Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02)

Abstract

We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance. Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance.

Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study

“…Because ctDNA clearance appears important for clinical evaluation, MAF is also appropriate to analyze ctDNA dynamics under treatment. Our results are consistent with previous findings showing that ctDNA normalization before the third cycle of treatment in EGFR -mutated patients is associated with improved OS [36,37]. …”

Total DNA input is a crucial determinant of the sensitivity of plasma cell-free DNA EGFR mutation detection using droplet digital PCR

“…Zhu et al [19] found that the plasma EGFR mutation testing sensitivity of ddPCR was greater than 80%, and the specificity was approximately 95.8-98.4%, compared with ARMS testing of matched tumor tissues. In our study, the specificity for plasma EGFR testing by ddPCR was 96.7-98.8%, similar to the results reported by Zhu et al However, the sensitivity in our study was lower than those previously reported for the ddPCR method [19, 20, 24] and the Cobas 4800 blood test [25], but higher than those reported for ARMS [12, 26] or other tests [27]. More than 200 NSCLC patients were enrolled in our study, and the blind method was adopted, so our study was closer to a clinical practice situation.…”

Circulating DNA in EGFR-mutated lung cancer

“…A prospective analysis of advanced NSCLC patients demonstrated that patients with complete resolution of ctDNA at either 2 or 6 weeks after treatment, exhibited a lower treatment discontinuation rate (0% at initial and 4% at second reimaging) compared to patients without complete resolution (33% at initial and 56% at second reimaging), presumably correlating with radiographic response and emergence of acquired resistance (11). Another prospective study followed 62 EGFR mutant NSCLC patients receiving TKI therapy with serial plasma ctDNA testing (56 (57). All 40 patients with EGFR mutations at baseline showed a significant reduction of mutant copies (>50%) in plasma during the first 2 months after treatment.…”