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

Ji Yun Lee,Sangah Chi,Jin Seok Ahn,Jong-Mu Sun,Xu Qing,Young Joo Min,So Hyeon Bak,Dong-Wan Kim,Hye Ryun Kim,Sin-Ho Jung,Myung-Ju Ahn,Eun Kyung Cho,Ho Yun Lee,Bai Yali,Keunchil Park,Wei Xiumin,Mao Mao,Se-Hoon Lee

doi:10.18632/oncotarget.6874

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.

Highlights

Non-small cell lung cancer (NSCLC) has a dismal prognosis with one of the highest mortality rates among cancer types [1, 2]
We conducted a multi-center prospective study to assess dynamic changes in epidermal growth factor receptor (EGFR) mutation profile using a droplet digital PCR (ddPCR) method in longitudinally collected plasma samples from NSCLC patients harboring activating EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs)
From January 2012 to October 2014, 81 EGFR mutant NSCLC patients who were treated with gefitinib or erlotinib and eventually developed acquired resistance

Summary

INTRODUCTION

Non-small cell lung cancer (NSCLC) has a dismal prognosis with one of the highest mortality rates among cancer types [1, 2]. Most patients with NSCLC treated with EGFR TKIs eventually develop acquired resistance [9, 10]. Multiple mechanisms are involved, EGFR T790M mutation accounts for more than 50% of the acquired TKI resistance [11, 12]. Bai et al showed the difference in response rates (59.5% and 23.1%, P = 0.002) for gefitinib between patients with and without activating EGFR mutation in plasma [18]. We hypothesized that plasma-based EGFR mutation analysis using ddPCR may be feasible in monitoring response and resistance to EGFR TKIs. we conducted a multi-center prospective study to assess dynamic changes in EGFR mutation profile using a ddPCR method in longitudinally collected plasma samples from NSCLC patients harboring activating EGFR mutations treated with EGFR TKIs

RESULTS

DISCUSSION

Study design