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Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.

ABSTRACT: Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumor-infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women.

SUBMITTER: Ahern TP

PROVIDER: S-EPMC5253974 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.

Ahern Thomas P TP Hertz Daniel L DL Damkier Per P Ejlertsen Bent B Hamilton-Dutoit Stephen J SJ Rae James M JM Regan Meredith M MM Thompson Alastair M AM Lash Timothy L TL Cronin-Fenton Deirdre P DP

American journal of epidemiology 20161217 2

Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 geno ...[more]

PMID: 27988492

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Project description:BackgroundAdjuvant 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.MethodsTumor 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.ResultsAfter 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.ConclusionThe results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.

Project description:Cytochrome P-450 2D6 (CYP2D6) is an important human drug-metabolizing enzyme responsible for the oxidation of more than 30 widely used therapeutic agents. The enzymes encoded by the published genomic [Kimura, Umeno, Skoda, Meyer and Gonzalez (1989) Am. J. Hum. Genet. 45, 889-904] and cDNA [Gonzalez, Skoda, Kimura, Umeno, Zanger, Nebert, Gelboin, Hardwick and Meyer (1988) Nature 331, 442-446] sequences of CYP2D6, and presumed to represent wild-type sequences, differ at residue 374 and encode valine (CYP2D6-Val) and methionine (CYP2D6-Met) respectively. The influence of this amino acid difference on cytochrome P-450 expression, ligand binding, catalysis and stereoselective oxidation of metoprolol was investigated by the heterologous expression of the corresponding cDNAs in the yeast Saccharomyces cerevisiae. The level of expression of apo- and holo-protein was similar with each form of CYP2D6 cDNA, and the binding affinities of a series of ligands to CYP2D6-Val and CYP2D6-Met were identical. The enantioselective O-demethylation and alpha-hydroxylation of metoprolol were also similar with each form of CYP2D6, O-demethylation being R-(+)- enantioselective (CYP2D6-Val: R/S, 1.6; CYP2D6-Met: R/S, 1.4), whereas alpha-hydroxylation showed a preference for S-(-)-metoprolol (CYP2D6-Val: R/S, 0.7; CYP2D6-Met: R/S, 0.8). However, although the favoured regiomer overall was O-demethylmetoprolol (ODM), the regioselectivity for O-demethylation of each metoprolol enantiomer was significantly greater for CYP2D6-Val [R-(+)-: ODM/alpha-hydroxymetoprolol (alpha OH), 5.9; S-(-)-: ODM/alpha OH, 2.5) than that observed for CYP2D6-Met [R-(+)-: ODM/alpha OH, 2.2; S-(-)-: ODM/alpha OH, 1.4]. The stereoselective properties of CYP2D6-Val were consistent with those observed for CYP2D6 in human liver microsomes. The difference in the stereoselective properties of CYP2D6-Val and CYP2D6-Met were rationalized with respect to a homology model of the active site of CYP2D6 based on an alignment with the crystal structure of the bacterial cytochrome P-450BM-3' CYP102.

Dataset Information

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.

Publications

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.

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