Thompson Jeffrey C, Yee Stephanie S, Troxel Andrea B, Savitch Samantha L, Fan Ryan, Balli David, Lieberman David B, Morrissette Jennifer D, Evans Tracey L, Bauml Joshua, Aggarwal Charu, Kosteva John A, Alley Evan, Ciunci Christine, Cohen Roger B, Bagley Stephen, Stonehouse-Lee Susan, Sherry Victoria E, Gilbert Elizabeth, Langer Corey, Vachani Anil, Carpenter Erica L
Division of Pulmonary, Allergy and Critical Care Medicine, Thoracic Oncology Group, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Clin Cancer Res. 2016 Dec 1;22(23):5772-5782. doi: 10.1158/1078-0432.CCR-16-1231. Epub 2016 Sep 6.
The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.
A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.
We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.
Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772-82. ©2016 AACR.
非小细胞肺癌（NSCLC）靶向治疗药物数量不断增加，这就需要进行实时肿瘤基因分型，但组织活检难以连续进行，且常常产生的DNA不足以用于下一代测序（NGS）。我们评估了使用游离循环肿瘤DNA（ctDNA）NGS作为组织NGS的补充或替代方法的可行性。
从对102例前瞻性入组的晚期NSCLC患者的连续研究中获得了112份血浆样本，尽可能对其进行多达70个基因的超深度测序，并与组织样本进行匹配。
我们在45个基因中检测到275个改变，102例患者中有86例（84%）的ctDNA中至少检测到一个改变，其中EGFR变异最为常见。ctDNA NGS检测到50个驱动突变和12个耐药突变，以及另外22个有实验性治疗方法（包括临床试验）可用的基因中的突变。虽然对102例连续患者完成了ctDNA NGS检测，但组织测序仅成功用于50例患者（49%）。在24份组织样本和19份ctDNA样本中检测到可操作的EGFR突变，一致性为79%，组织和血液采集之间的时间间隔越短，一致性越高（P = 0.038）。ctDNA测序确定了8例携带耐药突变的患者，他们在接受靶向治疗时病情进展，且无法进行组织测序。
即使在无法获得组织的情况下，也可通过ctDNA NGS检测到具有治疗靶点的驱动突变和耐药突变，从而实现更准确的诊断、改善患者管理，并进行连续采样以监测疾病进展和克隆演变。《临床癌症研究》；22(23)；5772 - 82。©2016美国癌症研究协会。
