Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Impact of CYP2D6 Polymorphisms on Tamoxifen Responses of Women with Breast Cancer: A Microarray-based Study in Thailand

  • Sukasem, Chonlaphat (Division of Pharmacogenomics and Personalized Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Sirachainan, Ekaphop (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Chamnanphon, Montri (Division of Pharmacogenomics and Personalized Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Pechatanan, Khunthong (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Sirisinha, Thitiya (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Ativitavas, Touch (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Panvichian, Ravat (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Ratanatharathorn, Vorachai (Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Trachu, Narumol (Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Chantratita, Wasun (Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University)
  • Published : 2012.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

This study was designed to investigate the frequency of CYP2D6 polymorphisms and evaluate the association between genetic polymorphisms of CYP2D6 and tamoxifen therapeutic outcome in Thai breast cancer patients. We recruited 48 breast cancer patients who received adjuvant tamoxifen for evaluating CYP2D6 genetic polymorphisms using microarray-based technology. Associations between genotypes-phenotypes and disease free survival were analyzed. Median follow up time was 5.6 years. The mean age of the subjects was 50 years. The 3 common allelic frequencies were 43.8% ($^*10$), 36.5 ($^*1$) and 10.4% ($^*2$) which are related to extensive metabolizer (EM) and intermediate metabolizer (IM) with 70.8% and 29.2 %, respectively. No association between CYP2D6 genotypes and DFS was demonstrated. Nevertheless, exploratory analysis showed statistically significant shorter DFS in the IM group of post-menopause patients (HR, 6.85; 95%CI, 1.48-31.69; P=0.005). Furthermore, we observed statistically significant shorter DFS of homozygous $CYP2D6^*10$ when compared with heterozygous CYP2D6*10 and other genotypes (P=0.005). $CYP2D6^*10$ was the most common genotype in our subjects. Post-menopause patients with homozygous $CYP2D6^*10$ and IM have shorter DFS. To confirm this relationship, larger samples and comprehensively designed trials in Thailand are required.

Keywords

References

  1. Borges S, Desta Z, Li L, et al (2006). Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther, 80, 61-74. https://doi.org/10.1016/j.clpt.2006.03.013
  2. Desta Z, Ward BA, Soukhova NV, et al (2004). Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther, 310, 1062-75. https://doi.org/10.1124/jpet.104.065607
  3. Early Breast Cancer Trialists' Collaborative Group (1992). Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet, 339, 1-15.
  4. Early Breast Cancer Trialists' Collaborative Group (2005). Effect of chemotherapy hormonal therapy for early breast cancer on recurrence 15-year survival: an overview of the randomized trials. Lancet, 365, 1687-717. https://doi.org/10.1016/S0140-6736(05)66544-0
  5. Goetz MP, Knox SK, Suman VJ, et al (2007). The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat, 101, 113-21. https://doi.org/10.1007/s10549-006-9428-0
  6. Goetz MP, Schaid DJ, Wickerham DL, et al (2011). Evaluation of CYP2D6 and efficacy of tamoxifen and realoxifene in women treated for breast cancer chemoprevention: results from the NSABP P1 and P2 clinical trials. Clin Cancer Res, 17, 6944-51. https://doi.org/10.1158/1078-0432.CCR-11-0860
  7. Higgins MJ, Stearns V (2009). Understanding resistance to tamoxifen in hormone receptor-positive breast cancer. Clin Chem, 55, 1453-5. https://doi.org/10.1373/clinchem.2009.125377
  8. Hoskins JM, Carey LA, McLeod HL (2009). CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer, 9, 576-86. https://doi.org/10.1038/nrc2683
  9. Irvin WJ, Walko CM, Weck KE, et al (2011). Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol, 29, 3232-9. https://doi.org/10.1200/JCO.2010.31.4427
  10. Johansson I, Oscarson M, Yue QY, et al (1994). Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol, 46, 452-9.
  11. Kiyotani K, Mushiroda T, Sasa M, et al (2008). Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Science, 99, 995-9. https://doi.org/10.1111/j.1349-7006.2008.00780.x
  12. Li H, Feng L, Xu Y, et al (2006). The association of CYP2D6 *10 polymorphism with breast cancer risk and clinico-pathologic characteristics in Chinese women. Acta Oncol, 45, 597-601. https://doi.org/10.1080/02841860600660803
  13. Lim HS, Ju Lee H, Seok Lee K, et al (2007). Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol, 25, 3837-45. https://doi.org/10.1200/JCO.2007.11.4850
  14. Lim JSL, Chen XA, Singh O, et al (2011). Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Bri J Clinical Pharmacol, 71, 737-50. https://doi.org/10.1111/j.1365-2125.2011.03905.x
  15. Lim YC, Li L, Desta Z, et al (2006). Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther, 318, 503-12. https://doi.org/10.1124/jpet.105.100511
  16. Nowell SA, Ahn J, Rae JM, et al (2005). Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat, 91, 249-58. https://doi.org/10.1007/s10549-004-7751-x
  17. Park HS, Choi J-Y, Lee M-J, et al (2011). Association between Genetic Polymorphisms of CYP2D6 and Outcomes in Breast Cancer Patients with Tamoxifen Treatment. J Korean Med Sci, 26, 1007-13. https://doi.org/10.3346/jkms.2011.26.8.1007
  18. Pechatanan K (2011). Cytochrome P450 2D6 polymorphisms of Thai breast cancer patients and their outcomes of adjuvant tamoxifen. Abstract No: e11037. ASCO Annual Meeting.
  19. Schroth W, Antoniadou L, Fritz P, et al (2007). Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol, 25, 5187-93. https://doi.org/10.1200/JCO.2007.12.2705
  20. Schroth W, Goetz MP, Hamann U, et al (2009). Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA, 302, 1429-36. https://doi.org/10.1001/jama.2009.1420
  21. Schroth W, Hamann U, Fasching P A, et al (2010). CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification. Clin Cancer Res, 16, 4468-77. https://doi.org/10.1158/1078-0432.CCR-10-0478
  22. Sirachainan E, Jaruhathai S, Trachu N, et al (2012). CYP2D6 polymorphisms influences the efficacy of adjuvant Tamoxifen in Thai breast cancer patients. Pharmacogenomics and Personalized Med, 5, 1-6.
  23. Stearns V, Johnson MD, Rae JM, et al (2003). Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst, 95, 1758-64. https://doi.org/10.1093/jnci/djg108
  24. Toyama T, Yamashita H, Sugiura H, et al (2009). No association between CYP2D6*10 genotype and survival of nodenegative Japanese breast cancer patients receiving adjuvant tamoxifen treatment. Jpn J Clin Oncol, 39, 651-6. https://doi.org/10.1093/jjco/hyp076
  25. Wegman P, Vainikka L, Stal O, et al (2005). Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res, 7, 284-90. https://doi.org/10.1186/bcr993
  26. Wegman P, Elingarami S, Carstensen J, et al (2007). Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res, 9, 7.
  27. Xu Y, Sun Y, Yao L, et al (2008). Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol, 19, 1423-9. https://doi.org/10.1093/annonc/mdn155

