title: Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA.
abstract: BACKGROUND
  Genotyping of EGFR (epidermal growth factor receptor) mutations is indispensable for making therapeutic decisions regarding whether to use EGFR tyrosine kinase inhibitors (TKIs) for lung cancer. Because some cases might pose challenges for biopsy, noninvasive genotyping of EGFR in circulating tumor DNA (ctDNA) would be beneficial for lung cancer treatment.
  
  
  METHODS
  We developed a detection system for EGFR mutations in ctDNA by use of deep sequencing of plasma DNA. Mutations were searched in >100 000 reads obtained from each exon region. Parameters corresponding to the limit of detection and limit of quantification were used as the thresholds for mutation detection. We conducted a multi-institute prospective study to evaluate the detection system, enrolling 288 non-small cell lung cancer (NSCLC) patients.
  
  
  RESULTS
  In evaluating the performance of the detection system, we used the genotyping results from biopsy samples as a comparator: diagnostic sensitivity for exon 19 deletions, 50.9% (95% CI 37.9%-63.9%); diagnostic specificity for exon 19 deletions, 98.0% (88.5%-100%); sensitivity for the L858R mutation, 51.9% (38.7%-64.9%); and specificity for L858R, 94.1% (83.5%-98.6%). The overall sensitivities were as follows: all cases, 54.4% (44.8%-63.7%); stages IA-IIIA, 22.2% (11.5%-38.3%); and stages IIIB-IV, 72.7% (60.9%-82.1%).
  
  
  CONCLUSIONS
  Deep sequencing of plasma DNA can be used for genotyping of EGFR in lung cancer patients. In particular, the high specificity of the system may enable a direct recommendation for EGFR-TKI on the basis of positive results with plasma DNA. Because sensitivity was low in early-stage NSCLC, the detection system is preferred for stage IIIB-IV NSCLC.
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.affiliation: Department of Molecular and Medical Genetics, Research Institute, and katou-ki@mc.pref.osaka.jp.
authors.forename: Kikuya
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Molecular and Medical Genetics, Research Institute, and.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kukita
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Toru
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishino
authors.affiliation: Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan;
authors.forename: Haruko
authors.initials: H
authors.lastname: Daga
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan;
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagatomo
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Takako
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Graduate School of Informatics, Kyoto University, Japan Science and Technology, Kyoto, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Oba
authors.affiliation: Center for Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan;
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan;
authors.forename: Koji
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Thoracic Oncology.
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000097:blood* / Q000235:genetics; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D012680:Sensitivity and Specificity
chemical_list: D004247:DNA; D066246:ErbB Receptors