Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles

Linda Thorén, Jonatan D Lindh, Gerd Ackehed, Marianne Kristiansen Kringen, Per Hall, Jonas Bergh, Espen Molden, Sara Margolin, Erik Eliasson, Linda Thorén, Jonatan D Lindh, Gerd Ackehed, Marianne Kristiansen Kringen, Per Hall, Jonas Bergh, Espen Molden, Sara Margolin, Erik Eliasson

Abstract

Aims: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects.

Methods: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records.

Results: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner.

Conclusion: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

Keywords: adjuvant treatment; breast cancer; personalized medicine; pharmacogenetics; phenotype; tamoxifen.

Conflict of interest statement

There are no competing interests to declare.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1
FIGURE 1
Plasma endoxifen concentrations in relation to major groups of CYP2D6 genotypes with regards to the combination of fully functional (CYP2D6*1), reduced activity (red) and null alleles (see methods). The dashed line indicates a previously suggested therapeutic threshold at 6.0 ng/mL for clinical efficacy.
FIGURE 2
FIGURE 2
Predicted vs observed CYP2D6 activity with focus on CYP2D6*41. The predicted CYP2D6 activity was based on activity scores in Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group guidelines for the diplotypes null/null, null/CYP2D6*41, CYP2D6*41/*41, CYP2D6*1/null, CYP2D6*1/*41, CYP2D6*1/*1, CYP2D6*1/*1x2 and CYP2D6*1/*1x3, respectively. The total activity of the normal genotype CYP2D6*1/*1 with 2 fully functional alleles was set to 2.0. The observed CYP2D6 activity was defined as the plasma concentration ratio of endoxifen over N‐desmethyl‐ tamoxifen (see methods). The regression line was constructed based on patients carrying wild‐type (*1), null and *41 alleles, and the 5 cases that carry CYP2D6*9 or CYP2D6*10 have been excluded to simplify the comparison. For additional visual clarity, a random jitter has been added to the predicted activity in the plot, but not in the statistical analyses
FIGURE 3
FIGURE 3
Reported side effects to tamoxifen in relation to endoxifen levels. Data on reported side effects during ongoing treatment with tamoxifen 20 mg daily were retrospectively retrieved form medical records. Side effects were considered severe if side effects led to tamoxifen discontinuation, if symptom‐relieving treatment was used or if the patient had sick leave due to side effects. Other notes of side effects were considered mild to moderate. Plasma levels of endoxifen were stratified using cut‐off values defined statistically in a larger clinical material.

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Source: PubMed

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