Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial

Ann Oncol. 2014 Apr;25(4):801-807. doi: 10.1093/annonc/mdt574. Epub 2014 Feb 26.


Background: Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status.

Patients and methods: Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays.

Results: Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients.

Conclusion: The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.

Keywords: cetuximab; human papillomavirus; p16; recurrent and metastatic; squamous cell carcinoma of the head and neck.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cetuximab
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / isolation & purification*
  • Disease-Free Survival
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / virology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / virology
  • Papillomaviridae / genetics
  • Papillomaviridae / isolation & purification
  • Papillomaviridae / pathogenicity
  • Prognosis


  • Antibodies, Monoclonal, Humanized
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cetuximab