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

Kazuma Kiyotani, Taisei Mushiroda, Chiyo K. Imamura, Yusuke Tanigawara, Naoya Hosono, Michiaki Kubo, Mitsunori Sasa, Yusuke Nakamura, Hitoshi Zembutsu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)137-145
Number of pages9
JournalBreast Cancer Research and Treatment
Volume131
Issue number1
DOIs
Publication statusPublished - 01-01-2012

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Cytochrome P-450 CYP2D6
Tamoxifen
Genotype
Breast Neoplasms
Alleles
Incidence
Tandem Mass Spectrometry
Liquid Chromatography
4-hydroxy-N-desmethyltamoxifen

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kiyotani, Kazuma ; Mushiroda, Taisei ; Imamura, Chiyo K. ; Tanigawara, Yusuke ; Hosono, Naoya ; Kubo, Michiaki ; Sasa, Mitsunori ; Nakamura, Yusuke ; Zembutsu, Hitoshi. / Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. In: Breast Cancer Research and Treatment. 2012 ; Vol. 131, No. 1. pp. 137-145.
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Kiyotani, K, Mushiroda, T, Imamura, CK, Tanigawara, Y, Hosono, N, Kubo, M, Sasa, M, Nakamura, Y & Zembutsu, H 2012, 'Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients', Breast Cancer Research and Treatment, vol. 131, no. 1, pp. 137-145. https://doi.org/10.1007/s10549-011-1777-7

Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. / Kiyotani, Kazuma; Mushiroda, Taisei; Imamura, Chiyo K.; Tanigawara, Yusuke; Hosono, Naoya; Kubo, Michiaki; Sasa, Mitsunori; Nakamura, Yusuke; Zembutsu, Hitoshi.

In: Breast Cancer Research and Treatment, Vol. 131, No. 1, 01.01.2012, p. 137-145.

Research output: Contribution to journalArticle

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T1 - Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Imamura, Chiyo K.

AU - Tanigawara, Yusuke

AU - Hosono, Naoya

AU - Kubo, Michiaki

AU - Sasa, Mitsunori

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AU - Zembutsu, Hitoshi

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