title: p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.
  
  
  METHODS
  p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.
  
  
  RESULTS
  p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.
  
  
  CONCLUSIONS
  Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO. cchung11@jhmi.edu.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kong
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Harris
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Dian
authors.initials: D
authors.lastname: Wang
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Redmond
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: George
authors.initials: G
authors.lastname: Shenouda
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Andy
authors.initials: A
authors.lastname: Trotti
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Maura L
authors.initials: ML
authors.lastname: Gillison
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jordan
authors.affiliation: Christine H. Chung and Elana J. Fertig, Johns Hopkins University, Baltimore, MD; Qiang Zhang and Jonathan Harris, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Christina S. Kong and Quynh-Thu Le, Stanford University, Stanford; Richard C. Jordan, University of California at San Francisco, San Francisco, CA; Paul M. Harari, University of Wisconsin Carbone Cancer Center, Madison; Dian Wang, Medical College of Wisconsin, Milwaukee, WI; Kevin P. Redmond, University of Cincinnati, Cincinnati; Maura L. Gillison, Ohio State University, Columbus, OH; George Shenouda, McGill University Health Centre, Montreal, Quebec, Canada; Andy Trotti, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and David Raben, University of Colorado, Denver, CO.
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000401:mortality / Q000821:virology*; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018572:Disease-Free Survival; D000077143:Docetaxel; D019583:Dose Fractionation, Radiation; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000150:complications / Q000401:mortality / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000378:metabolism*; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology*; D011379:Prognosis; D012907:Smoking; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D043823:Taxoids; D000077143:Docetaxel; D000068818:Cetuximab; D002945:Cisplatin