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

• Published in: Annals of oncology Vol. 29; no. 3; pp. 700 - 706
• Main Authors: Krug, A.K., Enderle, D., Karlovich, C., Priewasser, T., Bentink, S., Spiel, A., Brinkmann, K., Emenegger, J., Grimm, D.G., Castellanos-Rizaldos, E., Goldman, J.W., Sequist, L.V., Soria, J.-C., Camidge, D.R., Gadgeel, S.M., Wakelee, H.A., Raponi, M., Noerholm, M., Skog, J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2018; Oxford University Press
• Subjects: 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; ctDNA; DNA Mutational Analysis - methods; Editor's Choice; EGFR; ErbB Receptors - genetics; exoRNA; Exosomes; Female; Genes, erbB-1; Humans; liquid biopsy; Liquid Biopsy - methods; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; Middle Aged; NSCLC; Original; Pyrimidines - therapeutic use; RNA - blood; Sensitivity and Specificity; exoRNA; NSCLC; exosomes; liquid biopsy; ctDNA; EGFR
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdx765

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. 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. 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. 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. NCT01526928