Plasma EGFR mutation detection using a combined exosomal RNA and circulating tumor DNA approach in patients with acquired resistance to first-generation EGFR-TKIs

exosome rna

Presented at the AACR-NCI-EORTC conference.

After initial responses to tyrosine kinase inhibitors (TKIs), NSCLC patients harboring EGFR activating mutations inevitably progress, with the “gatekeeper” EGFR T790M resistance mutation accounting for approximately 60% of cases of acquired resistance (AR) to TKIs. EGFR activating and T790M resistance mutations can be found in plasma in both RNA contained within exosomes and in circulating free tumor DNA (ctDNA). While ctDNA is released by dying cells, exosomal RNA is actively released by many living cells (Schwarzenbach et al. Nat Rev Clin Oncol 2014; Jahr et al. Cancer Res 2001; Thery et al. Nat Rev Immunol 2009). Here we present matched tumor and plasma data from a subset of patients in TIGER-X (NCT01526928), a Ph1/2 study of rociletinib in previously treated mutant EGFR patients with advanced NSCLC. We demonstrate the detection of EGFR mutations in plasma using a spin-column based method (ExoLution Plus) for combined isolation of exosomal RNA (exoRNA) and ctDNA in a single step. This approach improves sensitivity and demonstrates the ability to detect mutations using exosomal RNA in patients previously described as negative by an external high-sensitivity qPCR method relying on ctDNA alone.

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