title: Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer.
abstract: BACKGROUND
  The discovery of distinct subsets of nonsmall cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly affected personalized therapy. It is hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.
  
  
  METHODS
  A total of 209 consecutive patients with stage IV nonsquamous NSCLC with an EGFR (epidermal growth factor receptor) mutation (N = 39), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation (N = 49), ALK (anaplastic lymphoma receptor tyrosine kinase) gene rearrangement (N = 41), or wild-type for all 3 (triple negative, N = 80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.
  
  
  RESULTS
  ALK gene rearrangement was significantly associated with pericardial disease (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 1.30, 16.37; P = .02) and pleural disease (OR = 4.80; 95% CI = 2.10, 10.97; P < .001). Patients with ALK gene rearrangements (OR = 5.50; 95% CI = 1.76, 17.18; P = .003) and patients with EGFR mutations (OR = 5.17; 95% CI = 1.63, 16.43; P = .006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, or adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than that of the triple negative cohort (mean = 3.6 sites vs 2.5 sites, P < .0001).
  
  
  CONCLUSIONS
  The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis.
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. robert.doebele@ucdenver.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Christopher
authors.initials: C
authors.lastname: Sumey
authors.forename: Delee A
authors.initials: DA
authors.lastname: Maxson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: Ana B
authors.initials: AB
authors.lastname: Oton
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D011905:Genes, ras; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins