title: Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer.
abstract: BACKGROUND
  Activation of the MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. Additionally, MET is activated as a compensatory pathway in the presence of EGFR blockade, thus resulting in a mechanism of resistance to EGFR inhibitors.
  
  
  METHODS
  We have investigated the impact of HGF and MET expression, MET activation (phosphorylation), MET gene status, and MET-activating mutations on cetuximab sensitivity in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients.
  
  
  RESULTS
  A single-institution retrospective analysis was performed in 57 patients. MET overexpression was detected in 58% patients, MET amplification in 39% and MET activation (p-MET) in 30%. Amplification was associated with MET overexpression. Log-rank testing showed significantly worse outcomes in recurrent/metastatic, MET overexpressing patients for progression-free survival and overall survival. Activation of MET was correlated with worse PFS and OS. In multivariate logistic regression analysis, p-MET was an independent prognostic factor for PFS. HGF overexpression was observed in 58% patients and was associated with MET phosphorylation, suggesting a paracrine activation of the receptor.
  
  
  CONCLUSIONS
  HGF/MET pathway activation correlated with worse outcome in recurrent/metastatic HNSCC patients. When treated with a cetuximab-based regimen, these patients correlated with worse outcome. This supports a dual blocking strategy of HGF/MET and EGFR pathways for the treatment of patients with recurrent/metastatic HNSCC.
authors: Molecular Pathology Laboratory, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. JMadoz@fjd.es.
authors: Juan
authors: J
authors: Madoz-Gúrpide
authors: Molecular Pathology Laboratory, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. SZazo@fjd.es.
authors: Sandra
authors: S
authors: Zazo
authors: Molecular Pathology Laboratory, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. cristina.chamizo@fjd.es.
authors: Cristina
authors: C
authors: Chamizo
authors: Oncology Department, Fundacion Jimenez Diaz, Madrid, Spain. VCasado@fjd.es.
authors: Victoria
authors: V
authors: Casado
authors: Oncology Department, Fundacion Jimenez Diaz, Madrid, Spain. CCarames@fjd.es.
authors: Cristina
authors: C
authors: Caramés
authors: Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. EGavin@fjd.es.
authors: Eduardo
authors: E
authors: Gavín
authors: Translational Oncology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain. ion.cristobal@fjd.es.
authors: Ion
authors: I
authors: Cristóbal
authors: Oncology Department, Fundacion Jimenez Diaz, Madrid, Spain. jgfoncillas@fjd.es.
authors: Jesús
authors: J
authors: García-Foncillas
authors: Molecular Pathology Laboratory, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. FRojo@fjd.es.|Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Avda. Reyes Catolicos 2, 28040, Madrid, Spain. FRojo@fjd.es.
authors: Federico
authors: F
authors: Rojo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D027383:Papillomaviridae / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab