High-Risk Human Papillomavirus Affects Prognosis in Patients With Surgically Treated Oropharyngeal Squamous Cell Carcinoma Lisa Licitra, Federica Perrone, Paolo Bossi, Simona Suardi, Luigi Mariani, Raffaella Artusi, Maria Oggionni, Chiara Rossini, Giulio Cantu `, Massimo Squadrelli, Pasquale Quattrone, Laura D. Locati, Cristiana Bergamini, Patrizia Olmi, Marco A. Pierotti, and Silvana Pilotti A B S T R A C T Purpose Human papillomavirus (HPV) DNA tumors actively integrating the E6 and E7 oncogenes have a distinct biologic behavior resulting in a more favorable prognosis. To which extent the viral integration by itself, and/or the associated wild-type (wt) TP53 status, and/or a functional p16 contribute to prognosis is unclear. Patients and Methods To clarify how the presence of high-risk (HR) -HPV, TP53, and p16 INK4a status interact with clinical outcome, we considered a retrospective series of 90 consecutive oropharyngeal cancer patients treated primarily with surgery. Results Seventeen (19%) patients showed integrated HPV 16 DNA (HPV positive), wt TP53 in all but two patients, normal p16 INK4a in 15 assessable patients, and p16 expression in all 17 patients. Thirty-five patients (39%), two of whom were HPV positive, harbored TP53 mutations. p16 INK4a deletion and p16 null immunophenotype occurred in 28 and 58 patients, respectively, and was similarly distributed in both patients with mutated TP53 (48% and 82%, respectively) and in patients with wt TP53 (46% and 77%, respectively). Statistical analysis showed that HPV-positive status significantly affects all investigated end points: overall survival (P = .0018), incidence of tumor relapse (P = .0371), and second tumor (P = .0152), whereas TP53 and p16 INK4a status and p16 expression were not prognostic by themselves. Conclusion Our molecular and clinical results are in agreement with previous findings but provide additional information into the biologic mechanisms involved in HR-HPV oropharyngeal cancer in comparison to HPV-negative tumors. According to the reduced risk of relapse and second tumors associated with HR-HPV positivity of oropharyngeal cancer, the therapeutic strategy and follow-up procedures should be reviewed. J Clin Oncol 24:5630-5636. © 2006 by American Society of Clinical Oncology INTRODUCTION Recent studies showed an etiologic role of infection with high-risk human papillomavirus (HR-HPV) in a subset of oropharyngeal squamous cell carcinomas (SCCs) and a distinct biologic behavior of tumors integrating E6 and E7 oncogenes, resulting in a more favorable prognosis. 1-4 In some studies, HPV- positive tumors were more prevalent in younger patients, 4,5 and they were associated with lower ex- posure to alcohol or tobacco 6,7 and advanced dis- ease. 8,9 These factors are implicated potentially in prognosis, regardless of HPV positivity. However, not all studies confirmed these associations, 10,11 due to an insufficient sample size to adjust for these and other important prognostic factors (such as sex and treatment), 9,12-14 so that some reports failed to de- tect a survival advantage of HPV-positive patients bearing tumors. 15,16 Oropharyngeal cancer is commonly treated with surgery and/or radiotherapy and, in advanced disease, also with concomitant chemoradiotherapy. In retrospective studies detecting the favorable prog- nostic effect of HPV status, the correlation between HPV status and the type of treatment was not spe- cifically addressed. 12,14,17,18 At the molecular level, in head and neck cancer, the presence of E6 oncoprotein, which mediates p53 From the Head and Neck Cancer Medical Oncology Unit, Unit of Experimental Molecular Pathology, Medical Statistics and Biometry, Department of Head and Neck Surgery, Department of Pathology, Radiotherapy Department, and Depart- ment of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori; and Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology, Milan, Italy. Submitted October 17, 2005; accepted April 27, 2006. Supported in part by grants from the Italian Association for Cancer Research (AIRC) Grant (S.P.) and Consiglio Nazionale delle Ricerche/ Ministero dell’Universita ´ e della Ricerca (CNR/MIUR). L.L. and S.P. contributed equally to this work. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Lisa Licitra, MD, Head and Neck Cancer Medical Oncology Unit, Cancer Medicine Depart- ment Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milano, Italy; e-mail: lisa.licitra@istitutotumori.mi.it. © 2006 by American Society of Clinical Oncology 0732-183X/06/2436-5630/$20.00 DOI: 10.1200/JCO.2005.04.6136 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 36  DECEMBER 20 2006 5630 Downloaded from jco.ascopubs.org on September 25, 2012. For personal use only. No other uses without permission. Copyright © 2006 American Society of Clinical Oncology. All rights reserved.