title: Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping.
abstract: 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.
authors.affiliation: Dept of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Dept of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: l.binkhorst@erasmusmc.nl.
authors.forename: Lisette
authors.initials: L
authors.lastname: Binkhorst
authors.affiliation: Dept of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Dept of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: Jager
authors.affiliation: Dept of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Dept of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D057285:Precision Medicine; D013629:Tamoxifen / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Endoxifen; Pharmacogenetics; Pharmacokinetics; Tamoxifen; Therapeutic drug monitoring