title: EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases.
abstract: OBJECTIVE
  Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients.
  
  
  METHODS
  Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure. EGFR mutations were tested by amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) methods. Gefitinib concentrations were evaluated by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS).
  
  
  RESULTS
  EGFR mutations were detected in all seven CSF samples, including three of E19-Del, three of L858R and one of E19-Del&T790M by both methods. On the other hand, majority of the matched plasma samples (5/7) were negative for EGFR mutations by both methods. The other two plasma samples were positive for E19-Del&T790M by ddPCR, and one of them had undetectable T790M by ARMS. Gefitinib concentration in CSF was much lower than that in plasma (mean CSF/plasma ratio: 1.8 %).
  
  
  CONCLUSIONS
  After EGFR-TKI failure, majority of the NSCLC patients with CNS metastases remained positive detection of EGFR sensitive mutations in CSF, but much less detection in the matched plasma. Significantly low exposure of gefitinib in CSF might explain the intracranial protection of the EGFR sensitive mutation positive tumor cells.
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
authors: Jing
authors: J
authors: Zhao
authors: Asia and Emerging Markets Innovative Medicine, AstraZeneca R&D, 199 Liangjing Road, Bldg 2, Shanghai, 201203, China.
authors: Xin
authors: X
authors: Ye
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
authors: Yan
authors: Y
authors: Xu
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
authors: Minjiang
authors: M
authors: Chen
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
authors: Wei
authors: W
authors: Zhong
authors: Asia and Emerging Markets Innovative Medicine, AstraZeneca R&D, 199 Liangjing Road, Bldg 2, Shanghai, 201203, China.
authors: Yun
authors: Y
authors: Sun
authors: Asia and Emerging Markets Innovative Medicine, AstraZeneca R&D, 199 Liangjing Road, Bldg 2, Shanghai, 201203, China.
authors: Zhenfan
authors: Z
authors: Yang
authors: Asia and Emerging Markets Innovative Medicine, AstraZeneca R&D, 199 Liangjing Road, Bldg 2, Shanghai, 201203, China.
authors: Guanshan
authors: G
authors: Zhu
authors: Asia and Emerging Markets Innovative Medicine, AstraZeneca R&D, 199 Liangjing Road, Bldg 2, Shanghai, 201203, China. yi.gu@astrazeneca.com.
authors: Yi
authors: Y
authors: Gu
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. mengzhaowang@sina.com.
authors: Mengzhao
authors: M
authors: Wang
mesh_terms: D000328:Adult; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008577:Meningeal Neoplasms / Q000556:secondary*; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use
chemical_list: D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Brain metastasis; Cerebrospinal fluid; EGFR mutation testing; Leptomeningeal metastasis; Non-small cell lung cancer