Male breast cancer and female breast cancer: A population-based study

Male breast cancer (MBC) is a rare disease. Due to limited information, MBC has always been understudied. We conducted a retrospective population-based cohort study by using the 2010–2014 Surveillance, Epidemiology, and End Results (SEER) program data. The clinical and biological features of female breast cancer (FBC) patients were compared with MBC patients. Survival curves were constructed with the Kaplan-Meier method. Multivariate Cox regression models and competitive risk models were separately built to identify factors associated with survival time in the MBC and FBC group. Our retrospective study showed that MBC patients suffered with higher TNM stages, higher grades, and more percent of hormone receptor–positive tumors, compared with FBC patients. In addition, the site of the primary breast cancer varied greatly different between genders. FBC patients demonstrated superior overall survival than MBC patients on Kaplan-Meier analysis. In multivariate COX analysis for FBC patients, older age, black race, higher T, N, M-stages, higher grades, estrogen receptor (ER)/progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative were associated with higher risk of death. MBC patients had similar independent prognostic factors, but PR and HER-2 status did not appear to independently inuence survival. Interestingly, primary site location was an independent prognostic factor for both MBC patients and FBC patients, which should be considered by clinicians as a prognostic factor.

the absolute risk of breast cancer related death. A two-sided p-value < 0.05 was considered statistically signi cant in this study.
Results: MBC (n = 1592/222120) represented 0.72% of all breast cancers. The common descriptive characteristics of both genders are presented in Table . The median age at diagnosis for MBC was 65 years (range, 26-85 + years) compared with 60 years (range, 2-85 + years) for FBC (p < 0.001). In MBC patients, the race of patients was predominantly white (80.0%), with 15.1% black and 4.9% other races. In FBC patients, 78.9% were white, 11.5% were black and 9.6% were of others races (p < 0.001). Laterality (distribution of breast cancer between right and left breast) also differed signi cantly between men and women, but there was a slight tendency for left breast predominance in both genders noted in our data (p < 0.05). In our study, there were signi cant differences noted for tumor size(p < 0.001), lymph node status (p < 0.001) and distant metastasis (p < 0.001) between men and women. MBC patients were also more likely to present with advanced grades (p < 0.001). In terms of pathological types, 81.5% of MBC patients were invasive ductal carcinoma compared with 75.0% in FBC patients. Lobular carcinomas accounted for only 0.7% of breast cancer in MBC patients by the contract of 8.5% in FBC patients (p < 0.001). Compared with FBC patients, MBC patients was more likely to express hormone receptor positive. 91.30% of men and 79.3% of women had ER positive tumor (p < 0.001). Similarly, MBC patients was more likely to have PR positive tumors than FBC patients (84.5% vs. 68.8%, p < 0.001). Compared with FBC patients, MBC patients exhibited lower HER-2 expression (11.2% vs. 14.5%, p < 0.001).
During the entire study period, 242 male patients and 23,953 female patients died from breast cancer. The median follow-up was 57 months (range, 1-95 months). The Kaplan-Meier method showed that the MBC patients had a worse overall survival (OS) than FBC patients. The log-rank test showed a signi cant difference in the OS between the two groups (log-rank, p < 0.001, Fig. 2).
Multivariate Cox regression models were generated to describe the association between clinicopathological characteristics and risk of death. Among FBC patients, results indicated that black race, elder age, larger tumor size, higher lymph node involvement, distant metastasis, type of lobular, and higher tumor grade were associated with a higher risk of death. On the contrary, ER positive (p < 0.001), PR positive (p < 0.001), HER-2 positive (p < 0.001) were associated with a signi cantly lower risk of death.
Additionally, females who underwent surgery had a 65% reduced risk of breast cancer-related death compared with patients who did not receive surgery (p < 0.001) (Table ). Similar with FBC patients, age, race, pathological type, TNM stages, histological grade, surgical history, and ER were also prognostic factors among MBC patients, but PR and HER-2 status did not appear to independently in uence survival (Table ). It is worth noting that the primary site location was an independent prognostic factor for both MBC and FBC patients. Internal location tumor was associated with a poorer prognosis compared with lateral location tumor.
12,707 non-breast cancer related death cases were observed before the occurrence of breast cancer related death. Table and summarizes crude and adjusted HRs (95%CI) for the association of clinicopathological characteristics with breast cancer related death after taking competing risk events (none-breast cancer related death) into consideration. No signi cant differences have been observed between multivariate Cox regression and the competing risk analysis after adjustments were made for the same confounders.

