Estrogen Metabolism-Related Lifestyle Score and Risk of Postmenopausal Breast, Endometrial, and Ovarian Cancers: Findings from Two Large Prospective Cohort Studies.

[UNLABELLED] High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential antitumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EM) 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 the Shanghai Women's Health Study (SWHS, n = 723) and the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n = 635), in which blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent Es and EMs. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of lifestyle scores with the risk of breast, endometrial, and ovarian cancers in SWHS (N = 35,453) and PLCO (N = 26,565). The lifestyle scores explained 10% to 11% of the total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with a 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 when comparing the highest with the lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than with ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with a lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention.

[PREVENTION RELEVANCE] Elevated estrogen 2-OH has been linked to reduced breast cancer risk. We showed that lifestyle patterns increasing the 2-OH EM/parent E ratio were associated with lower postmenopausal breast and endometrial cancer risk. Our findings suggest that targeted lifestyle modifications may benefit postmenopausal women with a low 2-OH EM/parent E ratio.