title: ALK fusion gene positive lung cancer and 3 cases treated with an inhibitor for ALK kinase activity.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer accounts for 4-5% of non-small cell lung carcinoma. A clinical trial of the specific inhibitor of ALK fusion-type tyrosine kinase is currently under way.
  
  
  METHODS
  ALK fusion gene products were analyzed immunohistochemically with the materials obtained by surgery or by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The echinoderm microtubule-associated protein-like 4(EML4)-ALK or kinesin family member 5B (KIF5B)-ALK translocation was confirmed by the reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). After eligibility criteria were met and informed consent was obtained, 3 patients were enrolled for the Pfizer Study of Crizotinib (PF02341066), Clinical Trial A8081001, conducted at Seoul National University.
  
  
  RESULTS
  Out of 404 cases, there were 14 of EML4-ALK non-small cell carcinoma (NSCLC) and one KIF5B-ALK NSCLC case (8 men, 7 women; mean age, 61.9 years, range 48-82). Except for 2 light smokers, all patients were non-smokers. All cases were of adenocarcinoma with papillary or acinar subtypes. Three were of stage IA, 5 of stage IIIA, 1 of stage IIIB and 6 of stage IV. Ten patients underwent thoracotomy, 3 received chemotherapy and 2 only best supportive care (BSC). One BSC and 2 chemotherapy cases were enrolled for the clinical trial. Patients with advanced stages who received chemotherapy or best supportive care were younger (54.0±6.3) than those who were surgically treated (65.8±10.1) (p<0.05). The powerful effect of ALK inhibitor on EML4-ALK NSCLC was observed. Soon after its administration, almost all the multiple bone and lymph node metastases quickly disappeared. Nausea, diarrhea and the persistence of a light image were the main side effects, but they diminished within a few months.
  
  
  CONCLUSIONS
  ALK-fusion gene was found in 3.7% (15/404) NSCLC cases and advanced disease with this fusion gene was correlated with younger generation. The ALK inhibitor presented in this study is effective in EML4-ALK NSCLC cases. A further study will be necessary to evaluate the clinical effectiveness of this drug.
authors.affiliation: Division of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan. hkimura@chiba-cc.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Soda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iizasa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsui
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yoshino
authors.forename: Masato
authors.initials: M
authors.lastname: Shingyoji
authors.forename: Meiji
authors.initials: M
authors.lastname: Itakura
authors.forename: Makiko
authors.initials: M
authors.lastname: Itami
authors.forename: Dai
authors.initials: D
authors.lastname: Ikebe
authors.forename: Sana
authors.initials: S
authors.lastname: Yokoi
authors.forename: Hajime
authors.initials: H
authors.lastname: Kageyama
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D005260:Female; D050939:Gene Fusion; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016547:Kinesins / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging / Q000379:methods; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C488101:KIF5B protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases; D016547:Kinesins