Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Mulder, Tessa A. M.; de With, Mirjam; del Re, Marzia; Danesi, Romano; Mathijssen, Ron H. J.; van Schaik, Ron H. N.

doi:10.3390/cancers13040771

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Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

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Department of Clinical Chemistry, Erasmus MC University Hospital, Wytemaweg 80, 3015CN Rotterdam, The Netherlands

Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Wytemaweg 80, 3015CN Rotterdam, The Netherlands

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 55, Via Roma, 56126 Pisa, Italy

Author to whom correspondence should be addressed.

Academic Editor: Daniel L. Hertz

Cancers 2021, 13(4), 771; https://doi.org/10.3390/cancers13040771

Received: 14 January 2021 / Revised: 5 February 2021 / Accepted: 8 February 2021 / Published: 12 February 2021

(This article belongs to the Special Issue Germline Pharmacogenetics of Cancer Treatment)

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Tamoxifen 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.

Abstract

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. View Full-Text

Keywords: tamoxifen; Pharmacogenetics; PGx; CYP2D6; Cytochrome P450 2D6; genotyping; tamoxifen treatment; review

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MDPI and ACS Style

Mulder, T.A.M.; de With, M.; del Re, M.; Danesi, R.; Mathijssen, R.H.J.; van Schaik, R.H.N. Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy. Cancers 2021, 13, 771. https://doi.org/10.3390/cancers13040771

AMA Style

Mulder TAM, de With M, del Re M, Danesi R, Mathijssen RHJ, van Schaik RHN. Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy. Cancers. 2021; 13(4):771. https://doi.org/10.3390/cancers13040771

Chicago/Turabian Style

Mulder, Tessa A.M., Mirjam de With, Marzia del Re, Romano Danesi, Ron H.J. Mathijssen, and Ron H.N. van Schaik. 2021. "Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy" Cancers 13, no. 4: 771. https://doi.org/10.3390/cancers13040771

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Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

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