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- Title
The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.
- Authors
Matthew Goetz; Stacey Knox; Vera Suman; James Rae; Stephanie Safgren; Matthew Ames; Daniel Visscher; Carol Reynolds; Fergus Couch; Wilma Lingle; Richard Weinshilboum; Emily Fritcher; Andrea Nibbe; Zeruesenay Desta; Anne Nguyen; David Flockhart; Edith Perez; James Ingle
- Abstract
<div class="abstract"><a name="abs1"/><span class="abstractheading">Abstract<div class="abstractsection"><div class=""><span class="abstractsectionheading">Background??Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme.CYP2D6genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death.Methods??Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling.Results??Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n?=?3), moderate (n?=?10)], resulting in the following CYP2D6 metabolism: extensive (n?=?115) and decreased (n?=?65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p?=?0.034; adj HR?=?1.91; 95% CI 1.05?3.45) and worse relapse-free survival (RFS) (p?=?0.017; adj HR?=?1.74; 1.10?2.74); relative to patients with extensive metabolism. Cox? modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12,p?=?0.007).Conclusion??CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.
- Publication
Breast Cancer Research & Treatment, 2007, Vol 101, Issue 1, p113
- ISSN
0167-6806
- Publication type
Academic Journal
- DOI
10.1007/s10549-006-9428-0