title: 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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Translational Bioscience and Diagnostics, WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Qing
authors.affiliation: Translational Bioscience and Diagnostics, WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiumin
authors.affiliation: Translational Bioscience and Diagnostics, WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Yali
authors.affiliation: Department of Biostatistics and Bioinformatics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sangah
authors.initials: S
authors.lastname: Chi
authors.affiliation: Department of Radiology, Kangwon National University Hospital, Chuncheon, Korea.
authors.forename: So Hyeon
authors.initials: SH
authors.lastname: Bak
authors.affiliation: Department of Radiology, Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ho Yun
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Gachon Medical School, Gil Medical Center, Inchon, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Cho
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Division of Oncology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Min
authors.affiliation: Department of Biostatistics and Bioinformatics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sin-Ho
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Translational Bioscience and Diagnostics, WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D018196:Carcinoma, Adenosquamous / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000097:blood / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D056910:Republic of Korea; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; NSCLC; TKI treatment; droplet digital PCR; liquid biopsy