TY - JOUR
T1 - CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients
AU - Rae, James M.
AU - Drury, Suzy
AU - Hayes, Daniel F.
AU - Stearns, Vered
AU - Thibert, Jacklyn N.
AU - Haynes, Ben P.
AU - Salter, Janine
AU - Sestak, Ivana
AU - Cuzick, Jack
AU - Dowsett, Mitch
N1 - Funding Information:
Conflict of interest declarations: J. M. Rae is a Scientific Advisor for Olema Pharmaceuticals, has received speaking honoraria from GTx Pharmaceuticals, and research funding from Pfizer, Inc. D. F. Hayes has research grants from Pfizer, Inc, Novartis, Inc, and AstraZeneca, Inc. V. Stearns has research funding from Novartis, Inc, and Pfizer, Inc, honoraria from AstraZeneca, Inc, and consults for Otsuka, Inc. M. Dowsett has research grants, given lectures, on the advisory board and given legal advice to AstraZeneca, Inc. J. Cuzick has a research grant and consulted for AstraZeneca. The authors are solely responsible for the study design, data collection, analysis and interpretation of the data, writing the article, and decision to submit the article for publication.
Funding Information:
This work was supported in part by The Breast Cancer Research Foundation (BCRF) (grant numbers N003173 to JMR and DFH and 1RO1GM099143 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).
PY - 2012/3/21
Y1 - 2012/3/21
N2 - 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 TaqMan 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.
AB - 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 TaqMan 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.
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U2 - 10.1093/jnci/djs126
DO - 10.1093/jnci/djs126
M3 - Article
C2 - 22395643
AN - SCOPUS:84859054082
SN - 0027-8874
VL - 104
SP - 452
EP - 460
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 6
ER -