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Head and Neck Cancers

Prognostic Significance of Epidermal Growth Factor Receptor Phosphorylation and Mutation in Head and Neck Squamous Cell Carcinoma

^aDivision of Molecular Epidemiology, ^bDepartment of Oto-Rhino-Laryngology, ^cDepartment of Pediatrics, ^dDepartment of Physiology, ^eDepartment of Anatomy, and ^fDNA Medicine Institute, Jikei University School of Medicine, Tokyo, Japan; ^gMeiji Pharmaceutical University, Tokyo, Japan

Key Words. EGFR • HNSCC • Head and neck squamous cell carcinoma • Prognostic factor • Phosphorylation

Correspondence: Mitsuyoshi Urashima, M.D., Ph.D., M.P.H., Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. Telephone: 81-3-3433-1111, ext 2405; Fax: 81-3-5400-1250; e-mail: urashima{at}jikei.ac.jp

Received March 25, 2009; accepted for publication August 4, 2009; first published online in THE ONCOLOGIST Express on September 2, 2009.

Disclosures: Takanori Hama: None; Yuki Yuza: None; Yoshimichi Saito: None; Jin O-uchi: None; Shu Kondo: None; Masataka Okabe: None; Hisashi Yamada: None; Takakuni Kato: None; Hiroshi Moriyama: None; Satoshi Kurihara: None; Mitsuyoshi Urashima: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers.

The molecular status of the epidermal growth factor receptor (EGFR) has not been as well studied in head and neck squamous cell carcinoma (HNSCC) as in lung cancer. We examined the frequencies of EGFR mutations as well as the expression/phosphorylation status of the EGFR protein in HNSCC patients. Moreover, we tried to elucidate associations between EGFR molecular status and patient characteristics and disease-free survival. In this prospective cohort study, clinical data and samples were obtained from 82 consecutive patients who had not been treated with EGFR molecular targeting therapy. Full-length EGFR was sequenced, and expression and phosphorylation of the EGFR protein were measured by Western blotting. Four novel mutations (E709K, V765G, Ins770G, and G1022S) and one mutation well-known in lung cancer (L858R) were identified in six HNSCC samples (7%), but we could not find any mutations in the extracellular domain of EGFR, such as EGFRvIII, in this study. E709K and Ins770G as well as L858R appear to be functional mutations based on the use of Ba/F3 cells. In terms of patient characteristics, the number of metastatic lymph nodes and node stage were associated with phosphorylation of EGFR. No patients with EGFR mutations relapsed during the study period. Excluding mutated cases, patients whose tumor samples showed phosphorylated EGFR relapsed significantly earlier than those without phosphorylated EGFR. This finding was still significant after adjusting for mutation and overexpression of EGFR protein using the Cox proportional hazard model. In conclusion, phosphorylated EGFR without mutations may be a marker of poor prognosis in patients with HNSCC.