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

Abstract

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±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 tamoxifentreated 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.

CYP2D6*3 (A2549del), *4 (G1846A), *10 (C100T) and *17 (C1023T) genetic polymorphisms in Iranian breast cancer patients treated with adjuvant tamoxifen

“…Previous study reported the prevalence of CYP2D6*10 as ~9.0% in Iranian Azerbaijanis (26), but another study of Iranians of different ethnicities reported the prevalence of the allele to be 39.3% (24.3% for homozygous T/T and 15.0% for heterozygous C/T) (25). The frequency of CYP2D6*4 varies across different races, and frequencies of 36.6, 28.6, 28.0, 13.8, 13.8, 7.3 and 0.2% have been reported in Iranians, Malaysian Indians, Turks, Spanish subjects, Brazilians, South-Indians and North Americans, respectively (18,(36)(37)(38)(39)(40)(41). Conversely, the frequency of CYP2D6*4 varies from 0.2 to 3.5% among Japanese, Chinese and Saudi Arabians, which is considered relatively low (20)(21)(22).…”

Contribution of ABCB1 and CYP2D6 Genotypes to the Outcome of Tamoxifen Adjuvant Treatment in Premenopausal Women With Breast Cancer

“…Indeed, some published studies demonstrate a higher risk of recurrence of the disease and shortening of DFS in patients carrying functionally variant alleles of CYP2D6 (Bonanni et al 2006, Goetz et al 2005, Newman et al 2008, Schroth et al 2007, Trojan et al 2013, Yazdi et al 2015.…”

Pharmacogenetics and pharmacogenomics: The impact of the single nucleotide polymorphisms in drug response

“…Nedavno je takođe pokazano da u poređenju sa drugim ženama koje imaju rak dojke i primaju tamoksifen, one koje imaju HER2 (engl. human epidermal growth factor receptor 2)/neu pozitivni rak dojke i koje su još i CYP2D6 izrazito brzi metabolizeri tamoksifena usled prisustva više kopija gena za CYP2D6, imaju manju stopu recidiva (27).…”