Evaluation of Emergent Mutations in Circulating Cell-Free DNA and Clinical Outcomes in Patients with Metastatic Colorectal Cancer Treated with Panitumumab in the ASPECCT Study
Evaluation of Emergent Mutations in Circulating Cell-Free DNA and Clinical Outcomes in Patients with Metastatic Colorectal Cancer Treated with Panitumumab in the ASPECCT Study
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DOI：
10.1158/1078-0432.ccr-18-2072
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发表时间：
2019-02-15
影响因子：
11.5
通讯作者：
Ang, Agnes
中科院分区：
文献类型：
--
作者：
Peeters, Marc;Price, Timothy;Ang, Agnes
目的：EGFR通路基因突变是转移性结直肠癌患者预后不良的指标。无细胞DNA的血浆分析是一种微创且高度灵敏的检测肿瘤体细胞突变的方法。通过下一代测序分析了ASPECCT研究中基线和安全性随访（SFU）时从帕尼单抗治疗患者中采集的血浆样本-基于扩展RAS突变等位基因频率作为连续变量的方法及其与临床结局和突变患病率的相关性63个癌症相关基因。患者预后和EGFR通路基因的基线突变状态之间的相关性也进行了检查。结果：总体而言，帕尼单抗组有261例患者具有可评估的血浆样本。基线时RAS突变等位基因频率较高的患者的临床结局比频率较低的患者差（P < 0.001，考克斯PH模型）;然而，RAS突变并不一定妨碍患者获益。基线RAS突变患者的客观缓解率（完全或部分缓解）为10.8%，BRAF突变患者为21.7%。63基因组分析揭示了肿瘤突变负荷从基线到SFU的增加（P < 0.001，Wilcoxon符号秩检验）。EGFR通路基因的基线突变，分类和连续分析时，与较短的survival.Conclusions：EGFR通路基因突变时，连续分析，较高的突变等位基因频率与较差的结果。然而，扩展RAS突变本身并不妨碍帕尼单抗单药治疗的临床应答。
Purpose: Mutations in EGFR pathway genes are poor prognostic indicators in patients with metastatic colorectal cancer. Plasma analysis of cell-free DNA is a minimally invasive and highly sensitive method to detect somatic mutations in tumors.Experimental Design: Plasma samples collected from panitumumab-treated patients in the ASPECCT study at baseline and safety follow-up (SFU) were analyzed by a next-generation sequencing-based approach for extended RAS mutant allele frequency as a continuous variable and their association with clinical outcomes and the mutational prevalence of 63 cancer-related genes. The correlation between patient outcome and baseline mutational status of EGFR pathway genes was also examined.Results: Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher RAS mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (P < 0.001, Cox PH model); however, RAS mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline RAS mutations and 21.7% for those with BRAF mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (P < 0.001, Wilcoxon signed rank test). Baseline mutations in EGFR pathway genes, when analyzed both categorically and continuously, were associated with shorter survival.Conclusions: When mutations in EGFR pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended RAS mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.