Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(10):2139-2142; doi:10.1093/carcin/bgm087
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Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use
Department of Radiation Oncology, Princess Margaret Hospital–University Health Network, Toronto, Ontario, Canada
1 Department of Medicine, Pharmacology and Psychiatry, University of Toronto, Toronto, Ontario M5G 2M9, Canada
2 Ventana Clinical Research Corporation, Toronto, Ontario M5T 3A9, Canada
3 Department of Surgical Oncology
4 Department of Gynecologic Oncology, Princess Margaret Hospital–University Health Network, Toronto, Ontario M5G 2M9, Canada
5 Department of Interdisciplinary Oncology, University of South Florida, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
6 Center for Research in Women's Health, Women's College Hospital, Toronto, Ontario, Canada
* To whom correspondence should be addressed. Tel: +1 416 351 3765; Fax: +1 416 351 3767 Email: steven.narod{at}wchospital.ca
Tamoxifen is a selective estrogen receptor modulator that is used to treat and to prevent breast cancer; however, its use is associated with an increased risk of endometrial cancer. Tamoxifen is metabolized by various cytochrome P450 (CYP) enzymes, but predominantly by CYP3A4. In this study, we examined whether a genetic variant of the CYP3A4 gene, CYP3A4*1B, influences endometrial cancer risk—alone and when associated with tamoxifen exposure. We conducted a case–control study on 566 endometrial cancer cases and 964 ethnically matched controls. The variant CYP3A4 allele was present in 6% of the controls and 9% of the endometrial cancer patients (OR = 1.6, 95% CI = 1.1–2.3, P = 0.02). The allele was more common in women with endometrial cancer who had been treated with tamoxifen for breast cancer (16%). Women who carried the CYP3A4*1B allele had 
3-fold increase in the risk of developing endometrial cancer following tamoxifen treatment, compared with women who did not take tamoxifen (P = 0.004). These findings suggest that a subgroup of breast cancer patients who carry the CYP3A4*1B allele and take tamoxifen may be at increased risk of developing endometrial cancer.
Abbreviations: CYP, cytochrome P450; 
-OHT, -hydroxytamoxifen; 4-OHT, 4-hydroxytamoxifen; N-DDMT, N-didesmethyltamoxifen; N-DMT, N-desmethyltamoxifen
Received August 15, 2006; revised March 29, 2007; accepted April 2, 2007.