Estrogen metabolism-related lifestyle score and risk of postmenopausal breast, endometrial, and ovarian cancers: findings from two large prospective cohort studies

High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential anti-tumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EMs) to parent estrogens (2-OH EM/parent E ratio) might lower estrogen-related cancer risk. We applied elastic net regularized regression to derive lifestyle scores correlated with the 2-OH EM/parent E ratio separately using data from subsets of cancer-free, postmenopausal women in Shanghai Women's Health Study (SWHS, n=723) and Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n=635), where blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent estrogens and EMs. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of lifestyle scores with risk of breast, endometrial, and ovarian cancers in SWHS (N=35,453) and PLCO (N=26,565). The lifestyle scores explained 10-11% of total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with 29% (HR=0.71, 95% CI=0.57-0.88, Ptrend<0.001) and 61% (HR=0.39, 95% CI=0.21-0.71, Ptrend<0.001) lower risk of breast and endometrial cancers comparing the highest to lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention.