The mechanisms of variable response to tamoxifen have been the subject of much scrutiny in the published literature. Early studies attempting to link a clinical response to tamoxifen therapy with plasma tamoxifen concentrations reported no statistically significant differences in outcomes between women who received 20 mg of tamoxifen daily and those who received 40 mg of tamoxifen daily, even though women in the 40 mg tamoxifen group had higher plasma tamoxifen concentrations than those in the 20 mg tamoxifen group. These results have been reported as evidence that plasma tamoxifen concentration is not a predictor of clinical outcome. Because there is evidence that tamoxifen is converted to anti-estrogenic metabolites, one hypothesis is that altered patterns of metabolism of tamoxifen might contribute to inter-individual variability in effects (Jin et al, 2005). Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype.
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