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

Experimental and clinical evidence suggests that 16 alpha -hydroxylated est rogen metabolites, biologically strong estrogens, are associated with breas t cancer risk, while 2-hydroxylated metabolites, with lower estrogenic acti vity, are weakly related to this disease, This study analyzes the associati on of breast cancer risk with estrogen metabolism, expressed as the ratio o f 2-hydroxyestrone to 16 alpha -hydroxyestrone, in a prospective nested cas e-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) wer e 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 his tory of cancer and women on hormone therapy were excluded at baseline. At r ecruitment, overnight urine was collected from all participants and stored at -80 degreesC, After an average of 5.5 years of follow up, 144 breast can cer 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 rati o 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 postmenopausa l women was 1.29 (95% Cl = 0.53-3.10). Results of this prospective study su pport the hypothesis that the estrogen metabolism pathway favoring 2-hydrox ylation over 16 alpha -hydroxylation is associated with a reduced risk of i nvasive breast cancer risk in premenopausal women.