Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non-Small Cell Lung Cancer

J Thorac Oncol. 2019 Feb;14(2):255-264. doi: 10.1016/j.jtho.2018.10.008. Epub 2018 Oct 24.


Introduction: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative.

Methods: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1552 patients with NSCLC.

Results: Evidence of ctDNA was detected in 80% of samples, and in 86% of these cases, at least one reportable genomic alteration (GA) was detected. Frequently altered genes were tumor protein p53 gene (TP53) (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (N = 21,500) showed similar frequencies of GAs per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both p < 0.0001), likely reflecting the use of liquid versus tissue biopsy after relapse during targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in their blood, 64% of GAs detected in tissue were also detected in ctDNA, including 78% of short variants (58 of 74) and 100% of rearrangements (four of four), but only 16% of amplifications (four of 25).

Conclusions: Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest the utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood-based ctDNA testing may be particularly useful at the time of progression during targeted therapy.

Keywords: Circulating tumor DNA; Genomic profiling; Liquid biopsy; NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Large Cell / genetics*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Squamous Cell / genetics*
  • Child
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA Copy Number Variations
  • DNA Mutational Analysis / methods
  • DNA, Neoplasm / blood*
  • ErbB Receptors / genetics
  • Female
  • Gene Rearrangement
  • Genomics / methods
  • Humans
  • INDEL Mutation
  • Liquid Biopsy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Neurofibromin 1 / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Retrospective Studies
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult


  • DNA, Neoplasm
  • KRAS protein, human
  • NF1 protein, human
  • Neurofibromin 1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)