Rae, J. M., Drury, S., Hayes, D. F., Stearns, V., Thibert, J. N., Haynes, B. P., Salter, J., Sestak, I., Cuzick, J., Dowsett, M., Trialists, Atac (2012) CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 104 (6). pp. 452-460. ISSN 0027-8874

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Abstract

Background Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy. Methods Tumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction based Taq Man assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided. Results After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P= .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P= .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients. Conclusion The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.

Item Type:	Article
Authors (ICR Faculty only):	Dowsett, Mitch
All Authors:	Rae, J. M., Drury, S., Hayes, D. F., Stearns, V., Thibert, J. N., Haynes, B. P., Salter, J., Sestak, I., Cuzick, J., Dowsett, M., Trialists, Atac
Additional Information:	ISI Document Delivery No.: 913PF Times Cited: 2 Cited Reference Count: 48 Rae, James M. Drury, Suzy Hayes, Daniel F. Stearns, Vered Thibert, Jacklyn N. Haynes, Ben P. Salter, Janine Sestak, Ivana Cuzick, Jack Dowsett, Mitch Breast Cancer Research Foundation (BCRF)[N003173, 1RO1GN1099143]; Fashion Footwear Charitable Foundation of New York/QVC; Breakthrough Breast Cancer; National Institute Health Research Royal Marsden Biomedical Research Centre; BCRF; Cancer Research United Kingdom program[C569-A10404, C569-A11449] This work was supported in part by The Breast Cancer Research Foundation (BCRF) (grant numbers N003173 to JMR and DIFH and 1RO1GN1099143 to JMR), Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale (to DFH), Breakthrough Breast Cancer and the National Institute Health Research Royal Marsden Biomedical Research Centre (MD, SD, BH) and BCRF (MD, BH), and Cancer Research United Kingdom program grants (C569-A10404 and C569-A11449 to JC). Oxford univ press inc Cary
Uncontrolled Keywords:	adjuvant treatment atac trial postmenopausal women aromatase inhibitors combination trial in-vitro therapy anastrozole polymorphisms metabolism
Research teams:	ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Users 11 not found.
Date Deposited:	16 Apr 2012 10:12
Last Modified:	30 Jan 2014 16:45
URI:	http://publications.icr.ac.uk/id/eprint/11521

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