title: Parallel FISH and immunohistochemical studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK) rearrangements occur in 1% to 7% of non-small-cell lung cancers (NSCLCs). Crizotinib, an ALK inhibitor, has been demonstrated to provide dramatic clinical benefits in ALK-positive advanced-stage NSCLC. Fluorescent in situ hybridization (FISH) has been established in clinical trials as the standard procedure method for detecting ALK rearrangements. Although the detection of ALK by immunohistochemistry (IHC) has been proposed for the screening of patients, large-scale studies are warranted to validate such a hierarchical approach.
  
  
  METHODS
  In this article, we report the largest series thus far of parallel FISH and IHC ALK testing in 3244 consecutive NSCLC cases analyzed at two independent French centers.
  
  
  RESULTS
  FISH-positive and/or IHC-positive results were demonstrated in 150 of 3244 cases (4.6%). An imbalanced sex ratio was detected, with women exhibiting a 2.2-fold relative risk for an alteration. Strikingly, only 80 of 150 specimens were classified as ALK positive by both techniques. The specimens with discordant FISH/IHC analyses were FISH-positive/IHC-negative (36), FISH-negative/IHC-positive (19), or FISH-noncontributive/IHC-positive (15). Thus, a single FISH or IHC analysis performed alone would have failed to detect approximately one-fourth of the ALK-positive cases with similar findings in our two centers.
  
  
  CONCLUSIONS
  This study highlights the feasibility of systematic NSCLC testing by both FISH and IHC in routine practice. Many preanalytical factors may account for the apparent discrepancies between both methods, suggesting that hierarchical screening may underscore ALK-positive cases. This significant level of discrepancy supports the need of combined testing to optimize the detection of ALK-inhibitor-eligible patients given that some patients with discordant testing were found to respond to crizotinib.
authors: *Université de Rennes 1, Faculté de Médecine, Rennes, France; †Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France; ‡Service de Cytogénétique et Biologie Cellulaire, CHU de Rennes, Rennes, France; §Service de Biologie des Tumeurs, CHU de Bordeaux, Bordeaux, France; ‖UMR CNRS 6290, IFR 140, Rennes, France; ¶Service de Pathologie, CHU de Bordeaux, Pessac, France; #Service d'Anatomie et Cytologie Pathologiques, CHU de Rennes, Rennes, France; **Service de Pneumologie, CHU de Rennes, Rennes, France; and ††Service de Génétique Moléculaire et de Génomique Médicale, CHU de Rennes, Rennes, France.
authors: Florian
authors: F
authors: Cabillic
authors: Audrey
authors: A
authors: Gros
authors: Frédéric
authors: F
authors: Dugay
authors: Hugues
authors: H
authors: Begueret
authors: Laura
authors: L
authors: Mesturoux
authors: Dan Cristian
authors: DC
authors: Chiforeanu
authors: Leila
authors: L
authors: Dufrenot
authors: Vincent
authors: V
authors: Jauffret
authors: Dominique
authors: D
authors: Dachary
authors: Romain
authors: R
authors: Corre
authors: Alexandra
authors: A
authors: Lespagnol
authors: Gwendoline
authors: G
authors: Soler
authors: Julien
authors: J
authors: Dagher
authors: Véronique
authors: V
authors: Catros
authors: Michèle
authors: M
authors: Le Calve
authors: Jean-Philippe
authors: JP
authors: Merlio
authors: Marc-Antoine
authors: MA
authors: Belaud-Rotureau
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018196:Carcinoma, Adenosquamous / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases