title: Dynamic plasma EGFR mutation status as a predictor of EGFR-TKI efficacy in patients with EGFR-mutant lung adenocarcinoma.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) mutation status in lung cancer can effectively predict EGFR-tyrosine kinase inhibitor (TKI) efficacy. We evaluated the role of dynamic plasma cell-free DNA EGFR mutation status in outcome prediction.
  
  
  METHODS
  Advanced lung adenocarcinoma patients were enrolled and prospectively observed for outcomes of EGFR-TKI treatment. Peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method was developed to assess EGFR mutations in matched tumor and serial plasma cell-free DNA specimens.
  
  
  RESULTS
  A total of 72 patients were enrolled in this study, of which 62 patients (86.1%) had EGFR-mutant tumors (34 patients with exon 19 deletions, and 28 patients with L858R). Pretreatment plasma used for EGFR mutation testing showed a sensitivity of 59.7% and a specificity of 100%. Detection sensitivity was significantly higher in stage IV-M1b patients compared with stage IIIb and IV-M1a patients (78.0% versus 23.8%, p < 0.001). All patients who presented with EGFR-mutant tumors received first-line EGFR-TKI therapy. The objective response rate and disease control rate were 74.2% and 82.3%, respectively. Median progression-free survival and overall survival were 8.8 months (95% CI: 6.6-11.0) and 20.5 months (95% CI 15.1-26.0), respectively. Failure to clear plasma EGFR mutations after EGFR-TKI treatment was an independent predictor of lower disease control rate (odds ratio 5.26 [95% CI: 1.13-24.44]; p = 0.034), shorter progression-free survival (hazard ratio: 1.97 [95% CI: 1.33-2.91]; p = 0.001), and shorter overall survival (hazard ratio: 1.82 [95% CI: 1.04-3.18], p = 0.036).
  
  
  CONCLUSIONS
  Changes in plasma EGFR mutation status can be successfully assessed using the peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method and can serve as an independent outcome predictor.
authors.affiliation: *Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan, ROC; †Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, ROC; ‡Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; §Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, ROC; ‖Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan, ROC; ¶Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, ROC; #Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC; **Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC; ††Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC; ‡‡Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC; §§Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC; ‖‖Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan, ROC; and ¶¶Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
authors.forename: Jeng-Sen
authors.initials: JS
authors.lastname: Tseng
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Yang
authors.forename: Chi-Ren
authors.initials: CR
authors.lastname: Tsai
authors.forename: Kun-Chieh
authors.initials: KC
authors.lastname: Chen
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Hsu
authors.forename: Meen-Hsin
authors.initials: MH
authors.lastname: Tsai
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.forename: Kang-Yi
authors.initials: KY
authors.lastname: Su
authors.forename: Jeremy J W
authors.initials: JJ
authors.lastname: Chen
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D011743:Pyrimidines / Q000494:pharmacology*; D015996:Survival Rate / Q000639:trends; D013624:Taiwan / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000813:Anilides; D004273:DNA, Neoplasm; C561722:EGFR tyrosine kinase inhibitor 324674; D011743:Pyrimidines; C512478:EGFR protein, human; D066246:ErbB Receptors