Originally published as JCO Early Release 10.1200/JCO.2008.20.2853 on March 16 2009

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Effect of HPV-Associated p16^INK4A Expression on Response to Radiotherapy and Survival in Squamous Cell Carcinoma of the Head and Neck

From the Department of Experimental Clinical Oncology and Institute of Pathology, Aarhus University Hospital, Denmark.

Corresponding author: Pernille Lassen, MD, Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark; e-mail: pernille{at}oncology.dk.

Purpose A subset of head and neck cancers is associated with the human papillomavirus (HPV). Viral infection is closely correlated with expression of p16^INK4A in these tumors. We evaluated p16^INK4A as a prognostic marker of treatment response and survival in a well-defined and prospectively collected cohort of patients treated solely with conventional radiotherapy in the Danish Head and Neck Cancer Group (DAHANCA) 5 trial.

Patients and Methods Immunohistochemical expression of p16^INK4A was analyzed in pretreatment paraffin-embedded tumor blocks from 156 patients treated with conventional primary radiotherapy alone. The influence of p16^INK4A status on locoregional tumor control, disease-specific survival, and overall survival after radiotherapy was evaluated.

Results p16^INK4A positivity was found in 35 tumors (22%). Tumor-positivity for p16^INK4A was significantly correlated with improved locoregional tumor control (5-year actuarial values 58% v 28%; P = .0005), improved disease-specific survival (72% v 34%; P = .0006), and improved overall survival (62% v 26%; P = .0003). In multivariate analysis, p16^INK4A remained a strong independent prognostic factor for locoregional failure (hazard ratio [HR], 0.35; 95% CI, 0.19 to 0.64), disease-specific death (HR, 0.36; 95% CI, 0.20 to 0.64), and overall death (HR, 0.44; 95% CI, 0.28 to 0.68).

Conclusion Expression of p16^INK4A has a major impact on treatment response and survival in patients with head and neck cancer treated with conventional radiotherapy.

Written on behalf of the Danish Head and Neck Cancer Group.

Supported by grants from the Danish Cancer Society, The Danish Council for Strategic Research, and the Lundbeck Foundation Research Centre for Interventional Research in Radiation Oncology.

Presented in part at the International Meeting on Innovative Approaches in Head and Neck Oncology, February 22-24, 2007, Barcelona, Spain.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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