title: ALK molecular phenotype in non-small cell lung cancer: CT radiogenomic characterization.
abstract: OBJECTIVE
  To present a radiogenomic computed tomographic (CT) characterization of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) (ALK+).
  
  
  METHODS
  In this HIPAA-compliant institutional review board-approved retrospective study, CT studies, ALK status, and clinical-pathologic data in 172 patients with NSCLC from three institutions were analyzed. A screen of 24 CT image traits was performed in a training set of 59 patients, followed by random forest variable selection incorporating 24 CT traits plus six clinical-pathologic covariates to identify a radiogenomic predictor of ALK+ status. This predictor was then validated in an independent cohort (n = 113). Test-for-accuracy and subset analyses were performed. A similar analysis was performed to identify a biomarker associated with shorter progression-free survival (PFS) after therapy with the ALK inhibitor crizotinib.
  
  
  RESULTS
  ALK+ status was associated with central tumor location, absence of pleural tail, and large pleural effusion. An ALK+ radiogenomic CT status biomarker consisting of these three imaging traits with patient age of younger than 60 years showed strong discriminatory power for ALK+ status, with a sensitivity of 83.3% (15 of 18), a specificity of 77.9% (74 of 95), and an accuracy of 78.8% (89 of 113) in independent testing. The discriminatory power was particularly strong in patients with operable disease (stage IIIA or lower), with a sensitivity of 100.0% (five of five), a specificity of 88.1% (37 of 42), and an accuracy of 89.4% (42 of 47). Tumors with a disorganized vessel pattern had a shorter PFS with crizotinib therapy than tumors without this trait (11.4 vs 20.2 months, P = .041).
  
  
  CONCLUSIONS
  ALK+ NSCLC has distinct characteristics at CT imaging that, when combined with clinical covariates, discriminate ALK+ from non-ALK tumors and can potentially identify patients with a shorter durable response to crizotinib.
authors.affiliation: From the Department of Radiological Sciences, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Box 951721, CHS 17-135, Los Angeles, CA 90095-1721 (S.Y., C.M., M.D.K.); Scottsdale Medical Imaging, Scottsdale, Ariz (R.L.K.); Scottsdale Healthcare, Scottsdale, Ariz (R.L.K.); Departments of Vascular Interventional Radiology (R.O.) and Pathology (A.J.I.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Department of Radiology, Mayo Clinic, Phoenix, Ariz (M.B.G.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (M.B.G.); Cancer Treatment Centers of America, Goodyear, Ariz (G.J.W.); Translational Genomics Research Institute, Phoenix, Ariz (G.J.W.); and Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea (D.W.K.).
authors.forename: Shota
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Korn
authors.forename: Rahmi
authors.initials: R
authors.lastname: Oklu
authors.forename: Christopher
authors.initials: C
authors.lastname: Migdal
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gotway
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kuo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics*; D000077547:Crizotinib; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins