Associations between tamoxifen and age during steady state tamoxifen treatment of postmenopausal women with breast cancer

Introduction: Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of tamoxifen is believed to be due to the potent metabolite 4-hydroxy-N-desmethyltamoxifen (4OHNDtam, endoxifen). whereas the demethylated metabolites of tamoxifen have been associated with its side effects. The hydroxylated metabolites are converted from tamoxifen to a major part through the cytochrome P450 enzyme (CYP) 2D6. The inter-individual variation of the activity of this enzyme due to genetic polymorphisms may be a predictor of outcome during tamoxifen treatment due to influence on the concentration of the active metabolite 4OHNDtam (endoxifen). However, the results from clinical studies are partly contradictory. The conflicting results have been explained by differences in study designs, including size or different genetic models for the assessment of phenotypes.

Methods: We measured tamoxifen and its metabolites by liquid chromatography-tandem mass spectrometry. Furthermore we examined the relationship between the serum levels of endoxifen and age in 90 postmenopausal breast cancer patients during steady state breast cancer treatment.

Results: The serum concentrations of endoxifen were highly associated with age (p = 0.006). Moreover, we observed a large variation of serum concentrations in each of CYP2D6 genotype groups.

Conclusion: The observed variation of endoxifen concentrations in serum of postmenopausal breast cancer patients by age may be of clinical relevance and may represent an additional explanation why studies of genetic polymorphisms of CYP2D6 including postmenopausal breast cancer patients have been inconclusive.