Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy

Cell Death Dis. 2014 Feb 27;5(2):e1091. doi: 10.1038/cddis.2014.62.


Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16(INK4a) expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16(INK4A)-positive and p16(INK4A)-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cetuximab
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Dose-Response Relationship, Drug
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / mortality
  • Head and Neck Neoplasms / virology
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / metabolism
  • Human papillomavirus 16 / pathogenicity*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / mortality
  • Papillomavirus Infections / virology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Squamous Cell Carcinoma of Head and Neck
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • E6 protein, Human papillomavirus type 16
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • oncogene protein E7, Human papillomavirus type 16
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab