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Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22

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Abstract

Tamoxifen use is often limited in some patients due to adverse effects including severe hot flash symptoms. Tamoxifen undergoes hepatic bioactivation by CYP2D6 and CYP3A4 to form the active metabolite endoxifen. It remains unclear whether the extent of attained endoxifen level or genetic polymorphisms in drug metabolizing enzymes is associated with the frequency and severity of hot flashes. We conducted a prospective study using self-reported surveys to assess tamoxifen side effects experienced during the week prior to clinic visits of 132 female breast cancer patients on tamoxifen therapy, and hot flash severity scores were tabulated. At the time of clinic visit, blood samples were obtained to determine tamoxifen and its metabolite levels and to determine CYP2D6 and CYP3A4 genotypes. The majority of participants (77 %) experienced hot flashes, with 11 % experiencing severe or very severe symptoms. We observed an inverse correlation between endoxifen concentration and hot flash severity score following adjustment for age, BMI, and menopausal status in patients with non-zero scores (p < 0.001). Interestingly, CYP2D6 genotype was not significantly associated with hot flash scores in patients on no known inhibitory medications. However, CYP3A4*22 carriers were less likely to have hot flashes with an odds ratio of 8.87 (p < 0.01) even when compared to a cohort with similar endoxifen levels. Our data demonstrate that patients with higher endoxifen levels tended to predict lower hot flash severity scores. Importantly, this is the first study to show CYP3A4*22 genotype as an independent predictor of hot flash severity during tamoxifen therapy.

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Acknowledgments

We would like to thank Matilde Leon-Ponte, Cameron Ross, and Sara Mansell for their technical support; and Julie Mayo for her administrative assistance. We would also like to thank Drs. Kylea Potvin, Theodore A. Vandenburg, Jawaid Younus, Brian Dingle, Francisco E. Perera, Karin Hahn, and Olga Vujovic as well as the entire Breast Disease Site Team at the London Regional Cancer Program. Dr. Richard B. Kim holds the Wolfe Medical Research Chair in Pharmacogenomics at Western. This study was funded by the Cancer Care Ontario (CCO) Research Chair Award (Tier-1) in Experimental Therapeutics (Richard B. Kim). Additionally, this study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, LHSC-University Hospital, Western University, Room B9-132, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Simon D. Baxter, Wendy A. Teft & Richard B. Kim

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

    Yun-Hee Choi

  3. Department of Oncology, Western University, London, ON, Canada

    Eric Winquist & Richard B. Kim

Authors
  1. Simon D. Baxter
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  2. Wendy A. Teft
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  3. Yun-Hee Choi
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  5. Richard B. Kim
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Correspondence to Richard B. Kim.

Additional information

S. D. Baxter and W. A. Teft contributed equally to this work.

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Baxter, S.D., Teft, W.A., Choi, YH. et al. Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22. Breast Cancer Res Treat 145, 419–428 (2014). https://doi.org/10.1007/s10549-014-2963-1

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  • DOI: https://doi.org/10.1007/s10549-014-2963-1

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