Evaluating Sex Disparity in Pancreatic Ductal Adenocarcinoma Risk in the UK Biobank Cohort

Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is lower in females than males (19.0 vs. 20.2 for 100,000 individuals in Europe). This disparity is commonly attributed to differences in exposure to lifestyle risk factors such as smoking and alcohol consumption; however, hormonal activity may also play a role. Objective: This study aimed to comprehensively examine the role of hormone exposure and reproductive factors in males and females in PDAC susceptibility. Methods: We analyzed 816 PDAC cases and 302,645 controls from the UK Biobank prospective cohort. Twenty hormone-related variables and a polygenic risk score (PRS) were examined in females and males using epidemiological methods and machine learning algorithms. Results: Oral contraceptives (OC) use increased PDAC risk (OR = 2.17 (95% CI: 1.70–2.80), p = 8.16 × 10−10), while each full-term pregnancy decreased it (OR = 0.83 (95% CI: 0.76–0.90), p = 2.60 × 10−5). In males increased level of sex hormone-binding globulin (SHBG) was associated with a decreased risk (OR = 0.98, 95% CI: 0.97–0.98, p = 7.38 × 10−10). The machine learning model performed well in both sexes, with AUCs of 0.95 and 0.92, specificity of 0.86 and 0.92 and sensitivity of 0.90 and 0.81 for females and males, respectively. The use of an explainer identified age and the PRS as significant features for both sexes, with additional factors such as age at menopause and OC use for females, and SHBG concentration in blood for males. Conclusion: We observed a consistent protective effect of the factors that decrease-the exposure to menstrual cycle related hormones. Additionally, exogenous hormones increase due to long exposure to OC and HRT increases the risk of the disease. Therefore, our result suggests that it is more important to which hormones an individual is exposed compared to the overall increase or decrease in exposure.