title: Clinical and prognostic implications of RET rearrangements in metastatic lung adenocarcinoma patients with malignant pleural effusion.
abstract: OBJECTIVE
  RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (NSCLC). However, the prevalence, clinical characteristics, and outcome of patients with RET-rearranged lung adenocarcinoma in metastatic disease remain uncertain.
  
  
  METHODS
  Multiplex reverse transcription-polymerase chain reaction (RT-PCR) was used to detect KIF5B-RET and CCDC6-RET fusions from specimens of malignant pleural effusion (MPE) in patients with metastatic lung adenocarcinoma. The demographic data and outcome of patients with RET-rearranged tumors were compared with those with EGFR-mutant, KRAS-mutant, EML4-ALK-rearranged, and quadri-negative tumors.
  
  
  RESULTS
  Of the 722 patients with MPE of lung adenocarcinoma screened, 17 (2.4%) had RET-rearranged tumors. The detected RET rearrangements comprised 11 (65%) KIF5B-RET and 6 (35%) CCDC6-RET fusions, including 2 novel fusion variants identified. The presence of RET rearrangements was not associated with age at diagnosis, gender or smoking history, but predominantly seen in solid histological subtype. None of patients with RET-rearranged tumors had received kinase inhibitors with activity against RET kinase. The median overall survival was 22.4 months (95% CI, 8.8-36.0) for the 17 patients with RET-rearranged tumors, compared with 21.3 months (95% CI, 18.7-23.9; P=0.57) for the 451 patients with EGFR-mutant tumors, 5.4 months (95% CI, 2.7-8.1; P=0.002) for the 13 patients with KRAS-mutant tumors, 18.9 months (95% CI, 10.7-27.1; P=0.82) for the 51 patients with EML4-ALK-rearranged tumors, and 12.0 months (95% CI, 9.0-15.0; P=0.07) for the 190 patients with quadri-negative tumors.
  
  
  CONCLUSIONS
  Multiplex RT-PCR from specimens of MPE is feasible for the screening of RET rearrangements in NSCLC. Metastatic RET-rearranged lung adenocarcinoma patients with MPE might have favorable survival comparable to those with metastatic EGFR-mutant tumors.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Tzu-Hsiu
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors.forename: Shang-Gin
authors.initials: SG
authors.lastname: Wu
authors.affiliation: Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Min-Shu
authors.initials: MS
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Department of Oncology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: jyshih@ntu.edu.tw.
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D018797:Cell Cycle Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D016066:Pleural Effusion, Malignant / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C088832:CCDC6 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C488101:KIF5B protein, human; C117307:KRAS protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases; D016547:Kinesins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: CCDC6–RET fusions; EGFR; KIF5B–RET fusions; Lung adenocarcinoma; NSCLC; RET rearrangements