Clinical response to
tamoxifen varies widely among women treated with this
drug for
hormone receptor-positive
breast cancer. The principal active metabolite -
endoxifen - is generated through hepatic metabolism of
tamoxifen, with key roles for
cytochrome P450 (CYP)
CYP2D6 and
CYP3A. By influencing
endoxifen formation, genetic variants of
CYP2D6 may affect response to
tamoxifen. After a decade of research, examining the effects of
CYP2D6 genetic variants on
tamoxifen efficacy, there is still no agreement on the clinical utility of
CYP2D6 genotype as
biomarker for the prediction of
breast cancer outcome, because studies revealed conflicting results. However,
tamoxifen metabolism is complex and involves several other
drug-metabolizing
enzymes. Genetic variants of other CYP
enzymes, including
CYP3A4 and
CYP2C9/19, as well as co-medication interfering with the metabolic activity of
CYP2D6 and
CYP3A4 have been shown to affect
endoxifen concentrations and may also contribute to the variability in response to
tamoxifen. Phenotyping strategies can predict
endoxifen exposure more accurately than
CYP2D6 genotype, but do not take into account all factors influencing
endoxifen exposure. Therapeutic
drug monitoring (TDM) is likely to be the optimal strategy for individualization of
tamoxifen treatment. According to a growing amount of literature,
endoxifen concentration seems to be a predictor of clinical outcome. The relationship between
endoxifen levels and
breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with
tamoxifen, including inhibitors and inducers of CYP
enzymes.