title: Diagnostic significance of cerebrospinal fluid EGFR mutation analysis for leptomeningeal metastasis in non-small-cell lung cancer patients harboring an active EGFR mutation following gefitinib therapy failure.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been successfully used to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, despite an initial excellent response, recurrence within one or two years is common. Diagnosis and treatment of leptomeningeal metastasis (LM), a form of NSCLC recurrence, remains particularly difficult. Here, we analyzed the EGFR mutation status of cerebrospinal fluid (CSF) directly using real-time polymerase chain reaction (PCR) and evaluated the efficacy of therapy with erlotinib, an EGFR TKI.
  
  
  METHODS
  Seven NSCLC patients harboring activating EGFR mutations who had developed LM during or after therapy with gefitinib, an EGFR TKI, were retrospectively analyzed. CSF was obtained and subjected to cytological examination and EGFR mutation analysis, including detection of the resistance-associated T790M mutation, using real-time PCR.
  
  
  RESULTS
  In all seven cases, the EGFR mutation detected in the CSF was the same as that detected in the primary tumor (sensitivity, 100%). Conversely, cytology results were positive in only two patients (sensitivity, 28.6%). No additional T790M mutations were detected. Erlotinib was efficacious in all cases, and improved performance status was achieved for five of the seven patients. The effect of erlotinib treatment was temporary, however, with time to treatment failure (TTF) ranging from 29 to 278 days (median, 65 days) and the interval between commencement of erlotinib treatment and death ranging from 45 to 347 days (median, 168 days).
  
  
  CONCLUSIONS
  Analysis of EGFR mutations in CSF using a highly sensitive real-time PCR assay is a potentially powerful diagnostic method for LM.
authors.affiliation: Department of Respiratory Medicine, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba 279-0021, Japan. Electronic address: ssasaki@juntendo-urayasu.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Department of Respiratory Medicine, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba 279-0021, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ko
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Katsura
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Namba
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Shukuya
authors.affiliation: Department of Respiratory Medicine, Juntendo University Nerima Hospital, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kido
authors.affiliation: Department of Respiratory Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Iwakami
authors.affiliation: Department of Respiratory Medicine, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba 279-0021, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tominaga
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000134:cerebrospinal fluid / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000556:secondary*; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: EGFR mutation; Leptomeningeal metastasis; Real-time PCR assay; T790M mutation; Tyrosine kinase inhibitor