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Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients

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Abstract

CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography–tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level.

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Acknowledgments

This study was mainly supported by a Grant-in-Aid for Leading Project of Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was also supported in part by Grant-in-Aids for the Kobayashi Institute for Innovative Cancer Chemotherapy, the Japan Research Foundation for Clinical Pharmacology, the Takeda Science Foundation, and Young Scientists (B) (22790179) of Ministry of Education, Culture, Sports, Science and Technology of Japan. We express our heartfelt gratitude to all the study participants. We thank Yuka Kikuchi and Kumi Matsuda for technical assistance. We thank all other members and stuffs for their contribution to the sample collection and the completion of our study.

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Authors and Affiliations

  1. Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, 230-0045, Japan

    Kazuma Kiyotani, Taisei Mushiroda & Yusuke Nakamura

  2. Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo, 160-8582, Japan

    Chiyo K. Imamura & Yusuke Tanigawara

  3. Laboratory for Genotyping Development, RIKEN Center for Genomic Medicine, Yokohama, 230-0045, Japan

    Naoya Hosono & Michiaki Kubo

  4. Department of Surgery, Tokushima Breast Care Clinic, Tokushima, 770-0052, Japan

    Mitsunori Sasa

  5. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yusuke Nakamura & Hitoshi Zembutsu

Authors
  1. Kazuma Kiyotani
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  2. Taisei Mushiroda
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  3. Chiyo K. Imamura
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  4. Yusuke Tanigawara
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  5. Naoya Hosono
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  6. Michiaki Kubo
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  7. Mitsunori Sasa
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  8. Yusuke Nakamura
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Correspondence to Yusuke Nakamura.

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Kiyotani, K., Mushiroda, T., Imamura, C.K. et al. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat 131, 137–145 (2012). https://doi.org/10.1007/s10549-011-1777-7

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  • DOI: https://doi.org/10.1007/s10549-011-1777-7

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