Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02)
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Ji Yun Lee1,*, Xu Qing2,*, Wei Xiumin2, Bai Yali2, Sangah Chi3, So Hyeon Bak4, Ho Yun Lee5, Jong-Mu Sun1, Se-Hoon Lee1, Jin Seok Ahn1, Eun Kyung Cho6, Dong-Wan Kim7, Hye Ryun Kim8, Young Joo Min9, Sin-Ho Jung3, Keunchil Park1, Mao Mao2 and Myung-Ju Ahn1
1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2 Translational Bioscience and Diagnostics, WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China
3 Department of Biostatistics and Bioinformatics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4 Department of Radiology, Kangwon National University Hospital, Chuncheon, Korea
5 Department of Radiology, Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6 Division of Hematology-Oncology, Department of Medicine, Gachon Medical School, Gil Medical Center, Inchon, Korea
7 Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
8 Division of Oncology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
9 Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea
* These authors have contributed equally to this study
Myung-Ju Ahn, email:
Mao Mao, email:
Keywords: NSCLC, EGFR, TKI treatment, droplet digital PCR, liquid biopsy
Received: August 31, 2015 Accepted: January 03, 2016 Published: January 09, 2016
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.
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