title: A Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer.
abstract: The presence of ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ∼1% of non-small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost- and time-efficient.
  
  
  
  A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken.
  
  
  
  IHC staining was 100% sensitive (95% confidence interval: 48-100) and 83% specific (95% confidence interval: 86-100) overall when an h-score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never-smokers, with the tumors all being adenocarcinomas with higher-grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively.
  
  
  
  IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Viola
authors.affiliation: Centre for Molecular Pathology, Royal Marsden Hospital, Sutton, United Kingdom.
authors.forename: Manisha
authors.initials: M
authors.lastname: Maurya
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Croud
authors.affiliation: Centre for Molecular Pathology, Royal Marsden Hospital, Sutton, United Kingdom.
authors.forename: Jana
authors.initials: J
authors.lastname: Gazdova
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Nadia
authors.initials: N
authors.lastname: Suleman
authors.affiliation: Department of Thoracic Surgery, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Oncology, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Newsom-Davis
authors.affiliation: Department of Oncology, St Bartholomew's Hospital, London, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Plowman
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rice
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Montero
authors.affiliation: Centre for Molecular Pathology, Royal Marsden Hospital, Sutton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: a.nicholson@rbht.nhs.uk.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D000077547:Crizotinib; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
keywords: FISH; Immunohistochemistry; Lung cancer; ROS1 gene rearrangement