Despite the availability of new treatment options, survival rates remain poor in patients diagnosed with BTC. In this study, the survival differences observed between male and female patients with biliary tract tumors are striking. Female patients demonstrated better OS compared to male patients, despite having similar disease stages and receiving comparable treatment protocols. Hormonal factors, immune system differences, and BRCA gene mutations may contribute to these distinct outcomes. This gender-related survival disparity raises critical questions about the influence of gender on BTC prognosis. Our study draws attention to this gap in the literature and provides a basis for better understanding the impact of gender differences on treatment response and prognostic outcomes

Several studies have suggested that female gender is associated with a more favorable prognosis in BTC. For instance, a systematic review analyzing 587 cholangiocellular cancer patients from different centers found that survival was longer in women than in men (Ledenko et al. 2022). A meta-analysis summarizing seventeen prospective study publications and three retrospective study publications involving nearly 1,000 participants, response rates to gemcitabine and cisplatin-based chemotherapy were 10% higher in women than in men (Park et al. 2015). In a study of 313 matched pairs of patients with intrahepatic cholangiocarcinoma, male gender was an independent risk factor for overall survival and tumor recurrence (Zou et al. 2024). More recently, data from the United States have shown that mortality from CCA is lower among females, with a risk ratio of 0.78 (95% CI 0.77–0.79) (Yao et al. 2016). Our study also reveals the difference of better survival in female gender in patients with BTC and makes a valuable contribution to the literature.

Furthermore, our analysis revealed that 73% of patients were diagnosed in the metastatic stage, which is associated with reduced treatment efficacy. The results of our study indicate that the gender factor, which represents a significant gap in treatment research, should be taken into consideration in this patient group, which is predominantly diagnosed at an advanced stage and has a poor prognosis. The effect of sex hormones may be one of the factors responsible for the significant difference in long-term prognosis between male and female BTC patients. Previous studies have investigated the association between sex hormones and the risk of ICC in women. A recent study on menopausal hormone therapy and the risk of biliary tract cancers revealed that estrogen-only formulations were associated with a lower risk of cholangiocarcinoma (Stieger et al. 2000). Although these results are on the risk of developing CCA, they suggest that estrogen may also have a protective effect during the treatment process. Addressing the gender factor adequately may clarify the reasons for survival differences and guide personalized treatment options to improve survival outcomes in this high-risk group.

Sex-specific differences in cancer mortality are most pronounced for malignant melanoma, lung, larynx, oesophagus and bladder cancers (Cook et al. 2009, 2011). Apart from cancer causes and hormonal regulation, differences in the immune system are believed to contribute to this male biased mortality rate. Studies indicate that women exhibit a stronger immune response than men, which may contribute to a reduced cancer mortality rate (Cook, Dawsey, Freedman, Inskip, Wichner, Quraishi, Devesa and McGlynn 2009; Cook et al. 2011; Klein and Flanagan 2016; Pennell et al. 2012). These immune system differences may impact tumor progression and treatment response in BTC patients, potentially hindering treatment efficacy in males.

Another possible explanation for the higher survival rates in women with BTC may be gender differences in CYP3A4 enzyme activity, which plays a critical role in drug metabolism. The CYP3A4 enzyme is involved in the processing of various drugs and steroid hormones, and generally has higher activity in women compared to men (Su et al. 2017; Yang et al. 2012). This may positively influence women’s treatment response and therefore survival rates, particularly by affecting the rate at which drugs used in some cancer treatments are metabolized. The higher activity of the CYP3A4 enzyme may lead to faster clearance of drugs in women, reducing the risk of side effects and making treatments easier to tolerate (Klein and Zanger 2013). This difference may also be reflected in the processing of hormones, as CYP3A4 may accelerate the breakdown of steroid hormones, influencing hormone-induced tumor development. These factors may potentially provide the biological basis for women responding better to bile cancer treatments than men. Addressing the gender factor more thoroughly could shed light on the mechanisms behind these survival differences and enable the development of personalized treatment options that enhance outcomes for both sexes.

It should be noted that this study is subject to several limitations. First, the relatively small number of patients included in this retrospective analysis limits the statistical power and generalizability of our findings. Second, the heterogeneity of the patient cohort, encompassing both early-stage and advanced-stage patients, may introduce variability that could affect the interpretation of gender-related survival differences. Third, the limited sample size restricted our ability to perform subgroup analyses, which could have provided more nuanced insights into the observed disparities. Fourth, the lack of data on differences in treatment care standards between patients prevents a comprehensive evaluation of how variations in clinical management might influence survival outcomes. Additionally, hormone levels and detailed pathological subtypes were not included in the analysis due to limitations in the data collected, which may restrict the scope of our interpretation. These limitations highlight the need for caution when interpreting our results and underscore the importance of further research to validate and expand upon the conclusions drawn from this study.