Association between female reproductive factors and new-onset pancreatic cancer risk: a prospective cohort study

The link between female reproductive factors and pancreatic cancer risk is unclear. This study examined these associations in a large prospective cohort and explored potential modification by genetic susceptibility. We analyzed data from 196 563 women in the UK Biobank using multivariable Cox proportional hazards models. Stratified analyses were performed by age, smoking status, BMI, and genetic susceptibility (polygenic risk score, dichotomized as low/high), with multiplicative interaction terms testing effect modification. Sensitivity analyses assessed robustness. Over a median 13.68-year follow-up, 624 pancreatic cancer cases occurred. Menopause at ages 47-49 [versus 50-52, hazard ratio: 0.75, 95% confidenc interval (CI): 0.56-0.99] and first live birth at ages 31-35 (versus 26-30, hazard ratio: 0.50, 95% CI: 0.31-0.82) were associated with lower risk, whereas prior hormone replacement therapy (HRT) use (versus never, hazard ratio: 1.26, 95% CI: 1.07-1.49) was linked to higher risk. Results were consistent in sensitivity analyses. Genetic susceptibility significantly modified associations for first live birth at ages 31-35 (stronger protection in high genetic risk), three live births (stronger protection in low genetic risk), and bilateral oophorectomy (increased risk in low genetic risk) ( P < 0.05 for interaction). These findings indicate that age at menopause, age at first live birth, and HRT use are associated with pancreatic cancer risk, and that certain reproductive factors - age at first live birth, parity, and bilateral oophorectomy - interact with genetic susceptibility. This provides further evidence for the role of reproductive factors in pancreatic cancer etiology.