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Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer

Cited 186 time in Web of Science Cited 212 time in Scopus
Authors
Lim, Hyeong-Seok; Lee, Han Ju; Lee, Keun Seok; Lee, Eun Sook; Jang, In-Jin; Ro, Jungsil
Issue Date
2007-09-01
Publisher
American Society of Clinical Oncology
Citation
J Clin Oncol 25:3837-3845
Keywords
AdultAgedBone Neoplasms/secondaryBreast Neoplasms/blood/*drug therapy/*geneticsCytochrome P-450 Enzyme System/*geneticsDisease-Free SurvivalFemaleGenotypeHumansLiver Neoplasms/secondaryLymphatic MetastasisMiddle AgedPilot ProjectsPolymorphism, GeneticProportional Hazards ModelsRespiratory Tract Neoplasms/secondaryTamoxifen/*pharmacokinetics/therapeutic use
Abstract
PURPOSE: The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. PATIENTS AND METHODS: Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. RESULTS: Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) CONCLUSION: CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.
ISSN
1527-7755 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17761971

http://hdl.handle.net/10371/24832
DOI
https://doi.org/10.1200/JCO.2007.11.4850
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College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Journal Papers (저널논문_협동과정-임상약리학전공)
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