Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Tamoxifen Treatment [T88.7]

OMIM numbers: 608902, 124030 (CYP2D6)

Dipl.-Biol. Birgit Busse

Scientific Background

Tamoxifen is a prodrug which is converted into the active metabolite endoxifen in the body. The polymorphic enzyme CYP2D6 plays an important role in this process.

Clinical data indicate that polymorphisms in the CYP2D6 gene, which lead to a reduced CYP2D6 activity, have a negative impact on tamoxifen treatment. This applies in particular to homozygosity for non-functional CYP2D6 alleles (poor metabolizer phenotype). Female patients with lacking CYP2D6 activity showed significantly reduced endoxifen levels.

Several studies showed that women with functionally impaired CYP2D6 alleles benefited less from treatment with tamoxifen than women with two functioning alleles. Most of the studies on the association of CYP2D6 genotype and the clinical outcomes of tamoxifen treatment were conducted on postmenopausal women. Newer studies showed that this association can also be seen in premenopausal women. Since these results were not reproduced in all studies, the clinical relevance of the CYP2D6 genotype in the context of a tamoxifen therapy is still discussed controversially.

According to the current data, CYP2D6 genotyping can be useful in the case of women with high-risk classification that wish to use tamoxifen instead of an aromatase inhibitor, in order to minimize a CYP2D6-associated residual risk of relapse.

Information regarding the association of CYP2D6 genotypes and endoxifen levels are by now included in the prescribing information for tamoxifen.

It has been shown that parallel administration of CYP2D6 inhibitors (e.g. paroxetin) and tamoxifen lead to reduced endoxifen levels due to drug interactions.