Dynamic Assessment of Tissue and Plasma EGFR-Activating and T790M Mutations with Droplet Digital PCR Assays for Monitoring Response and Resistance in Non-Small Cell Lung Cancers Treated with EGFR-TKIs.

Abstract

Assessing tumor EGFR mutation status is necessary for the proper management of patients with advanced non–small cell lung cancer (NSCLC). We evaluated the impact of dynamic analyses of the plasma and tissue EGFR mutation using ultra-sensitive droplet digital PCR (ddPCR) assays to manage NSCLC patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Paired tumor tissues and plasma samples from 137 EGFR-mutated lung adenocarcinoma patients prior to the first-line EGFR-TKIs treatment (at baseline) and at disease progression were subjected to EGFR mutation analysis using ddPCR, together with the analyses of the clinicopathological characteristics and treatment outcomes. Patients with EGFR-activating mutations detected in baseline plasma were associated with bone metastasis (p = 0.002) and had shorter progression-free survival (12.9 vs. 17.7 months, p = 0.02) and overall survival (24.0 vs. 39.4 months, p = 0.02) compared to those without. Pre-treatment EGFR T790M mutation found in baseline tumor tissues of 28 patients (20.4%; 28/137) was significantly associated with brain metastasis (p = 0.005) and a shorter brain metastasis-free survival (p = 0.001). The presence of EGFR T790M mutations in baseline tumor tissues did not correlate with the emergence of acquired EGFR T790M mutations detected at progression. At disease progression, acquired EGFR T790M mutations were detected in 26.6% (21/79) of the plasma samples and 42.9% (15/35) of the rebiopsy tissues, with a concordance rate of 71.4% (25/35). The dynamic monitoring of tissue and plasma EGFR mutation status at baseline and progression using ddPCR has a clinical impact on the evaluation of EGFR-TKIs treatment efficacy and patient outcomes, as well as the emergence of resistance in NSCLC.