Cited by

  1. Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies vol.58, pp.6, 2013, https://doi.org/10.1038/jhg.2013.39
  2. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis vol.72, pp.2, 2013, https://doi.org/10.1007/s00280-013-2195-9
  3. genotypes and the clinical outcomes of adjuvant tamoxifen for breast cancer: a meta-analysis vol.15, pp.1, 2014, https://doi.org/10.2217/pgs.13.221
  4. Developing and Evaluating the HRM Technique for Identifying Cytochrome P450 2D6 Polymorphisms vol.29, pp.3, 2015, https://doi.org/10.1002/jcla.21754
  5. CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6783
  6. A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen vol.159, pp.1, 2016, https://doi.org/10.1007/s10549-016-3932-7
  7. Impact of Pharmacogenetic Markers of CYP2D6 and DRD2 on Prolactin Response in Risperidone-Treated Thai Children and Adolescents With Autism Spectrum Disorders vol.36, pp.2, 2016, https://doi.org/10.1097/JCP.0000000000000474
  8. Genotypes and Third-Generation Aromatase Inhibitors vol.57, pp.9, 2017, https://doi.org/10.1002/jcph.896
  9. Impact of CYP2D6 polymorphisms on endoxifen concentrations and breast cancer outcomes pp.1473-1150, 2017, https://doi.org/10.1038/tpj.2017.36
  10. Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy vol.10, pp.1, 2014, https://doi.org/10.2217/fon.13.168
  11. Catalpol promotes cellular apoptosis in human HCT116 colorectal cancer cells via microRNA-200 and the downregulation of PI3K-Akt signaling pathway vol.14, pp.3, 2017, https://doi.org/10.3892/ol.2017.6580
  12. Real time PCR detection of common CYP2D6 genetic variants and its application in a Karen population study vol.17, pp.1, 2018, https://doi.org/10.1186/s12936-018-2579-8
  13. genotype analysis of a Thai population: platform comparison vol.19, pp.12, 2018, https://doi.org/10.2217/pgs-2018-0075