Abstract
Simple SummaryTamoxifen is an important adjuvant endocrine therapy in estrogen receptor (ER)-positive breast cancer patients. It is mainly catalyzed by the enzyme CYP2D6 into the most active metabolite endoxifen. Genetic variation in the CYP2D6 gene influences endoxifen formation and thereby potentially therapy outcome. However, the association between CYP2D6 genotype and clinical outcome on tamoxifen is still under debate, as contradictory outcomes have been published. This review describes the latest insights in both CYP2D6 genotype and endoxifen concentrations, as well CYP2D6 genotype and clinical outcome, from 2018 to 2020.Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.
Highlights
For many years, tamoxifen has been known as the most important adjuvant endocrine treatment in patients with estrogen receptor (ER) positive breast cancer [1,2]
As genetic variation in cytochrome P450 2D6 (CYP2D6) leads to altered enzyme activity and thereby potentially to an affected efficacy [5], pharmacogenetic (PGx) testing could play a major role in optimizing tamoxifen treatment
We reviewed the literature for publications from 2018 to 2021 on CYP2D6 and clinical outcome to see if new information has arisen
Summary
Tamoxifen has been known as the most important adjuvant endocrine treatment in patients with estrogen receptor (ER) positive breast cancer [1,2]. It is a selective estrogen receptor modulator (SERM), which inhibits tumor growth and promotes apoptosis in ER-positive tumors [3], resulting in a reduced risk of recurrence and death from breast cancer [4]. As genetic variation in CYP2D6 leads to altered enzyme activity and thereby potentially to an affected efficacy [5], pharmacogenetic (PGx) testing could play a major role in optimizing tamoxifen treatment. PGx testing is available for an increasing number of drugs, mainly in psychiatric and for cardiologic and oncologic applications
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