Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Kazuma Kiyotani, Taisei Mushiroda, Chiyo K. Imamura, Naoya Hosono, Tatsuhiko Tsunoda, Michiaki Kubo, Yusuke Tanigawara, David A. Flockhart, Zeruesenay Desta, Todd C. Skaar, Fuminori Aki, Koichi Hirata, Yuichi Takatsuka, Minoru Okazaki, Shozo Ohsumi, Takashi Yamakawa, Mitsunori Sasa, Yusuke Nakamura, Hitoshi Zembutsu

Research output: Contribution to journalArticle

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Abstract

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.

Original languageEnglish
Pages (from-to)1287-1293
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number8
DOIs
Publication statusPublished - 10-03-2010

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Cytochrome P-450 CYP2D6
Tamoxifen
Breast Neoplasms
Alleles
Therapeutics
Recurrence
Single Nucleotide Polymorphism
Survival
Genotype
Haplotypes
Genes
Regression Analysis
Hormones

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kiyotani, Kazuma ; Mushiroda, Taisei ; Imamura, Chiyo K. ; Hosono, Naoya ; Tsunoda, Tatsuhiko ; Kubo, Michiaki ; Tanigawara, Yusuke ; Flockhart, David A. ; Desta, Zeruesenay ; Skaar, Todd C. ; Aki, Fuminori ; Hirata, Koichi ; Takatsuka, Yuichi ; Okazaki, Minoru ; Ohsumi, Shozo ; Yamakawa, Takashi ; Sasa, Mitsunori ; Nakamura, Yusuke ; Zembutsu, Hitoshi. / Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 8. pp. 1287-1293.
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title = "Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients",
abstract = "Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95{\%} CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95{\%} CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.",
author = "Kazuma Kiyotani and Taisei Mushiroda and Imamura, {Chiyo K.} and Naoya Hosono and Tatsuhiko Tsunoda and Michiaki Kubo and Yusuke Tanigawara and Flockhart, {David A.} and Zeruesenay Desta and Skaar, {Todd C.} and Fuminori Aki and Koichi Hirata and Yuichi Takatsuka and Minoru Okazaki and Shozo Ohsumi and Takashi Yamakawa and Mitsunori Sasa and Yusuke Nakamura and Hitoshi Zembutsu",
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Kiyotani, K, Mushiroda, T, Imamura, CK, Hosono, N, Tsunoda, T, Kubo, M, Tanigawara, Y, Flockhart, DA, Desta, Z, Skaar, TC, Aki, F, Hirata, K, Takatsuka, Y, Okazaki, M, Ohsumi, S, Yamakawa, T, Sasa, M, Nakamura, Y & Zembutsu, H 2010, 'Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients', Journal of Clinical Oncology, vol. 28, no. 8, pp. 1287-1293. https://doi.org/10.1200/JCO.2009.25.7246

Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. / Kiyotani, Kazuma; Mushiroda, Taisei; Imamura, Chiyo K.; Hosono, Naoya; Tsunoda, Tatsuhiko; Kubo, Michiaki; Tanigawara, Yusuke; Flockhart, David A.; Desta, Zeruesenay; Skaar, Todd C.; Aki, Fuminori; Hirata, Koichi; Takatsuka, Yuichi; Okazaki, Minoru; Ohsumi, Shozo; Yamakawa, Takashi; Sasa, Mitsunori; Nakamura, Yusuke; Zembutsu, Hitoshi.

In: Journal of Clinical Oncology, Vol. 28, No. 8, 10.03.2010, p. 1287-1293.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Imamura, Chiyo K.

AU - Hosono, Naoya

AU - Tsunoda, Tatsuhiko

AU - Kubo, Michiaki

AU - Tanigawara, Yusuke

AU - Flockhart, David A.

AU - Desta, Zeruesenay

AU - Skaar, Todd C.

AU - Aki, Fuminori

AU - Hirata, Koichi

AU - Takatsuka, Yuichi

AU - Okazaki, Minoru

AU - Ohsumi, Shozo

AU - Yamakawa, Takashi

AU - Sasa, Mitsunori

AU - Nakamura, Yusuke

AU - Zembutsu, Hitoshi

PY - 2010/3/10

Y1 - 2010/3/10

N2 - Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.

AB - Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.

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