Institute of Clinical Pharmacology, Stuttgart, Germany.
Clin Cancer Res. 2010 Sep 1;16(17):4468-77. doi: 10.1158/1078-0432.CCR-10-0478. Epub 2010 Jun 1.
This study aimed to validate matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)/Taqman copy number assay (CNA) CYP2D6 genotyping by AmpliChip CYP450 Test for the prediction of tamoxifen metabolizer phenotypes in breast cancer, and to investigate the influence of CYP2D6 variant coverage on genotype-phenotype relationships and tamoxifen outcome.
Hormone receptor-positive postmenopausal breast cancer patients (n = 492) treated with adjuvant tamoxifen, previously analyzed by MALDI-TOF MS/CNA, were reanalyzed by AmpliChip CYP450 Test and validated by independent methods. Cox proportional hazard ratios (HR) were calculated for recurrence of poor (PM) relative to extensive metabolizer (EM) phenotypes with increasing numbers of CYP2D6 variants. Kaplan-Meier distributions were calculated for different phenotype classifications.
Concordance was 99.2% to 99.5% for CNA and 99.8% to 100% per CYP2D6 allele (*3, *4, *5, *9, *10, and *41). The prevalence of predicted phenotypes was 1.2% for ultrarapid metabolizer (UM), 37.2% for EM without variant, 43.5% for heterozygous EM, 9.7% for intermediate metabolizer (IM), and 8.3% for PM. Approximately, one third of patients were misclassified based on a *4 analysis only, but inclusion of all reduced-function alleles increased the PM-associated HR from 1.33 (P = 0.58) to 2.87 (P = 0.006). Kaplan-Meier analyses showed highest and lowest clinical benefit for UM and PM with respect to both the AmpliChip-based and a redefined phenotype assignment. The latter revealed significant allele-dose-dependent associations (P = 0.011) and largest effect size (HR(PM_EM) = 2.77; 95% confidence interval, 1.31-5.89).
MALDI-TOF MS/CNA is suitable for accurate CYP2D6 genotyping. For tamoxifen pharmacogenetics, broad CYP2D6 allele coverage is recommended to reduce phenotype misclassification. Classification based on refined EM and reduced-function metabolizers is advisable. AACR.
本研究旨在通过基质辅助激光解吸/电离-飞行时间质谱（MALDI-TOF MS）/Taqman 拷贝数分析（CNA）CYP2D6 基因分型验证 AmpliChip CYP450 检测在乳腺癌中预测他莫昔芬代谢物表型的能力，并探讨 CYP2D6 变异体覆盖率对基因型-表型关系和他莫昔芬结果的影响。
对先前通过 MALDI-TOF MS/CNA 分析的接受辅助性他莫昔芬治疗的激素受体阳性绝经后乳腺癌患者（n=492）进行重新分析，采用 AmpliChip CYP450 检测，并通过独立方法进行验证。计算 CYP2D6 变异体数量增加时不良（PM）相对于广泛代谢物（EM）表型的复发的风险比（HR）。计算不同表型分类的 Kaplan-Meier 分布。
CNA 的一致性为 99.2%至 99.5%，每个 CYP2D6 等位基因（*3、*4、*5、9、10 和41）的一致性为 99.8%至 100%。超快速代谢物（UM）的预测表型患病率为 1.2%，无变异的 EM 为 37.2%，杂合 EM 为 43.5%，中间代谢物（IM）为 9.7%，PM 为 8.3%。大约三分之一的患者仅根据4 分析被错误分类，但包含所有功能降低的等位基因会使 PM 相关 HR 从 1.33（P=0.58）增加至 2.87（P=0.006）。Kaplan-Meier 分析表明，在基于 AmpliChip 的表型和重新定义的表型赋值方面，UM 和 PM 具有最高和最低的临床获益。后者显示出显著的等位基因剂量依赖性关联（P=0.011）和最大的效应大小（HR（PM_EM）=2.77；95%置信区间，1.31-5.89）。
MALDI-TOF MS/CNA 适用于准确的 CYP2D6 基因分型。对于他莫昔芬药物遗传学，建议广泛覆盖 CYP2D6 等位基因，以减少表型错误分类。建议基于改良的 EM 和功能降低的代谢物进行分类。AACR。
