Background: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE1) and 16-hydroxyestrone (16-OHE1) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer. Methods: This population-based study was initiated in 1996–1997 with spot urine samples obtained shortly after diagnosis (mean ¼ 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE1 and 16-OHE1 using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n ¼ 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided. Results: Urinary concentrations of the 2-OHE1 to 16-OHE1 ratio (>median of 1.8 vs <median) were inversely associated with all-cause mortality (HR ¼ 0.74, 95% CI ¼ 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR ¼ 0.73, 95% CI ¼ 0.45 to 1.17) and cardiovascular diseases mortality (HR ¼ 0.76, 95% CI ¼ 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n ¼ 118, HR ¼ 0.42, 95% CI ¼ 0.22 to 0.81) than among those who had not (n ¼ 559, HR ¼ 0.98, 95% CI ¼ 0.72 to 1.34; Pinteraction ¼ .008). Conclusions: The urinary 2-OHE1 to 16-OHE1 ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection
