Key Points

• Patients with BRCA mutant or wild-type male breast cancer (MBC) had similar clinical features.

• Patients with BRCA mutant or wild-type MBC had similar pathological features.

• Patients with BRCA mutant or wild-type MBC had similar survival outcomes.

Introduction

Breast cancer is rarely diagnosed in men and accounts for less than 1% of cancers in men (1). Many risk factors have been identified in the development of male breast cancer (MBC), such as age, obesity, orchitis, and radiation exposure (2). About 5% of patients present with de novo metastatic disease (3). In terms of tumor subtypes, more than 80% are hormone-positive and less than 5% are triple-negative (4). In general, the treatment approach in MBC patients is similar to that in female breast cancer (FBC) patients. However, the prognosis in patients with MBC was found to be worse than in patients with FBC (5).

BRCA1 and BRCA2 mutations are risk factors for the development of many cancers, including breast, ovarian, prostate, and pancreatic cancer. The BRCA1 gene is located at position 21 of the q arm of chromosome 17, while the BRCA2 gene is located at positions 12 and 13 of the q arm of chromosome 13 (6). BRCA1 and BRCA2 genes maintain the genomic stability of DNA by repairing double-strand breaks (7). The presence of BRCA mutation may lead to the development of cancer due to the disruption of DNA repair mechanisms. BRCA1 and BRCA2 mutations have been defined as risk factors for the development of MBC. The cumulative risk of developing breast cancer in men with a BRCA1 mutation is around 1%, while it is around 7% in those with a BRCA2 mutation (8). Also, in patients with MBC, BRCA1 mutation is detected in approximately 0–5%, and BRCA2 mutation in approximately 5–15% (9). In the literature, there are limited data on the clinicopathological features and prognosis of MBC patients based on the BRCA mutation status. The aim of this study was to compare the disease characteristics according to the BRCA mutation status in a cohort of patients with MBC.

Materials and Methods

Patients and Data Collection

The study was designed retrospectively. Ethics committee and academic board approval were obtained before the study. The local ethics committee approved this study at the Istanbul University Faculty of Medicine (approval no: 1398, date: 28.11.2019). The study was conducted according to good clinical practice guidelines. The patients were identified from the hospital data processing system and cancer genetic center database, Patients that were diagnosed and treated in the outpatient clinic of a single oncology center between 2005 and 2020 were evaluated. Patients with MBC whose BRCA mutation was analyzed were included in the study. Patients with insufficient statistical data were excluded from the study. Genetic, pathological, clinical, and radiological features of the patients were recorded. All treatments (surgery, chemotherapy, radiotherapy, and hormone therapy) administered to the patients during the entire follow-up period were recorded.

Estrogen receptor (ER) and progesterone receptor (PR) were examined by the immunohistochemistry (IHC) method. Patients with a score of 3+ by IHC or positive by fluorescence in situ hybridization were considered human epidermal growth factor 2 (HER2)/neu positive. BRCA mutation analysis was performed with next-generation sequencing and multiplex ligation-dependent probe amplification methods. The smoking histories of the patients were recorded as never, current and former. Alcohol use more than three times a week was defined as regular alcohol intake. Body Mass Index was calculated as kilograms/height in metres². Tumor staging was performed according to the 8^th TNM Classification of malignant tumors, and molecular subtyping was performed according to the St Gallen consensus. Histopathological type, ER, PR, HER2, tumor grade, tumor stage, smoking history, and alcohol use history were compared between groups stratified by BRCA mutation status of the patients.

The time from diagnosis to death from all causes was defined as overall survival (OS). The living conditions of the patients were evaluated through the death notification system of the Ministry of Health. The factors affecting the survival of the patients were analyzed, and the effect of BRCA mutation status on OS was evaluated.

Statistical Analysis

Statistical analysis was performed with SPSS, version 25 (IBM Inc., Armonk, NY, USA). Continuous variables are shown as median value (with minimum–maximum value), and categorical variables are shown as numbers and percentages. The Kaplan–Meier method was used for survival analysis and curve. Multivariate analysis was performed with Cox regression analysis. Clinical and pathological differences between groups were evaluated using chi-square and Fisher’s Exact test. Independent sample t–test was used for comparison to mean values. A p-value of <0.05 was assumed to indicate significance.

Results

Patient Characteristic

The data of 43 MBC patients were evaluated. Thirty-two (74.4%) patients had no BRCA mutations, and 11 (25.6%) patients had BRCA mutations. There were six (14%) patients with BRCA2 mutations and four (9.3%) patients with BRCA1 mutations. One (2.3%) patient had both BRCA1 and BRCA2 mutations. All patients with BRCA mutations had pathogenic variants. The median age was 62 in BRCA wild-type patients and 57 in BRCA mutant patients. The mean value of age between the two groups was similar (p = 0.7). BRCA mutant or wild-type MBC patients had similar clinical features (Table 1). Although a multifocal tumor was detected more frequently in BRCA mutant patients, no statistically significant difference was found (p = 0.07). When the two groups were compared in terms of pathological features, ER positivity and invasive ductal adenocarcinoma histology were found more frequently in BRCA wild-type patients (Table 2). The patients showed similar characteristics in terms of surgery, chemotherapy, radiotherapy, and endocrine therapy (Table 3).

