title: MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.
abstract: OBJECTIVE
  Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study.
  
  
  METHODS
  From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization.
  
  
  RESULTS
  Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (-30% and -16%) and experienced progression after 3.7 and 3.5 months.
  
  
  CONCLUSIONS
  MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).
authors: Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
authors: Jochen K
authors: JK
authors: Lennerz
authors: Eunice L
authors: EL
authors: Kwak
authors: Allison
authors: A
authors: Ackerman
authors: Michael
authors: M
authors: Michael
authors: Stephen B
authors: SB
authors: Fox
authors: Kristin
authors: K
authors: Bergethon
authors: Gregory Y
authors: GY
authors: Lauwers
authors: James G
authors: JG
authors: Christensen
authors: Keith D
authors: KD
authors: Wilner
authors: Daniel A
authors: DA
authors: Haber
authors: Ravi
authors: R
authors: Salgia
authors: Yung-Jue
authors: YJ
authors: Bang
authors: Jeffrey W
authors: JW
authors: Clark
authors: Benjamin J
authors: BJ
authors: Solomon
authors: A John
authors: AJ
authors: Iafrate
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D000077547:Crizotinib; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met