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CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy

  • Clinical trial
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Abstract

Purpose

Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy.

Methods

We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS).

Results

Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0–4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45–59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity.

Conclusions

Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen.

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Abbreviations

HFSS :

Hot flash severity score

SNP :

Single-nucleotide polymorphism

UM, NM, IM, PM :

Ultra, normal, intermediate, poor metabolizer

CYP :

Cytochrome P450

4-OH-tam :

4-hydroxytamoxifen

NDM-tam :

N-desmethyl-tamoxifen

LC-MS/MS:

Liquid chromatography-mass spectrometry

SSRI :

Selective serotonin reuptake inhibitor

BMI :

Body mass index

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Acknowledgements

We would like to thank Cameron Ross and Sara Mansell for their technical support; and Jody Murray for her administrative assistance. We would also like to thank the team at the London Regional Cancer Program. This work was supported by the Wolfe Medical Research Chair in Pharmacogenomics, Canadian Institutes of Health Research, Drug Safety and Effectiveness Network (DSEN-PREVENT, FRN-117588), and the Ontario Research Fund-Research Excellence Grant from the Ontario Ministry of Research and Innovation.

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Authors and Affiliations

  1. Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, N6A 5K5, Canada

    Laura E. Jansen, Wendy A. Teft & Richard B. Kim

  2. Department of Epidemiology and Biostatistics, Western University, London, ON, N6A 5K5, Canada

    Rhiannon V. Rose & Daniel J. Lizotte

  3. Department of Oncology, Western University, London, ON, N6A 5K5, Canada

    Richard B. Kim

  4. Department of Medicine, LHSC-University Hospital, Room A-LL-152, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Richard B. Kim

Authors
  1. Laura E. Jansen
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  2. Wendy A. Teft
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Corresponding author

Correspondence to Richard B. Kim.

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The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed in this study were approved by the University of Western Ontario Research Ethics Board and in accordance with the ethical standards of 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all participants.

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Jansen, L.E., Teft, W.A., Rose, R.V. et al. CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy. Breast Cancer Res Treat 171, 701–708 (2018). https://doi.org/10.1007/s10549-018-4876-x

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  • DOI: https://doi.org/10.1007/s10549-018-4876-x

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