American Journal of Epidemiology Advance Access originally published online on September 7, 2007
American Journal of Epidemiology 2007 166(12):1392-1399; doi:10.1093/aje/kwm239
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ORIGINAL CONTRIBUTIONS |
Pharmacogenetic Modulation of Combined Hormone Replacement Therapy by Progesterone-Metabolism Genotypes in Postmenopausal Breast Cancer Risk
1 Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
2 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
4 Department of Medicine, University of Pennsylvania, Philadelphia, PA
5 Johnson and Johnson Pharmaceutical Research and Development, Titusville, NJ
Correspondence to Dr. Timothy Rebbeck, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021 (e-mail: trebbeck{at}cceb.med.upenn.edu).
Received for publication April 11, 2007. Accepted for publication July 27, 2007.
Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999–2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided pinteraction = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.
breast neoplasms; genotype; hormone replacement therapy; metabolism; pharmacogenetics; postmenopause; progesterone; risk
Abbreviations: CHRT, combined hormone replacement therapy; CI, confidence interval; ER, estrogen receptor; hPR, human progesterone receptor; HRT, hormone replacement therapy; PR, progesterone receptor
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 RE: "PHARMACOGENETIC MODULATION OF COMBINED HORMONE REPLACEMENT THERAPY BY PROGESTERONE-METABOLISM GENOTYPES IN POSTMENOPAUSAL BREAST CANCER RISK" Am. J. Epidemiol., April 1, 2008; 167(7): 888 - 888. [Full Text] [PDF]
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