Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases
Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases
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DOI：
10.1002/cncr.32876
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发表时间：
2020-05-04
期刊：
影响因子：
6.2
通讯作者：
Gandara, David R.
中科院分区：
文献类型：
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作者：
Mack, Philip C.;Banks, Kimberly C.;Gandara, David R.
基于循环无细胞肿瘤DNA（ctDNA）的突变谱，如果足够敏感和全面，可以有效地识别晚期肺腺癌的基因组靶点。因此，作者研究了商业上可用的数字下一代测序平台在大量非小细胞肺癌（NSCLC）患者中的准确性和临床实用性。方法分析了8388例连续检测的晚期NSCLC患者的基于血浆的综合基因组分析结果。驱动和耐药突变进行了检查，就其分布，频率，共现，和相互exclusivity.Results体细胞变异检测到86%的样品。变异等位基因比例中位数为0.43%（范围：0.03%-97.62%）。在48%的患者中发现了可操作癌基因的激活性改变，包括EGFR（26.4%）、MET（6.1%）和BRAF（2.8%）改变和融合（ALK、RET和ROS 1）（2.3%）。治疗诱导的耐药突变在该队列中很常见，包括驱动因子依赖性和驱动因子非依赖性改变。在EGFR治疗期间发生疾病进展的患者亚组中，64%的患者在血浆中检测到已知或推定的耐药改变。子集分析显示，ctDNA在诊断时将驱动突变的识别率提高了65%，高于标准护理，基于组织的测试。一个汇总的数据分析，这种血浆为基础的检测表明，有针对性的治疗反应率相当于从tissue analysis.Conclusions报告的治疗靶向的驱动程序和耐药突变的频率和分布预测的研究人群检测的存在下，综合ctDNA分析。这些发现为在诊断时未完全检测的患者进行全面的ctDNA检测提供了支持，并作为靶向治疗进展时的主要选择。
Background Circulating cell-free tumor DNA (ctDNA)-based mutation profiling, if sufficiently sensitive and comprehensive, can efficiently identify genomic targets in advanced lung adenocarcinoma. Therefore, the authors investigated the accuracy and clinical utility of a commercially available digital next-generation sequencing platform in a large series of patients with non-small-cell lung cancer (NSCLC).Methods Plasma-based comprehensive genomic profiling results from 8388 consecutively tested patients with advanced NSCLC were analyzed. Driver and resistance mutations were examined with regard to their distribution, frequency, co-occurrence, and mutual exclusivity.Results Somatic alterations were detected in 86% of samples. The median variant allele fraction was 0.43% (range, 0.03%-97.62%). Activating alterations in actionable oncogenes were identified in 48% of patients, including EGFR (26.4%), MET (6.1%), and BRAF (2.8%) alterations and fusions (ALK, RET, and ROS1) in 2.3%. Treatment-induced resistance mutations were common in this cohort, including driver-dependent and driver-independent alterations. In the subset of patients who had progressive disease during EGFR therapy, 64% had known or putative resistance alterations detected in plasma. Subset analysis revealed that ctDNA increased the identification of driver mutations by 65% over standard-of-care, tissue-based testing at diagnosis. A pooled data analysis on this plasma-based assay demonstrated that targeted therapy response rates were equivalent to those reported from tissue analysis.Conclusions Comprehensive ctDNA analysis detected the presence of therapeutically targetable driver and resistance mutations at the frequencies and distributions predicted for the study population. These findings add support for comprehensive ctDNA testing in patients who are incompletely tested at the time of diagnosis and as a primary option at the time of progression on targeted therapies.