Abstract
Male breast cancer (BC) is a rare disease that accounts for approximately 1% of all breast cancers. Approximately 5% of these cases are diagnosed as ductal carcinoma in situ (DCIS) and 95% as invasive BC, making DCIS of the male breast very uncommon. Due to its low prevalence, dedicated male
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BC research is challenging, and only few studies have been able to include a large cohort. Studies on male invasive BC that have been performed showed similarities with female breast cancer but also differences on several levels. But, as a consequence of the limited number of studies, male BC management is largely extrapolated from female BC studies. Therefore, there is an urgent need for more research in this field in order to improve risk stratification and optimize patient management.
For this thesis we included patients from the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program, a large male BC cohort. Paraffin embedded male BC tissue was retrospectively collected by the Dutch Breast Cancer Research Group (BOOG). We aimed to further characterize male BC by describing and evaluating histologic features including histological subtype, grade, mitotic activity index (MAI), presence of a fibrotic focus, density of tumor-infiltrating lymphocytes (TILs) and elastosis. We found that histological grade was not significantly associated with overall survival (OS) but MAI, presence of a fibrotic focus and a low TILs density were correlated to an unfavorable OS. BC subtype was correlated with TILs density. In addition, despite high ERα expression, male BC showed significantly less elastosis than female BC.
In addition we aimed at enhancing our understanding of male breast carcinogenesis by comparing male DCIS to male invasive carcinoma. For the latter we studied the activated hypoxia response by conducting immunohistochemical stainings for the hypoxia related proteins HIF-1α, CAIX and Glut-1. This revealed that the hypoxia response is already at its maximum in the pre-invasive DCIS stage. We also studied oncogene amplification using multiplex ligation-dependent probe amplification (MLPA) and promotor hypermethylation using methylation specific MLPA (MS-MLPA). These studies showed that male DCIS and invasive cancer have a similar copy number profile and methylation of the studied genes is more likely to occur early in the male breast carcinogenesis.
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