To the best of our knowledge, this is the largest sex-specific survival study that considered the major established cancer and patient characteristics in breast cancer to elucidate potential sex-specific differences in the survival of breast cancer patients in China within a time span of more than 15 years. This study's main finding was the long-term survival of male patients with breast cancer that was significantly lower compared to female patients after matching for age, diagnosis year, TNM stage, and histological subtype.
Similar to previous reports, male patients in this study accounted for 0.85% of all patients with breast cancer and were more likely to receive a diagnosis at a later age and higher stage than female cases [1, 3, 18]. Men in this study were less likely to be diagnosed with a ductal histologic type (54.38%), which is not consistent with previous findings reported by studies in the SEER database and from European countries (>75%) [1, 19], A large number of missing histological cases in this study (26.50%), the population difference, and potentially different diagnostic criteria applied across different countries might partially contribute to this gap.
Our matched-pair study showed that the survival rate of male breast cancer was significantly lower compared to female breast cancer, which was in line with the observations reported in the single-institute studies from Guangdong, Tianjin, and Shandong, showing a worse prognosis for male breast cancer patients both in overall and disease-free survival [9-12]. Still, the population-based study from Hong Kong showed that male patients had poorer OS in an early stage but better breast-cancer-specific survival compared with their female counterparts [2], however, given the limited number of male cases (n=132) and breast cancer-specific deaths (n = 12), these results need to be further confirmed. The sample size is crucial in the analysis of population-based survival data. For instance, most US studies before the year 2015 showed similar overall survival rates for male and female breast cancer patients [8, 20-22]. Yet, the most recent updated analysis in the SEER program, which included 2254 men with early breast cancer, and in the National Cancer Database, which comprised 16,025 men with breast cancer, revealed a significant survival disadvantage for male patients [18, 23]. The results from a worldwide study including 2665 men diagnosed with breast cancer from 5 European countries and 1 country from southeast Asia were different from the findings of the present study, which revealed a better survival for male breast cancer patients than females after adjusting for region, time since diagnosis, age, and year of diagnosis, stage, and treatment (relative excess risk: 0.78, 95% CI: 0.62-0.97)[3], thus suggesting the regional diversity in the sex disparity of breast cancer survival.
Several possible factors might explain the sex disparity in the breast cancer survival rate. First, population-based studies have shown that the prevalence of breast cancer susceptibility gene 2 (BRCA2) mutations in men with breast cancer was 4%-16% [24, 25], which is slightly higher than that in women with breast cancer (around 4%) [26]. A meta-analysis showed that BRCA2 mutations are associated with worse overall survival among breast cancer patients [27]. Second, the treatment patterns for men differed from that for women, although male breast cancer patients' management was mainly extrapolated from the knowledge about female breast cancer [28, 29], compared with women, the compliance of adjuvant radiotherapy was lower for men among many countries [3], and more than 50% of men who were treated with breast-conserving surgery did not receive radiotherapy [4, 30], which could explain the more obvious sex disparity among patients with early-stage breast cancer in our study. In addition, our results confirming the changes in risk of death for male breast cancer patients that occur over time suggest that the improvement of treatment could narrow the survival gap between men and women but could not eliminate it. Third, the lifestyle risk factors, which are closely related to breast cancer survival, such as smoking and obesity, might be differently distributed among male and women breast cancer patients [31, 32].
This study has several limitations that need to be pointed out. The major limitation is the lack of information on the specific cause of death (breast cancer, other cancers, cardiovascular disease, and others) and factors closely related to breast cancer survival, such as treatment strategies [breast surgery, (neo)adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, etc.], molecular subtypes (estrogen receptor, progesterone receptor, androgen receptor, HER-2, etc.). The linkage of population-based cancer registry database and hospital-based treatment database is expected in the future to eliminate this limitation. Also, lifestyle factors (smoking, body mass index, etc.) were not available in this study due to the deficiencies of cancer registry data. Second, a large number of male breast cancer cases (45%) missed the information on the TNM stage, leading to the unprecise estimation of breast cancer survival. However, we matched male cases with female cases by TNM stage, including the missing class, which reduced the potential bias in the comparison of the sex disparity for breast cancer survival.
The study's strength includes the coverage of all residents in Shanghai, the well-established follow-up system of SCR, and the 17-year follow-up for overall and cancer-specific death, which enabled us to examine the differences in long-term survival rates among men and women diagnosed with breast cancer in Shanghai, China. Additionally, the analysis was conducted using the matched-pair approach and considering the established factors that could affect breast cancer survival (age, diagnosis year, TNM stage, and histological subtype), reducing the major clinical and demographic bias in the survival analysis.
In summary, our study provided further evidence that male patients with breast cancer have lower long-term survival rates than women in China, particularly younger patients and those at an early clinical stage. Future studies with more detailed clinical treatment, cancer subtype, and lifestyle information are needed to deepen the understanding of male breast cancer biology and identify the factors that could eliminate this sex disparity.