Key Points
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The selective oestrogen receptor modulator tamoxifen is the most widely used antioestrogen for the treatment of hormone-dependent breast cancer.
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Hepatic, drug-metabolizing cytochrome P450s (CYPs) catalyse the oxidation of tamoxifen to several metabolites. The metabolites, endoxifen and 4-hydroxytamoxifen, have greater binding affinities for oestrogen receptors and suppress cell proliferation more effectively than tamoxifen does. Plasma concentrations of endoxifen are considerably higher than those of 4-hydroxytamoxifen, suggesting that endoxifen is the main pharmacologically active species of tamoxifen in vivo. The conversion of tamoxifen to endoxifen is predominantly catalysed by CYP2D6.
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Many polymorphisms in CYP2D6 have been identified. In Caucasian populations, 6–10% of people inherit two alleles containing polymorphisms and/or a gene deletion, leading to no protein expression or the expression of a protein with no CYP2D6 enzymatic activity. These individuals have impaired metabolism of CYP2D6 substrates and are called poor metabolizers of CYP2D6. Some drugs, such as the antidepressants fluoxetine or paroxetine, are potent inhibitors of CYP2D6 and can confer a poor metabolizer phenotype on individuals with normal CYP2D6 activity.
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The findings of pharmacokinetic studies indicate that the conversion of endoxifen is reduced in poor metabolizers of CYP2D6, either by genotype or by co-prescribed fluoxetine or paroxetine, which are commonly prescribed to manage hot flashes.
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Recent data suggest that poor metabolizers of CYP2D6 do not derive as much benefit from tamoxifen therapy as other patients do; however, some studies have yielded conflicting results.
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The analysis of CYP2D6 genotype might represent an early example of a pharmacogenetic tool for optimizing breast cancer therapy; however, the findings of larger, well-designed studies that support the current data are necessary before a change in clinical practice is advocated.
Abstract
Tamoxifen is the most widely used anti-oestrogen for the treatment of hormone-dependent breast cancer. The pharmacological activity of tamoxifen is dependent on its conversion by the hepatic drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6) to its abundant metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the co-administration of drugs that inhibit CYP2D6 function, produce little endoxifen and seem to derive inferior therapeutic benefit from tamoxifen. Here we review the existing data that relate CYP2D6 genotypes to response to tamoxifen and discuss whether the analysis of the CYP2D6 genotype might be an early example of a pharmacogenetic tool for optimizing breast cancer therapy.
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Acknowledgements
This work was supported by the US National Institutes of Health Pharmacogenetics Research Network (Grant U01 GM63340).
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Supplementary information
Supplementary information S1
Genes encoding many drug metabolizing enzymes and the nuclear factor NR1I2 have been evaluated in relation to steady-state tamoxifen and metabolite pharmacokinetics and clinical outcomes in women with breast cancer treated with adjuvant tamoxifen therapy. (PDF 184 kb)
Supplementary information S2
Summary of clinical studies that have evaluated the association between CYP2D6 genotype and response to tamoxifen therapy (PDF 264 kb)
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Glossary
- Adjuvant treatment
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Refers to additional treatment, which is usually given after surgery, in cases in which all detectable disease has been removed but there remains a statistical risk of relapse.
- Haem-thiolate enzymes
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The collective name given to a class of haemoproteins in which a thiolate group (typically from a cysteine residue) is the axial ligand of haem iron.
- Hazard ratio
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In a survival analysis, this is the effect of an explanatory variable on the hazard risk of an event.
- Allozyme
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Variant forms of an enzyme that are encoded by different alleles at the same locus.
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Hoskins, J., Carey, L. & McLeod, H. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer 9, 576–586 (2009). https://doi.org/10.1038/nrc2683
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DOI: https://doi.org/10.1038/nrc2683