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Tamoxifen metabolism in breast cancer treatment: Taking the focus off the CYP2D6 gene

The Pharmacogenomics Journal volume 17, pages 109–111 (2017)Cite this article

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Tamoxifen (TAM) has been widely used to treat estrogen receptor (ER)-positive breast cancer, and has led to reduction of 50% in the annual recurrence rate and 30% in breast cancer mortality after 5 years of treatment.1 The prodrug TAM is a selective ER modulator that antagonizes ERs in cancer cells. However, compared with its two active metabolites 4-hydroxy-TAM (4-OH-TAM) and endoxifen, it is a relatively weak antiestrogen.

Both 4-OH-TAM and endoxifen are produced through CYP2D6-mediated phase I metabolism, and a relationship between CYP2D6 genetic variability and plasma concentrations of these two metabolites in treated patients has been previously reported.2, 3 However, interindividual variability in TAM-active metabolite concentrations can only, in part, be attributed to the CYP2D6 genotype. Although poor metabolizers according to CYP2D6 genotype have been related to low endoxifen levels, Madlensky et al.4 reported that 24% of patients described as poor metabolizers were still able to generate therapeutic concentrations of endoxifen. Teft et al.5 also observed in poor metabolizers showing no CYP2D6 metabolic activity that some were able to produce endoxifen. In another study, in over 50% of patients with low endoxifen levels, no relation was noted with CYP2D6 status.6 Hence the clear gene-exposure effect observed for the CYP2D6 genotype, only partially explains interindividual variability. Several factors have contributed to this controversy including discrepancies in methods of quantifying concentrations of TAM and its metabolites,7 concomitant medication such as CYP2D6 inhibitor antidepressants8 or the lack of a validated accurate CYP2D6 genotyping method.9

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  1. Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain

    A Novillo, A Romero-Lorca, M Gaibar, M Rubio & A Fernández-Santander

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  1. A Novillo
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  2. A Romero-Lorca
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  3. M Gaibar
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Correspondence to A Fernández-Santander.

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Novillo, A., Romero-Lorca, A., Gaibar, M. et al. Tamoxifen metabolism in breast cancer treatment: Taking the focus off the CYP2D6 gene. Pharmacogenomics J 17, 109–111 (2017). https://doi.org/10.1038/tpj.2016.73

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