Abstract
Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D6*4) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the * 4/*4 genotype (HR = 4.1, CI 95% 1.1-15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1-3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D6*4 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Alleles
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Antineoplastic Agents, Hormonal / pharmacokinetics*
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Antineoplastic Agents, Hormonal / therapeutic use
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Biotransformation / genetics
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology
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Breast Neoplasms / genetics*
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Cohort Studies
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Cytochrome P-450 CYP2D6 / deficiency
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Cytochrome P-450 CYP2D6 / genetics*
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Cytochrome P-450 CYP2D6 / physiology
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Cytochrome P-450 CYP2D6 Inhibitors
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Female
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Genotype
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Humans
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Middle Aged
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Netherlands / epidemiology
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Polymorphism, Single Nucleotide*
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Prodrugs / pharmacokinetics*
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Prodrugs / therapeutic use
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Proportional Hazards Models
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Survival Analysis
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Tamoxifen / analogs & derivatives
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Tamoxifen / metabolism
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Tamoxifen / pharmacokinetics*
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Tamoxifen / therapeutic use
Substances
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Antineoplastic Agents, Hormonal
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Cytochrome P-450 CYP2D6 Inhibitors
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Prodrugs
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Tamoxifen
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4-hydroxy-N-desmethyltamoxifen
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Cytochrome P-450 CYP2D6