Survival Outcomes and Prognosis

The patients were followed up for a median of 35 months (2.2–225). Ten (23.2%) patients had died by the time of analysis. Median OS was 115.6 (95% confidence interval, 76–155) in all patients (Figure 1). When parameters affecting OS were evaluated in univariate analysis, BRCA mutation status was not found to be statistically significant (p = 0.6) for OS (Figure 2). Also, age (p = 0.6), tumor stage at diagnosis (p = 0.7), tumor focality (p = 0.1), histopathological type (p = 0.1), ER status (p = 0.2), PR status (p = 0.09), and HER2 status (p = 0.5) were not statistically significant for OS. Multivariate analysis could not be performed due to the limited number of events.

Discussion and Conclusion

In this study, we compared the clinical and pathological features of MBC patients according to the presence of BRCA mutations. In one of the rare studies in the literature published by Ottini et al. (10) it was reported that family history of breast cancer, contralateral breast cancer, grade 3 tumor, PR negativity, and HER2 positivity was more common in patients with MBC with BRCA2 mutation compared to BRCA wild type patients. Although the number of patients is limited due to being a rare tumor, we found that BRCA mutant and wild-type patients showed similar characteristics in our study. However, although it was not statistically significant in terms of tumor focality, histopathological subtype and ER positivity, we detected proportional differences between patient groups. MBC is a tumor that shows biological differences from FBC, and hormone receptor positivity and BRCA2 mutation are detected more frequently (11). In addition, in a multicenter study comparing BRCA mutant MBC and FBC in terms of pathological features, it was found that BRCA2 mutant MBC patients showed more aggressive features than FBC patients in terms of stage and tumor grade at the time of diagnosis, and hormone positivity was more frequent (12). Studies evaluating breast cancer characteristics according to BRCA mutation status were mostly conducted in patients with FBC. In a study conducted by Atchley et al. (13), when evaluated according to the BRCA mutation status, triple-negative and high-grade tumors were significantly more common in patients with BRCA1 mutation in FBC. In another study, the relationship between triple-negative disease and BRCA mutation in FBC was evaluated with a meta-analysis, and it was found that BRCA1 mutation was associated with triple-negative disease, larger tumor burden, and higher-grade tumor (14).

In the literature, there are very limited studies evaluating survival according to BRCA mutation status in MBC. In a study published by Gargiulo et al. (15), which included 17 patients with MBC with known BRCA mutation status, OS was found to be better in patients with BRCA wild type in the survival analysis performed according to BRCA mutation status. Seven of the patients included in this study were BRCA mutant, ten were BRCA wild type, and the p-value was borderline significant (p = 0.044). In our study, patients with BRCA wild type showed a better trend in terms of OS compared to BRCA mutant patients, but this trend was not significant. This inconsistency can be explained by the limited number of patients in both studies, and patient heterogeneity. In a meta-analysis conducted on patients with FBC according to BRCA mutation status, it was found that patients with a BRCA1 mutation had a worse prognosis in terms of OS than those with BRCA wild type. Also, patients with BRCA2 mutation were shown to have a worse prognosis in terms of breast cancer-specific mortality than those with BRCA wild type (16). In another meta-analysis, it was reported that patients with FBC with BRCA1 mutation had a significantly worse prognosis in terms of OS but similar characteristics in terms of progression-free survival (PFS). Also, the presence of BRCA2 mutation did not make a difference in terms of OS and PFS (17). There seems to be a need for better-designed studies showing the impact of BRCA mutations on the prognosis in MBC and FBC.

Study Limitations

Our study had some limitations. Due to the rarity of MBC, the number of patients in our study was limited. The patient group in the study was heterogeneous, and some data were missing.

In our study, we showed the real-life outcomes of MBC patients, and compared the clinicopathological features in BRCA mutant or wild-type patients. We found that patients with BRCA mutations or wild-type MBC had similar clinical and pathological features.

This study is one of the few published studies examining the differences in MBC according to BRCA mutation status. In our study, some clinical and pathological factors remained at the limit in terms of statistical significance. Multicenter studies with larger patient groups are needed for verification of our findings. Furthermore, cancer development and treatment processes will be better understood with translational studies examining the relationship between BRCA mutation and the development of MBC.

Presentation at a meeting: This study was presented as a poster at 2020 San Antonio Breast Cancer symposium.

Ethics Committee Approval: The local ethics committee approved this study at the Istanbul University Faculty of Medicine (approval no: 1398, date: 28.11.2019).

Informed Consent: For this type of research, informed consent is not required.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: İ.D., E.A., H.Y., P.S.; Concept: İ.D., E.A., H.Y., P.S.; Design: İ.D., E.A., H.Y., P.S.; Data Collection and/or Processing: İ.D., E.A., H.Y., P.S.; Analysis and/or Interpretation: İ.D., E.A., H.Y., P.S.; Literature Search: İ.D., E.A., H.Y., P.S.; Writing: İ.D., E.A., H.Y., P.S.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.