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Reproductive Factors and Lung Cancer Risk among Never-Smoking Japanese Women with 21 Years of Follow-Up: A Cohort Study

Background: Previous studies have reported inconsistent associations between reproductive factors and lung cancer. Methods: We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models. Results: Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07–2.06, Ptrend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01–1.96, Ptrend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02–3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33–5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28–0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected. Conclusions: Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis. Impact: Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.