title: Expression of amphiregulin and EGFRvIII affect outcome of patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment.
abstract: OBJECTIVE
  Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown.
  
  
  METHODS
  Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, and uni- and multivariate Cox regression analysis.
  
  
  RESULTS
  High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P = 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P = 0.002) and PFS (HR 2.2, P = 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS.
  
  
  CONCLUSIONS
  High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel.
authors.affiliation: Department of Radiotherapy Campus Mitte, Translational Radiobiology and Radiooncology Research Laboratory, Charite Universit€atsmedizin Berlin, Chariteplatz 1, 10117Berlin, Germany. ingeborg.tinhofer@charite.de
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Tinhofer
authors.forename: Konrad
authors.initials: K
authors.lastname: Klinghammer
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Maren
authors.initials: M
authors.lastname: Knödler
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Gauler
authors.forename: Volker
authors.initials: V
authors.lastname: Budach
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D066258:Amphiregulin; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism*; D000068818:Cetuximab; D000077143:Docetaxel; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D043823:Taxoids; C410723:epidermal growth factor receptor VIII; D000077143:Docetaxel; D066246:ErbB Receptors; D000068818:Cetuximab