title: MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors.
abstract: BACKGROUND
  The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors.
  
  
  METHODS
  Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors.
  
  
  RESULTS
  MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment.
  
  
  CONCLUSIONS
  MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: denis.ljardim@hsl.org.br.
authors.forename: Denis L F
authors.initials: DL
authors.lastname: Jardim
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Débora
authors.initials: D
authors.lastname: de Melo Gagliato
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Nizar
authors.initials: N
authors.lastname: Tannir
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Paul
authors.initials: P
authors.lastname: Corn
authors.affiliation: Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Sinchita
authors.initials: S
authors.lastname: Roy-Chowdhuri
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014565:Urogenital Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Bladder cancer; MET amplification; MET mutation; Prostate cancer; Renal cell cancer
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