Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. gierachg@mail.nih.gov sampsonjn@mail.nih.gov.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
- University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health, Little Rock, Arkansas.
- University of Maryland School of Public Health, College Park, Maryland.
- University of California at San Francisco, San Francisco, California.
- University of Maryland School of Medicine, Baltimore, Maryland.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
- Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918-25. ©2017 AACR.