CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients

  • Yazdi, Mohammad Forat (Department of Internal Medicine, Shahid Sadoughi Training Hospital) ;
  • Rafieian, Shiva (Department of Internal Medicine, Shahid Sadoughi Training Hospital) ;
  • Gholi-Nataj, Mohsen (Department of Internal Medicine, Shahid Sadoughi Training Hospital) ;
  • Sheikhha, Mohammad Hasan (Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences and Health Services) ;
  • Nazari, Tahereh (Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences and Health Services) ;
  • Neamatzadeh, Hossein (Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences and Health Services)
  • Published : 2015.10.06


Background: Despite consistent pharmacogenetic effects of CYP2D6 on tamoxifen exposure, there is considerable controversy regarding the validity of CYP2D6 as a predictor of tamoxifen outcome. Understanding the current state of evidence in this area and its limitations is important for the care of patients who require endocrine therapy for breast cancer. Materials and Methods: A total of 101 patients with breast cancer who received tamoxifen therapy for at least 3 years, were genotyped for common alleles of the CYP2D6 gene by nested-PCR and restriction fragment length polymorphism PCR. Patients were classified as extensive or poor metabolizers (PM) based on CYP2D6*4 alleles in 3 different groups according to the menopause, Her2-neu status, and stage 3. Results: The mean age of the patients with the disease recurrence was $50.8{\pm}6.4$ and in non recurrent patients was $48.2{\pm}6.8$. In this study 63.3% (n=64) patients were extensive metabolizers and 36.6% (n=37) were poor metabolizers. Sixty four of the 101 patients (63.3%) were Her2-neu positive. For tamoxifen-treated patients, no statistically significant difference in rate of recurrence observed between CYP2D6 metabolic variants in stage 3 and post-menopausal patients. However, there was a significant association between CYP2D6 genotype and recurrence in tamoxifen-treated Her2-neu positive patients. Compared with other women with breast cancer, those with Her2-neu positive breast cancer and extensive metabolizer alleles had a decreased likelihood of recurrence. Conclusions: This study for the first time demonstrated significant effects of CYP2D6 extensive metabolizer alleles on risk of recurrence in Her2-neu positive breast cancer patients receiving adjuvant tamoxifen therapy. Therefore, CYP2D6 metabolism, as measured by genetic variation, can be a predictor of breast cancer outcome in Her2-neu positive women receiving tamoxifen.


Breast cancer;tamoxifen;recurrent;menopause;CYP2D6


Supported by : Shahid Sadoughi University of Medical Sciences


  1. Abraham JE, Maranian MJ, Driver KE, et al (2010). CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res, 12, 64.
  2. Bijl MJ, van Schaik RH, Lammers LA, et al (2009). The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat, 118, 125-30.
  3. Brauch H, Schroth W, Eichelbaum M, et al (2008). Clinical relevance of CYP2D6 genetics for tamoxifen response in breast cancer. Breast Care, 3, 43-50.
  4. Darakhshan S, Bidmeshkipour A, Khazaei M, et al (2013). Synergistic effects of tamoxifen and tranilast on VEGF and MMP 9 regulation in cultured human breastcancer cells. Asian Pac J Cancer Prev, 14, 6869-74.
  5. Dowsett M, Procter M, McCaskill-Stevens W, et al (2009). Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol, 27, 2962-9.
  6. Hassan BA, Yusoff ZB (2011). Genetic polymorphisms in the three Malaysian races effect granisetron clinical antiemetic actions in breast cancer patients receiving chemotherapy. Asian Pac J Cancer Prev, 12, 185-91.
  7. Hayes DF, Stearns V, Rae J, Flockhart D (2008). A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients? J Natl Cancer Inst, 100, 610-3.
  8. Goetz MP, Rae JM, Suman VJ, et al (2005). Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol, 23, 9312-8.
  9. Goetz MP, Kamal A, Ames MM (2008). Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 83, 160-6.
  10. Gonzalez-Santiago S, Zarate R, Haba-Rodriguez J, et al (2007). CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen. J Clin Oncol, 18, 590.
  11. Forat-Yazdi M, Neamatzadeh H, Sheikhha MH, Zare-Shehneh M, Fattahi M (2015). BRCA1 and BRCA2 common mutations in iranian breast cancer patients: a meta analysis. Asian Pac J Cancer Prev, 16, 1219-24.
  12. Jin TB, Ma LF, Zhang JY, et al (2013). Polymorphisms and phenotypic analysis of cytochrome P450 2D6 in the Tibetan population. Gene, 527, 360-5.
  13. Kirchheiner J, Schmidt H, Tzvetkov M, et al (2007). Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J, 7, 257-65.
  14. Lash TL, Cronin-Fenton D, Ahern TP, et al (2011). CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. J Natl Cancer Inst, 103, 489-500.
  15. Martinez de Duenas E, Ochoa Aranda E, Blancas Lopez-Barajas I, et al (2014). Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype. Breast, 23, 400-6.
  16. Morrow PK, Serna R, Broglio K, et al (2012). Effect of CYP2D6 polymorphisms on breast cancer recurrence. Cancer, 118, 1221-7.
  17. Martins DM, Vidal FC, Souza RD, et al (2014). Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in Sao Luis, Brazil, and itsassociation with prognostic factors and disease-free survival. Braz J Med Biol Res, 47, 1008-15.
  18. Meiyanto E, Hermawan A, Anindyajati (2012). Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev, 13, 427-36.
  19. Motamedi S, Majidzadeh K, Mazaheri M, et al (2012). Tamoxifen resistance and CYP2D6 copy numbers in breast cancer patients. Asian Pac J Cancer Prev, 13, 6101-4.
  20. Nelson R (2012). CYP2D6 has impact on effectiveness of tamoxifen. medscape medical news. Available at:
  21. 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.
  22. Okishiro M, Taguchi T, Jin Kim S, et al (2009). Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer, 115, 952-61.
  23. Park IH, Ro J, Park S, et al (2013). Lack of any association between functionally significant CYP2D6 polymorphisms and clinical outcomes in early breast cancer patients receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat, 131, 455-61.
  24. Serin A, Canan H, Alper B, Gulmen M (2012). The frequencies of mutated alleles of CYP2D6 gene in a Turkish population. Forensic Sci Int, 222, 332-4.
  25. Schorth 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.
  26. 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.
  27. Shiryazdi SM, Kargar S, Taheri-Nasaj H, Neamatzadeh H (2015). BreastLight apparatus performance in detection of breast masses depends on mass size. Asian Pac J Cancer Prev, 16, 1181-4.
  28. Sukasem C, Sirachainan E, Chamnanphon M, et al (2012). Impact of CYP2D6 polymorphisms on tamoxifen responses of women with breast cancer: a microarray-basedstudy in Thailand. Asian Pac J Cancer Prev, 13, 4549-53.
  29. 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.
  30. 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, 284-290.
  31. Zhou LP, Luan H, Dong XH, et al (2012). Genetic variants of CYP2D6 gene and cancer risk: a HuGE systematic review and meta-analysis. Asian Pac J Cancer Prev, 13, 3165-72.