title: Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies.
abstract: Tamoxifen contributes to decreased recurrence and mortality of patients with hormone receptor-positive breast cancer. As this drug is metabolized by phase I and phase II enzymes, the interindividual variations of their enzymatic activity are thought to be associated with individual responses to tamoxifen. Among these enzymes, CYP2D6 is considered to be a rate-limiting enzyme in the generation of endoxifen, a principal active metabolite of tamoxifen, and the genetic polymorphisms of CYP2D6 have been extensively investigated in association with the plasma endoxifen concentrations and clinical outcome of tamoxifen therapy. In addition to CYP2D6, other genetic factors including polymorphisms in various drug-metabolizing enzymes and drug transporters have been implicated to their relations to clinical outcome of tamoxifen therapy, but their effects would be small. Although the results of association studies are controversial, accumulation of the evidence has revealed us the important and critical issues in the tamoxifen pharmacogenomics study, namely the quality of genotyping, the coverage of genetic variations, the criteria for sample collection and the source of DNAs, which are considered to be common problematic issues in pharmacogenomics studies. This review points out common critical issues in pharmacogenomics studies through the lessons we have learned from tamoxifen pharmacogenomics, as well as summarizes the results of pharmacogenomics studies for tamoxifen treatment.
authors: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors: Kazuma
authors: K
authors: Kiyotani
authors: Taisei
authors: T
authors: Mushiroda
authors: Hitoshi
authors: H
authors: Zembutsu
authors: Yusuke
authors: Y
authors: Nakamura
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6