Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma

Ann Oncol. 2018 Mar 1;29(3):700-706. doi: 10.1093/annonc/mdx765.


Background: A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients.

Patients and methods: Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing.

Results: For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection.

Conclusions: Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone.

Clinical trials: NCT01526928.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Acrylamides / therapeutic use
  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / blood*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Circulating Tumor DNA / blood*
  • DNA Mutational Analysis / methods*
  • ErbB Receptors / genetics
  • Exosomes
  • Female
  • Genes, erbB-1
  • Humans
  • Liquid Biopsy / methods
  • Lung Neoplasms / blood*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Pyrimidines / therapeutic use
  • RNA / blood*
  • Sensitivity and Specificity


  • Acrylamides
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Pyrimidines
  • RNA
  • rociletinib
  • EGFR protein, human
  • ErbB Receptors

Associated data