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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1B1
  • Estradiol / analogs & derivatives
  • Estradiol / biosynthesis
  • Estrogens / metabolism*
  • Estrogens, Catechol
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Middle Aged
  • Models, Theoretical*
  • Phenotype
  • Risk Factors

Substances

  • Estrogens
  • Estrogens, Catechol
  • Estradiol
  • 4-hydroxyestradiol
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1