title: Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer.
abstract: BACKGROUND
  Fluorescence in situ hybridization (FISH), using break-apart red (3') and green (5') ALK (anaplastic lymphoma kinase) probes, consistently shows rearrangements in <100% of tumor cells in ALK-positive (ALK+) nonsmall cell lung cancer (NSCLC). Increased copy numbers of fused and rearranged signals also occur. Here, correlations are explored between the percentage of ALK+ cells and signal copy number and their association with response to ALK inhibition.
  
  
  METHODS
  Ninety ALK+ NSCLC cases were evaluated. The percentage of positive cells, pattern of positivity (split, single red, or both), and copy number of fused, isolated red and green signals were recorded. Thirty patients had received crizotinib.
  
  
  RESULTS
  Increased isolated red signal copy number (contributing to both single red and split patterns of positivity) correlated with a higher percentage of ALK+ cells (r = 0.743, P < .0001). Mean fused copy number was negatively associated with isolated red signal copy number (r = -0.409, P < .0001). Neither percentage of positive cells (r = 0.192, P = .3), nor copy number of isolated red signal (r = 0.274, P = .195) correlated with maximal tumor shrinkage with crizotinib.
  
  
  CONCLUSIONS
  The strong association between increased copy number of key ALK signals and percentage of positive cells suggests that the <100% rate of cellular positivity in ALK+ tumors is due to technical factors, not biological factors. In ALK+ tumors, neither the percentage of positive cells nor signal copy number appear to be informative variables for predicting benefit from ALK inhibition. The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct "near-diploid" subtype of NSCLC that develops before significant chromosomal aneusomy occurs.
authors.affiliation: University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA. ross.camidge@ucdenver.edu
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Mariana
authors.initials: M
authors.lastname: Theodoro
authors.forename: Delee A
authors.initials: DA
authors.lastname: Maxson
authors.forename: Margaret
authors.initials: M
authors.lastname: Skokan
authors.forename: Tara
authors.initials: T
authors.lastname: O'Brien
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D000077547:Crizotinib; D056915:DNA Copy Number Variations; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases