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首页> 外文期刊>Molecular cancer therapeutics >Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies
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Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

机译：纳流数字PCR和RAS和BRAF的扩展基因分型可改善转移性结直肠癌患者的抗EGFR治疗选择

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The clinical significance of low-frequent RAS pathway-mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. (C) 2016 AACR.
机译：在转移性结直肠癌（mCRC）患者中，低频率RAS途径突变的等位基因和最佳抗敏性临界值在预测抗EGFR治疗反应中的临床意义仍然存在争议。我们旨在评估使用强大的纳米流体数字PCR（dPCR）方法对扩展的RAS面板进行基因分型的附加价值。在来自102名接受抗EGFR治疗的mCRC患者的肿瘤FFPE样品中，分析了34个热点，包括RAS（KRAS和NRAS外显子2/3/4）和BRAF（V600E）。将dPCR与常规定量PCR（qPCR）进行了比较。应答率，无进展生存期（PFS）和总生存期（OS）与突变状态和突变的等位基因分数相关。 9例患者没有进行肿瘤反应评估，因此排除了反应率分析。 22％的患者通过qPCR对一种突变呈阳性（突变的等位基因范围为2.1％至66.6％）。 dPCR分析将阳性患者的数量增加到47％。仅通过dPCR检测到的患者的突变等位基因范围为0.04％至10.8％。观察到突变的等位基因的分数与放射反应之间呈负相关。 ROC分析表明，对于RAS和BRAF分析的所有组合，任何突变的等位基因中只有1％或更高的比例提供了最佳的预测值。此外，该阈值还优化了PFS和OS的预测。我们得出的结论是，使用扩展的基因组（包括RAS和BRAF，阈值1％）进行的突变测试可提高对抗EGFR治疗反应的预测。 （C）2016 AACR。

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