CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast
cancer patients.
Author(s): Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J, Sestak I,
Cuzick J, Dowsett M; ATAC trialists.
Affiliation(s): Department of Internal Medicine, University of Michigan Medical Center, Ann
Arbor, MI, USA. jimmyrae@umich.edu
Publication date & source: 2012, J Natl Cancer Inst. , 104(6):452-60
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.
Erratum in
J Natl Cancer Inst. 2012 Nov 21;104(22):1772.
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