e16017 Background: Cetuximab is an 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 cetuximab activity have yet been identified. Methods: We report on a patient with HNSCC who had a complete tumor regression following treatment with cetuximab given as a single agent after initial surgery and radiation therapy. The EGFR protein expression level, gene copy number and sequence were assessed from both normal and tumor tissues from this patient. Results: Besides protein overexpression and gene amplification in the tumor 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 the P546S mutation sensitized NIH-3T3 cells to cetuximab, R705G had a marginal effect. The double mutant (P546S/R705G) behaved the same as 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 there was no indication that the tumor was HPV-positive. Conclusions: Our results support a role for the P546S mutation in cetuximab sensitivity. To our knowledge, this is the first report of a somatic mutation in the EGFR ligand binding domain that may contribute to increased sensitivity to cetuximab. Other factors including EGFR copy number, EGFR over-expression and the immune response, as indicated by a very adverse side effect that correlated with the antitumor activity, may have also contributed to the observed response. It remains to be determined how frequently this mutation occurs in patients with HNSCCs and other cancers. Prospective evaluation of cetuximab anti-tumor activity in patients harboring P546S mutation needs to be clinically evaluated.