title: A patient-derived somatic mutation in the epidermal growth factor receptor ligand-binding domain confers increased sensitivity to cetuximab in head and neck cancer.
abstract: BACKGROUND
  Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer, but no predictive biomarkers of activity have been yet identified. Establishment of such biomarkers will help identify a subset of patients that will benefit from cetuximab therapy.
  
  
  METHODS
  In this paper, we report on a patient with HNSCC who had a complete tumour regression following treatment with cetuximab given as a single agent after initial surgery and radiation therapy. The EGFR protein expression level, the EGFR gene copy number and the EGFR gene sequence were assessed from both normal and tumour tissues.
  
  
  RESULTS
  Besides protein overexpression and gene amplification in the tumour tissue, sequencing of the EGFR gene from the patient revealed the presence of two somatic mutations, one in the kinase domain (R705G) and the other in the ligand binding domain (P546S). Cells that stably express these EGFR mutants were treated with cetuximab and their sensitivity to the drug was compared to cells expressing the wildtype gene. While P546S mutation sensitised NIH-3T3 cells to cetuximab, R705G had a marginal effect. The double mutant (P546S/R705G) behaved like the P546S mutant, indicating that the mutation in the kinase domain does not contribute to the increased sensitivity to cetuximab. No mutations were found in K-RAS or B-RAF genes and no HPV protein or DNA was detected in the tumour. This is the first report of a somatic mutation in the EGFR ligand binding domain that may contribute to increased sensitivity to cetuximab.
  
  
  CONCLUSIONS
  Our results support a role for the P546S mutation in cetuximab sensitivity. Other factors including EGFR protein high copy number and protein overexpression may have also contributed to the observed response. The severity of a skin rash developed by this patient and its correlation with the antitumour activity does not exclude the involvement of the immune system (i.e. complement-mediated immune response) as well. The occurrence of the P546S mutation needs to be evaluated in HNSCC, as a well as a prospective evaluation of cetuximab anti-tumour activity in patients with tumours harbouring the mutation.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, UC Cancer Institute, University of Cincinnati, Cincinnati, OH, USA. bhassiem@uc.edu
authors.forename: El Mustapha
authors.initials: el M
authors.lastname: Bahassi
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Li
authors.forename: Trisha M
authors.initials: TM
authors.lastname: Wise-Draper
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.forename: Colleen N
authors.initials: CN
authors.lastname: Darnell
authors.forename: Keith M
authors.initials: KM
authors.lastname: Wilson
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
mesh_terms: D000328:Adult; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001665:Binding Sites / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005076:Exanthema / Q000139:chemically induced; D017809:Fatal Outcome; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008024:Ligands; D066246:ErbB Receptors; D000068818:Cetuximab