CYP2D6 and tamoxifen: DNA matters in breast cancer

The selective oestrogen receptor modulator tamoxifen is the most widely used antioestrogen for the treatment of hormone-dependent breast cancer.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.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.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.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.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.