Since male breast cancer is a less common malignancy, the clinical management of male breast cancer mainly refers to female breast cancer,9 and there is a lack of treatment guidelines and clinical trials specifically for male breast cancer patients.10 Moreover, previous studies have concluded that the biological characteristics of male breast cancer are different from those of female breast cancer.11、12 Leone et al. concluded that the prognosis of MBC is worse than that of FBC.13 Adjuvant radiotherapy has an irreplaceable place in female breast cancer, whereas adjuvant radiotherapy for male breast cancer has rarely been reported, so this paper focuses on the prognostic impact of adjuvant radiotherapy on male breast cancer.
Recruiting a sufficient number of male patients for clinical analysis can pose a significant challenge for a single center. To overcome this limitation, we conducted our analysis utilizing the SEER database, which provided data from 3,124 cases between 2010 and 2018.Retrospective clinical studies often encounter numerous known and unknown confounding factors that can have unpredictable impacts on the study results. Traditionally, researchers would employ methods such as stratified analysis and multiple regression to control for these confounding factors. However, when the number of confounding factors increases, these methods may have limitations in achieving proper control.
In comparison, propensity score matching (PSM) demonstrates better capability in balancing covariates and minimizing selection bias between groups. This method addresses confounding factors to a greater extent and enhances matching accuracy. In this study, we utilized the nearest-neighbor matching method within PSM to eliminate the influence of perceivable confounders between the two groups. However, it is important to note that PSM does not completely resolve all endogeneity issues. Therefore, to enhance the robustness of the results, we combined the matching method with traditional approaches.
By employing this combined approach, we aimed to increase the credibility and reliability of our findings by addressing confounding factors and reducing bias in the study.
Studies have shown that the average age of male patients at diagnosis is older than the average age of women at diagnosis, which could be explained by a general lack of awareness of this rare disease in men and ignorance of the risk factors associated with breast cancer in men.14 Our study found that male breast cancer patients tended to have more frequent lymph node metastases and higher rates of estrogen receptor and progesterone receptor positivity than female breast cancer patients, consistent with a previous study by Massarweh et al..15
In the matched cohort of this study, our analysis found that adjuvant radiotherapy before PSM improved BCSS only (p = 0.006), whereas adjuvant radiotherapy after PSM significantly improved OS (p = 0.023) with BCSS (p = 0.035), while,5-year BCSS was lower in the unmatched preradiotherapy group (87.9%) than in the non-radiotherapy group (91.6%) (p = 0.006), and 5-year OS (74.9%) and BCSS (88.4%) were higher in the matched postradiotherapy group than in the non-radiotherapy group (67.2%) (p = 0.023) and BCSS (83.2%) (p = 0.035). This outcome could be related to the finding with the chi-square test that a higher proportion of the population in the unirradiated group before matching was older than 60 years old, with nonmetastatic lymph nodes, ER+, and no chemotherapy, than in the radiotherapy group and that PSM could maximize the effect of confounding factors other than radiotherapy between the two groups, making the results more credible. In the K-M analysis, we found that radiotherapy was a better prognostic indicator for OS in patients ≥ 60 years old with ER+, PR status, HER2+, T1, and N0; patients ≥ 60 years old with ER+, PR-, T1, and M0 had a BCSS survival benefit with radiotherapy, which was largely consistent with the results of the subsequent subgroup analysis.
In the present study, univariate analysis showed a significant difference with radiotherapy in both OS and BCSS (p = 0.024, p = 0.037). After multivariate analysis, radiotherapy also showed a significant difference in OS and BCSS (p = 0.025, p = 0.028), suggesting that postoperative radiotherapy improves OS and BCSS in male breasts. Previously, Lin et al. searched 40 studies, and pooled estimates of overall survival (OS) showed that the adjuvant radiotherapy group had significantly increased OS compared to the non-radiotherapy group.16 In contrast, the study by Ruddy et al. did not find an OS benefit with adjuvant radiotherapy,17 which was inconsistent with our study. We believe that the failure to improve BCSS or OS might be related to the small sample size, and different inclusion criteria could also lead to different results, a phenomenon that has been reported previously. The large sample size of the present study increased the sensitivity of the chi-square test when it was used to detect differences between groups, thus allowing for detection of survival benefits that cannot be detected in clinical trials.