Discussion:
This large-scale population-based study, which makes comparisons between MBC and FBC patients, provides intriguing etiologic and prognostic clues to this disease. Several signi cant conclusions were made. First, MBC patients has a worse prognosis than FBC patients. Second, the independent prognostic factors between MBC and FBC patients were incompletely same, PR and HER-2 were independent prognostic factors for FBC patients, but not for MBC patients. Finally, breast tumor location between the two genders were different, which might have an important in uence on prognostic results.
In our analysis, we have demonstrated that MBC patients has a worse overall prognosis than FBC counterparties. Previous studies agree with our nding. Nahleh et al. found that FBC patients had a signi cantly longer OS than MBC patients. The median OS for MBC patients was 7.0 years compared with 9.8 years for FBC patients (log-rank test; p < 0.05) 9 . Similarly, a study including 2,537 MBC patients also demonstrated that MBC patients had a shorter relative a 5-year survival rate than FBC patients 4 . Several explanations may help to explain this phenomenon. Better prognosis in FBC patients is partly due to the introduction of screening, public awareness, diagnosis at an earlier age with less complications, accurate clinical TNM staging, advances in treatment, and standardization of treatment regimens in international guidelines. However, the situation in MBC patients is differed a lot compared with female counterparts. Firstly, MBC patients tend to be older and are more likely to be a icted with other chronic diseases including hypertension, coronary heart disease, diabetes and so on, thus affects the prognosis, they also suffer from higher prevalence of advanced breast cancer at presentation, this may re ect a general lack of public awareness about MBC. Secondly, the breast tissue in men is sparser. A small tumor can invade the breast skin rapidly. The tumor can be easily drained into the subareolar lymphatic plexus and thus could lead to a high propensity to metastasize 15 . Third, the prevalence of adjuvant therapies for MBC patients are far behind from FBC patients. A recent analysis of the SEER data from 1996 to 2005 demonstrated that there is a 42% decrease in breast cancer-speci c mortality among women compared with only a 28% decrease among men, suggesting that the treatments being used in MBC patients are not as effective as they are for FBC patients 10 . Furthermore, the use of adjuvant therapy in MBC patients is not widespread as FBC patients. In a paper which included 10,173 men with HR-positive breast cancer, men were less likely to receive adjuvant endocrine therapy than women (67.3% vs 78.9%, p < 0.001) 16 .
There maybe different risk factors between FBG and MBG especially when it related to PR and HER-2.
Likewise, a population-based study indicated PR status did not appear to independently in uence survival among MBC patient 4 . Matthew J's study also demonstrated PR status did not affect survival in MBC patients 21 . This may be related to the fact that PR status is not a crucial factor for endocrine therapy, and MBC patients are not as sensitive towards endocrine therapy. Little data are available on HER-2 expression in men. The effectiveness of trastuzumab in HER-2 overexpressing male breast cancer is unproven 22 . In addition, MBC patients with HER-2 positive only comprise of a small portion of all MBC population 23,24 , making it di cult to draw a reliable conclusion.
In this current study, the primary location of tumor between the MBC and FBC patients were markedly different. In FBC patients, tumor primarily located in upper-outer, account for 33.6%, other sites in the breast were discovered at lower frequencies, which agrees with previous studies [25][26][27][28] . This basic observation has become a common sense, but lack an adequate scienti c explanation for this asymmetric occurrence of breast cancer. A possible explanation was the upper-outer quadrant of the breast contains a greater proportion of the epithelial tissue, which had a great chance to occur cancer 29  This discrepancy may cause by the anatomy of male breast, as there is a larger volume of epithelial breast tissue in the central portion in men 29 . In addition, the prognostic role of the tumor location is also under appreciated, as almost all breast cancer guidelines do not include tumor location as a prognostic factor 30,31 . Yet in our study, tumor location affected the prognosis for both MBC and FBC patients, tumors situated in the internal quadrants of the breast have a worse prognosis compared with those located in lateral quadrants. This nding was compatible with other papers. A paper from David K have suggested that internal tumor location adversely impacts breast cancer-speci c survival and OS in breast cancer patients 32 . Similarly, the Caroline trials indicated that internal location was associated with a 50% excess risk of systemic relapse and breast cancer death compared with lateral tumors 33 .
The poor prognosis of tumor with internal location may be associated with internal mammary nodes (IMN), which were not conventional treated. Patients with negative and positive axillary lymph node have positive IMN rates ranging from 8-13.7% and 28-48% respectively, as indicated by extensive radical mastectomy data 34-37 . And even there were 5% of breast cancer patients metastasis to IMNs alone 38 .
These metastasis IMNs, which is more often involved in internal quadrants, are usually clinically silent and might disseminate the disease, thus affects the prognosis of these patients 39 .
The strength of this current study is the large quantity of data regarding MBC and FBC patients, which allows for a reliable extrapolation of results. Furthermore, we analyzed the tumor location within the breast, which has been rarely focused on. Moreover, competing risk regressions were further used to validate our results, increasing the accuracy of the study. However, the main limitations of this study were its missing data, especially on antigen identi ed by monoclonal antibody Ki-67 status, disease free survival and adjuvant therapy information. The pathologic information was collected from different hospitals and failed to undergo a centralized review. In addition, because of the special status of the disease, the number of MBC and FBC patients were very asymmetric.

Conclusions:
Our retrospective study showed that MBC has a worse overall prognosis than FBC and the independent prognostic factors between MBC and FBC were incompletely the same. In addition, there are such vast differences between genders for tumor location, which should be considered by clinicians as a prognostic factor. MBC should be considered as an independent disease. Future research on MBC is needed in many aspects, including molecular pathology, risk factors, genetic contributions diagnostic and therapeutic tools. Declarations Nan Yao and Wenzai Shi executed the study and drafted the manuscript. Nan Yao, Sarah Tan Siyin and Tong Liu participated in the study design and performed the statistical analyses. Weiqi Wang, Ning Duan and Guoshuai Xu contributed to the discussion. Jun Qu reviewed the manuscript.

Competing interests
The authors declare no competing interests.

Ethics approval and consent to participate
The study was approved by the Ethics Committee of Aerospace Center Hospital and was complied with the Declaration of Helsinki. The work has been reported in line with the STROCSS criteria and in its references.

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