Abstract
Tamoxifen has been successfully used for treating breast cancer and preventing cancer recurrence. Cytochrome P450 2D6 (CYP2D6) plays a key role in the process of metabolizing tamoxifen to its active moiety, endoxifen. Patients with variants of the CYP2D6 gene may not receive the full benefit of tamoxifen treatment. The CYP2D6*10 variant (the most common variant in Asians) was analyzed to optimize the prescription of tamoxifen in China. To ensure referring clinicians have accurate information for genotype-guided tamoxifen treatment, the Chinese National Center for Clinical Laboratories (NCCL) organized a national proficiency testing (PT) to evaluate the performance of laboratories providing CYP2D6*10 genotyping. Ten genomic DNA samples with CYP2D6 wild-type or CYP2D6*10 variants were validated by PCR-sequencing and sent to 28 participant laboratories. The genotyping results and pharmacogenomic test reports were submitted and evaluated by NCCL experts. Additional information regarding the number of samples tested, the accreditation/certification status, and detecting technology was also requested. Thirty-one data sets were received, with a corresponding analytical sensitivity of 98.2% (548/558 challenges; 95% confidence interval: 96.7–99.1%) and an analytic specificity of 96.5% (675/682; 95% confidence interval: 97.9–99.5%). Overall, 25/28 participants correctly identified CYP2D6*10 status in 10 samples; however, two laboratories made serious genotyping errors. Most of the essential information was included in the 20 submitted CYP2D6*10 test reports. The majority of Chinese laboratories are reliable for detecting the CYP2D6*10 variant; however, several issues revealed in this study underline the importance of PT schemes in continued external assessment and provision of guidelines.
Highlights
Tamoxifen is widely used as an anti-estrogenic drug for the treatment of estrogen receptor (ER)positive breast cancer [1]
The genotype of each DNA sample extracted from cell lines provided by Coriell was confirmed by the National Center for Clinical Laboratories (NCCL) laboratory using the Sanger sequencing method (Table 1)
Two of the 28 participants were accredited according to ISO 15189, 2 laboratories were accredited according to ISO 17025, and another 2 laboratories were accredited by the College of American Pathologists (CAP)
Summary
Tamoxifen is widely used as an anti-estrogenic drug for the treatment of estrogen receptor (ER)positive breast cancer [1]. Assessment of CYP2D6*10 Genotyping in China cancer recurrences and improve patient survival rates [2, 3]. PM and IM patients have lower plasma concentrations of endoxifen and benefit less from tamoxifen therapy [7]. The CYP2D6Ã10 (100C>T, rs1065852; 4180G>C, rs1135840) allele, with decreased enzymatic activity, has been found in 40–50% of Asians [8, 9]. Xu et al reported that out of 152 Chinese women receiving tamoxifen therapy, patients with the CYP2D6Ã10/Ã10 genotype had a lower 4OHT plasma level and a worse disease-free survival rate [10]. Another study showed that the CYP2D6Ã10 variant affected the efficacy of combined tamoxifen citrate and testosterone undecanoate treatment in 230 infertile Chinese men [11]. Genotyping of CYP2D6Ã10 can be used to optimize the selection [8, 10, 11] and dosing [12] of tamoxifen in eastern Asian patients
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