Reproductive factors and lung cancer risk in never-smoking women: a prospective cohort study

BACKGROUND: The association between endogenous estrogen and lung cancer in never-smoking women remains unclear. This study investigated the associations of various reproductive factors, as proxies for cumulative estrogen exposure, with lung cancer risk among never-smoking women from a lung cancer screening cohort. METHODS: Associations between reproductive factors and lung cancer risk were evaluated using multivariable logistic regression and restricted cubic splines. Mediation analysis assessed the mediating role of body mass index (BMI). Subgroup analyses were stratified by baseline characteristics. Robustness was verified through propensity score matching and inverse probability of treatment weighting. RESULTS: The study included 155,103 never-smoking women, identifying 657 incident lung cancer cases. Early menarche (< 13 years: OR, 1.41; 95% CI, 1.06-1.87), a shorter reproductive span (≤ 32 years: OR, 1.25; 95% CI, 1.02-1.54), and parity (≥ 1) (OR, 2.02; 95% CI, 1.16-3.52) were associated with increased risk. Later age at first birth (≥ 30 years) (OR, 0.63; 95% CI, 0.41-0.98) and a history of benign breast disease (OR, 0.64; 95% CI, 0.47-0.87) were inversely associated with lung cancer risk, with age at first birth showing a non-linear dose-response relationship. Mediation analyses suggested a potential role of BMI in these associations. Stratified analyses revealed significant effect modification by age, BMI, and clinical history. CONCLUSION: Reproductive factors are associated with lung cancer risk among never-smoking women. Integrating reproductive histories into routine lung cancer screening programs will facilitate more precise risk stratification.