LB-15

Background: Historically, U.S. breast cancer incidence rates have been 4-7 times higher than in Asian countries. When Asian women migrate to the U.S., rates rise over several generations to approach those of U.S. Whites. Modifiable factors must contribute to variations in risk; however, accepted risk factors, including endogenous estrogens, do not account for these differences. In our study of breast cancer in Asian-American women, women born in the West have a 60% higher risk than those born in Asia. Here we compare urinary estrogen metabolite levels by birthplace among study controls to explore the role of estrogen metabolism in international differences.
 Methods: In a population-based case-control study of breast cancer in women of Chinese, Japanese and Filipino ancestry, aged 20-55 years, and living in San Francisco-Oakland, Los Angeles, and Oahu, 966 controls were interviewed. Overnight (12 h) urines were collected from 379 premenopausal and 161 postmenopausal women with no recent history of pregnancy, lactation, or exogenous hormone use. Fifteen estrogens and estrogen metabolites (EM), specifically, estrone (E1); estradiol (E2); three catechol estrogens; five 16α pathway estrogens, including estriol (E3); and five methoxylated estrogens, were measured using a liquid chromatography-tandem mass spectrometry (LC-MS2) method. Each EM was expressed as a percentage of total EM (%) and log transformed. General linear models were used to compare EM profiles separately in pre- and postmenopausal women by place of birth, adjusting for age and Asian ethnicity.
 Results: Absolute total urinary EM (pg/mg creatinine) did not differ significantly by birthplace in pre- or postmenopausal women. E1, E2 and E3 (%) did not show consistent associations with birthplace. Among premenopausal women, in each ethnicity, 2-hydroxyestrone, 2-methoxyestrone, and total 2-hydroxylated estrogens (%) were significantly lower in women born in the West compared to those born in Asia. In addition, each of five 16α pathway EM were higher in women born in the West; differences reached statistical significance for 17-epiestriol, 16-ketoestradiol, and 16-epiestriol (%). Among postmenopausal women findings differed by ethnicity, with results for Chinese and, to some extent, Filipino women paralleling those in premenopausal women. Continuing analysis will extend these findings and assess 4-hydroxylation and methoxylation pathways.
 Discussion: Preliminary results suggest that whether estrogen is metabolized by 2 or 16α-hydroxylation may be related to Asian vs. Western lifestyles, and that 2-hydroxylation may contribute to lower breast cancer rates in Asian populations. With the development of accurate, precise, sensitive LC-MS2 methods for concurrently measuring EM, individual patterns of estrogen metabolism and their role in hormonal carcinogenesis can be systematically evaluated.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA