Estrogen metabolism and risk of breast cancer:: A prospective study of the 2:16α-hydroxyestrone ratio in premenopausal and postmenopausal women

Experimental and clinical evidence suggests that 16 alpha -hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease, This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16 alpha -hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the "Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degreesC, After an average of 5.5 years of follow up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16 alpha -hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (Cl) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% Cl = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16 alpha -hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.