Abstract 2306: Estrogen metabolism-related lifestyle scores and breast cancer risk among 62,000 Chinese and American postmenopausal women: Findings from two large prospective cohort studies

Background: An increased 2-hydroxylation (2-OH) of estrogen has been linked to reduced risk of breast cancer (BC). We hypothesized that lifestyle patterns related to an elevated estrogen 2-OH metabolism were associated with lower BC risk and tested this hypothesis among post-menopausal women in two prospective cohorts. Methods: Estrogens and estrogen metabolites (EMs) were profiled by liquid chromatography-mass spectrometry in a subset of post-menopausal women in the Shanghai Women’s Health Study (SWHS, n=804) and Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n=842), respectively. Blood (PLCO) or urine (SWHS) samples used in these assays were collected at baseline prior to any cancer diagnosis. We applied elastic net regularized regression to derive two lifestyle scores that characterize relative abundance of 2-OH pathway EMs, estimated separately by the ratio of 2-OH EMs to parent estrogens and the ratio of 2-OH EMs to parent estrogens and all EMs combined. Intakes of foods and nutrients assessed by baseline food frequency questionnaires, and measures of body fat, alcohol intake, cigarette smoking, and leisure-time physical activity were included as predictors. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of derived lifestyle scores with post-menopausal BC risk in the larger SWHS (N=35,453) and PLCO (N=26,758) cohorts, after adjusting for potential confounders. Results: The lifestyle scores explained 10-12% of the total variance in the 2-OH EM ratios. A high lifestyle score for the ratio of 2-OH EMs to parent estrogens was associated with decreased BC risk in the SWHS (HR=0.73, 95% CI=0.59-0.90 for the highest versus lowest quartile, Ptrend=0.001). This inverse association was seen only among estrogen receptor (ER)-positive BC cases (Pheterogeneity=0.03). A similar association was observed for the lifestyle score for the ratio of 2-OH EMs to the combined parent estrogens and EMs. In the PLCO, the score for the ratio of 2-OH EMs to parent estrogens was inversely related to BC risk (HR=0.83, 95% CI=0.70-0.99, Ptrend=0.06), whereas no significant association was found for the other lifestyle score. Conclusion: A lifestyle pattern reflecting elevated estrogen 2-OH metabolism may lower post-menopausal BC risk. Women with a low 2-OH of estrogen may benefit from diet and lifestyle modifications. Citation Format: Fangcheng Yuan, Wanqing Wen, Steven C. Moore, Wei Zheng. Estrogen metabolism-related lifestyle scores and breast cancer risk among 62,000 Chinese and American postmenopausal women: Findings from two large prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2306.