into estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 210), ER-positive/HER2-positive (n = 22) and triple-negative (n = 20). One ER-negative/HER2-positive case was excluded due to n-of-1. The genomics of the final MaBC cohort (n = 252) were compared to a FBC cohort (n = 2708) stratified by molecular subtype, with adjusted p-values. In the overall MaBC and FBC cohorts, we compared mutational prevalence in cancer susceptibility genes (CSG) (ATM/BRCA1/BRCA2/CHEK2/PALB2). Results Comparing ER-positive/HER2-negative cases, MaBc had increased alterations in GATA3 (26.2% vs. 15.9%, p = 0.005), BRCA2 (13.8% vs. 5.3%, p < 0.001), MDM2 (13.3% vs. 6.14%, p = 0.004) and CDK4 (7.1% vs. 1.8%, p < 0.001); and decreased frequency of TP53 (11.0% vs. 42.6%, p < 0.001) and ESR1 mutations (5.7% vs. 14.6%, p < 0.001). Comparing ER-positive/HER2-positive cases, MaBC had increased short variants in ERBB2 (22.7% vs. 0.6%, p = 0.002), GATA3 (36.3% vs. 6.2%, p = 0.004), and MDM2 (36.3% vs. 4.9%, p = 0.002); decreased frequency of TP53 alterations was seen in MaBC versus FBC (9.1% vs. 61.7%, p < 0.001). Within triple-negative cases, MaBC had decreased alterations in TP53 compared to FBC (25.0% vs. 84.4%, p < 0.001). MaBC had higher frequency of CSG variants than FBC (22.6% vs. 14.6%, p < 0.05), with increased BRCA mutations in MaBC (14.6% vs. 9.1%, p < 0.05). Conclusions Although MaBC and FBC share some common alterations, our study revealed several important differences relevant to tumor biology and implications for targeted therapies.