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Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients

The Pharmacogenomics Journal volume 9, pages 258–264 (2009)Cite this article

Abstract

The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r2=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.

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Acknowledgements

We thank Dr C Kent Osborne and Dr Michael D Johnson for their valuable input. This work was supported in part by grants U-01 GM61373 and T-32 GM007767, Indiana University GCRC grant M01RR00750, University of Michigan GCRC grant M01-RR00042 and Georgetown University (NIH M01-RR13297), from the National Institute of General Medical Sciences (Bethesda, MD, USA), Damon Runyon-Lilly Clinical Investigator award CI-3 from the Damon Runyon Cancer Research Foundation (VS), Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale (DFH) and Breast Cancer Research Foundation grant N003173 (JMR), and by grant number M01-RR000042 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

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Author notes

  1. J M Rae, M J Sikora, N L Henry, L Li, S Kim, S Oesterreich, T C Skaar, A T Nguyen, Z Desta, A M Storniolo, D A Flockhart, D F Hayes and V Stearns: COBRA is the Consortium on Breast Cancer Pharmacogenomics, an NIH-supported Consortium of investigators at these institutions studying pharmacogenomics in the treatment of breast cancer.

Authors and Affiliations

  1. Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    J M Rae, N L Henry & D F Hayes

  2. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    J M Rae, N L Henry & D F Hayes

  3. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    J M Rae & M J Sikora

  4. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    L Li, S Kim, T C Skaar, A T Nguyen, Z Desta, A M Storniolo & D A Flockhart

  5. Baylor College of Medicine, Houston, TX, USA

    S Oesterreich

  6. Department of Oncology; Johns Hopkins University School of Medicine, Breast Cancer Program,

    V Stearns

  7. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    V Stearns

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Rae, J., Sikora, M., Henry, N. et al. Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients. Pharmacogenomics J 9, 258–264 (2009). https://doi.org/10.1038/tpj.2009.14

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