Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: A prospective study

Background: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16 alpha-hydroxyestrone (16 alpha-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors. Methods: 24,697 postmenopausal Danish women were enrolled in the "Diet, Cancer and Health" cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16 alpha-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CD were estimated for total and estrogen receptor- specific breast cancer and were stratified according to HRT use. Results: A higher incidence of estrogen receptor- positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% Cl, 0.69-1.45). The association between estrogen receptor- positive breast cancer and the 16 alpha-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor-negative breast cancer, no significant associations were seen. Conclusions: The risk of breast cancer, in particular the estrogen receptor- positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.