BRCA2 Mutations and Androgen Receptor Expression as Independent Predictors of Outcome of Male Breast Cancer Patients Eliza Kwiatkowska, Marek Teresiak, Violetta Filas, Aldona Karczewska, Danuta Bre ¸borowicz, and Andrzej Mackiewicz 1 Departments of Cancer Immunology [E. K., A. K., A. M.] and Pathology [V. F.], University of Medical Sciences, and Departments of Cancer Immunology [E. K., A. K., A. M.], Surgery II [M. T.], and Pathomorphology [D. B.], Great Poland Cancer Center, Poznan, Poland ABSTRACT Purpose: Germline mutations of the BRCA2 gene are involved in the development of a considerable number of male breast cancer cases. Although phenotypic differences have been observed between sporadic and BRCA-related breast carcinomas, conflicting data exist on the differences in prognosis of women with hereditary and sporadic breast cancer. The purpose of the study was to investigate the prognostic value of BRCA2 status in male breast carcinoma (MBC). Experimental Design: We studied 43 male breast cancer patients, including 12 with BRCA2 mutations. Tumor sam- ples were characterized immunohistochemically using anti- bodies to estrogen receptor, progesterone receptor, and an- drogen receptor (AR). Results: BRCA2-related tumors presented at the earlier age compared with sporadic tumors (P  0.005). Patients positive and negative for BRCA2 mutations did not differ with respect to tumor size, lymph node involvement, histo- logical grade, and sex hormone receptor status. Five-year disease-free survival (DFS) and overall survival (OS) were significantly decreased in BRCA2-positive patients (67% versus 28% for BRCA2-negative versus positive patients, respectively, P  0.017 for DFS; 86% versus 25%, P  0.006 for OS). Shorter survival was also correlated with expres- sion of AR in tumor tissue (74% versus 33% for patients with tumors staining negatively and positively for AR, P  0.029 for DFS; 71% versus 57%, P  0.05 for OS). Conclusions: The BRCA2 mutations and AR expression in tumor tissue are independent adverse factors for MBC prognosis. BRCA2-related MBC presents at the earlier age compared with non-BRCA2-related cancer, but do not differ with respect to other clinicopathological features. INTRODUCTION Breast cancer is an uncommon disease in men. It represents 1% of all breast cancer cases and 1% of cancers in men (1). Several factors have been reported to influence the risk for breast carcinoma in men. These include clinical conditions causing hypoandrogenism (Klinefelter’s syndrome, testicular trauma, infertility), liver cirrhosis causing hyperestrogenism, the use of exogenous estrogens, obesity, gynecomastia, environ- mental factors such as exposure to electromagnetic field and ionizing radiation, or family history of breast cancer (1–9). The overall survival for male breast cancer patients has ranged between 49 and 87% at 5 years (10 –14). The male breast cancer is usually more advanced at diagnosis than female breast cancer. In men, skin infiltration and ulceration with involvement of axillary lymph nodes are more common (15). More advanced stage and higher incidence of lymph node metastases have been linked to a poorer prognosis (1, 11, 16). However, the survival when corrected for age and stage is similar in men and women. The histological grade tends to be lower in men, whereas estro- gen receptor and progesterone receptor is higher (17). It is postulated that aggressive behavior of male breast cancer may be a result of close proximity to skin and nipple which facilitates early invasion of dermal lymphatics and spread to axillary lymph nodes (15). Beside classical prognostic factors such as tumor size, lymph node involvement, histological grade, prognostic value of a number of new molecular markers including c-myc, c-erbB-2, p53, MIB-1, cyclin D expression, DNA ploidy, and microvas- cular density have been investigated (10, 12, 18 –20). However, for the majority of markers analyzed, the results are incon- sistent. One of the most important risk factors for breast cancer in both women and men seems to be inherited predisposition. Two genes, BRCA1 and BRCA2, account for the disease in large majority of breast cancer families (21). Unlike BRCA1 muta- tions, germline mutations of BRCA2 are involved in develop- ment of a considerable number of male breast cancer (22–26). In women, the pathological features of hereditary breast cancers, especially tumors that occur in BRCA1 mutation carriers, i.e., high grade and proliferation rate, aneuploidy, lack of estrogen receptor, are associated with poor prognosis (27, 28). BRCA2- related breast cancers are also higher grade tumors, are more frequently lobular type, and show less tubule formation than do sporadic cases (29). Several studies have investigated the out- come of BRCA1- and BRCA2-associated breast cancer (29 –34). However, there are conflicting data on the differences in prog- nosis of hereditary and sporadic cases. To our knowledge, there are no data on prognostic value of Received 12/10/02; revised 5/7/03; accepted 5/7/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Department of Cancer Immunology, Great Poland Cancer Center, Garbary 15, 61-866 Poznan, Poland. Phone: (+48 61) 8540665; Fax: (+48 61) 8528502; E-mail: amac@amu.edu.pl. 4452 Vol. 9, 4452– 4459, October 1, 2003 Clinical Cancer Research Cancer Research. on January 30, 2016. © 2003 American Association for clincancerres.aacrjournals.org Downloaded from