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

Mohammad Forat Yazdi,Tahereh Nazari,Mohsen Gholi-Nataj,Hossein Neamatzadeh,Shiva Rafieian,Mohammad Hasan Sheikhha

doi:10.7314/apjcp.2015.16.15.6783

Abstract

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. 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. The mean age of the patients with the disease recurrence was 50.8±6.4 and in non recurrent patients was 48.2±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. 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.

Highlights

Breast cancer is the most common cause of mortality among women accounting for 23% all cancers (Foratyazdi et al, 2015)
Clinical impact of cytochrome P450 2D6 (CYP2D6)*4 on breast cancer recurrence was the main subject of this study
Previous studies have shown that genetic polymorphism in CYP2D6 may predict the benefit of tamoxifen therapy with a significantly improved disease free survival in patients that were carriers of the CYP2D6*4 allele (Wegman et al, 2005; Wegman et al, 2007; Sukasem et al, 2012)

Summary

Introduction

Breast cancer is the most common cause of mortality among women accounting for 23% all cancers (Foratyazdi et al, 2015). Tamoxifen is used for breast cancer prevention in women older than 35 years with a calculated Gail Model 5-year risk of invasive breast cancer greater than 1.67%.9. 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. 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. CYP2D6 metabolism, as measured by genetic variation, can be a predictor of breast cancer outcome in Her2-neu positive women receiving tamoxifen

Methods

Results

Conclusion