After multivariate analysis, age, marital status, grade, T stage, and chemotherapy were also independent predictors of OS (all p < 0.05), and metastatic status, PR status, T stage, and procedure were significant independent predictors of BCSS (p < 0.05). Human epidermal growth factor receptor-2 (HER-2) is a transmembrane glycoprotein with tyrosine kinase activity that plays a very important role in the growth and differentiation of epithelial cells,18 a molecular subgroup that has been shown to be effective in determining therapeutic strategies and predicting clinical outcomes compared to FBC.19、20 Holowatyj et al. concluded that HER-2 is not a factor affecting the prognosis of male breast cancer,21 and there was no significant difference in OS or BCSS between patients with different HER2 statuses in this study, consistent with previous studies.22
Indeed, it is worth noting that most existing articles on male breast cancer do not establish a clear association between adjuvant radiotherapy and survival through subgroup analysis based on clinical characteristics. Consequently, it remains uncertain whether all male patients should receive adjuvant radiotherapy. In this study, we employed Kaplan-Meier analysis and Cox analysis, which demonstrated benefits in overall survival (OS) and breast cancer-specific survival (BCSS) with postoperative adjuvant radiotherapy.To ensure the robustness of our findings and assess whether the results hold true across various subgroups, we conducted a subgroup analysis and generated a forest plot. This analysis allowed us to explore potential variations in the observed benefits of adjuvant radiotherapy among different subgroups based on age, marital status, tumor grading, T-stage, and chemotherapy status. Furthermore, considering the impact of marital status on OS and BCSS in breast cancer patients, as indicated by data from a study in 2019 involving 298,434 breast cancer cases, we included marital status as an additional subgroup analysis parameter.By conducting these subgroup analyses, we aimed to provide a more comprehensive understanding of the relationship between adjuvant radiotherapy and survival outcomes in male breast cancer patients, while considering various clinical and demographic factors that may influence the treatment effect.23 The forest plot analysis revealed several subgroups that exhibited better overall survival (OS) and breast cancer-specific survival (BCSS) benefits with adjuvant radiotherapy. Specifically, the following subgroups demonstrated improved OS: patients aged 60 years or older, with estrogen receptor (ER) positivity, absence of distant metastasis (M0), married status, and presence of local or regional metastasis, as well as those with Grade I or Grade II tumors after breast-conserving surgery or total excision. Additionally, the following subgroups displayed enhanced BCSS: patients aged 60 years or older, with ER positivity, progesterone receptor (PR) negativity, absence of distant metastasis (M0), married status, and presence of regional metastasis, as well as those with male breast cancer (MBC) receiving radiotherapy.These findings suggest that adjuvant radiotherapy is associated with better OS and BCSS outcomes in the male breast cancer population aged 60 years or older, with ER-positive, PR-negative tumors, absence of distant metastasis (M0), married status, and regional metastases. Moreover, the nonsignificant P-values for the interactions indicate that there is no significant interaction between these subgroups regarding the administration of radiotherapy, further reinforcing the reliability of the results. Consequently, adjuvant radiotherapy is recommended for the aforementioned population. Wang et al. highlighted the need for cautious consideration of radiotherapy or chemotherapy in male patients with ER-positive tumors.These findings contribute valuable insights for clinicians in determining the optimal treatment approach for male breast cancer patients, particularly those within the specified subgroups.24 while our study recommended postoperative radiotherapy more for ER + patients. This difference could be related to previous studies not further using matched analysis with subgroup analysis, and there was a high level of confounding interference. There are clinical results showing that post-BCS radiotherapy in women plays an irreplaceable role in reducing local recurrence and prolonging survival.25 With a subgroup analysis, we sought to determine who was more likely to benefit from postoperative radiotherapy. We did not find that the procedure was a factor in radiation efficacy, and patients could have OS benefits from postoperative radiotherapy whether they underwent breast-conserving surgery or total excision. The absence of a BCSS benefit in postoperative radiotherapy by procedure might be related the number of male breast cancer deaths being too small in the postgroup data to be statistically represented. A previous study of a group of 6,217 male breast cancer patients found an OS benefit from radiotherapy after BCS and no OS benefit after MS,26 which could have been due to the exclusion of stage IV male breast cancer patients from this study and the large confounding factor of not performing PSM.
There are also some unavoidable limitations of this article. First, family history is one of the strongest risk factors for breast cancer, but there is no relevant information about family history in the SEER database. Second, most male breast cancer patients have an increased risk of BRCA mutations,27、28 and BRCA mutations are not registered in SEER. Third, detailed information about adjuvant therapy, chemotherapy, endocrine therapy, targeted therapy, and biologic therapy is not available, which could have led to biased information.
The limitations of the SEER database itself contribute to the aforementioned factors. Firstly, as a retrospective cohort study, despite employing statistical corrections such as PSM analysis, Cox multifactorial regression, and subgroup analysis, it was not possible to fully account for all potential confounding factors. Therefore, there are inherent limitations when compared to prospective studies. However, overall, the present study maintains a high level of reliability.One of the strengths of the study is the reduction of selection bias between groups through PSM analysis, allowing for a more focused analysis of the benefits of adjuvant radiotherapy in male breast cancer patients based on their clinical characteristics. Additionally, the data used in our study is sourced from the SEER database, which strictly excludes missing data, ensuring the reliability of our findings.Importantly, this study provides valuable insights to clinicians regarding the survival benefits of adjuvant radiotherapy in male breast cancer patients. Specifically, it highlights that adjuvant radiotherapy is associated with improved overall survival (OS) and breast cancer-specific survival (BCSS) in male breast cancer patients, particularly in the age group of 60 years and above, with estrogen receptor-positive, progesterone receptor-negative, T1 stage, absence of distant metastasis (M0), and married status for OS. Additionally, BCSS is notably improved with radiotherapy. It is crucial to note that further large-scale clinical trials are necessary to validate these findings in order to advance individualized medicine, prolong patients' survival time, and enhance their quality of life.
