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Cancer Epidemiol Biomarkers Prev. 2011 Jul;20(7):1502-15. doi: 10.1158/1055-9965.EPI-11-0060. Epub 2011 May 24.

Estrogen metabolism and exposure in a genotypic-phenotypic model for breast cancer risk prediction.

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  • 1Department of Mathematics, Vanderbilt University, Nashville, TN 37232, USA.

Abstract

BACKGROUND:

Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites.

METHODS:

We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE(2)), expressed as area under the curve metric (4-OHE(2)-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE(2). We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls).

RESULTS:

In the GENICA study, premenopausal women at the 90th percentile of 4-OHE(2)-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE(2)-AUC percentile (95% CI: 1.7-3.2, P = 2.9 × 10(-7)). This relative risk was 1.89 (95% CI: 1.5-2.4, P = 2.2 × 10(-8)) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3-2.6, P = 7.6 × 10(-4)), which increased to 1.83 (95% CI: 1.4-2.3, P = 9.5 × 10(-7)) when a history of proliferative breast disease was included in the model.

CONCLUSIONS:

The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk.

IMPACT:

The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates.

©2011 AACR

PMID:
21610218
[PubMed - indexed for MEDLINE]
PMCID:
PMC3472969
Free PMC Article
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