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Original Investigation
February 2017

Immune Response to HPV16 E6 and E7 Proteins and Patient Outcomes in Head and Neck Cancer

Author Affiliations
  • 1Masonic Cancer Center, University of Minnesota, Minneapolis
  • 2Division of Epidemiology and Community Health, University of Minnesota, Minneapolis
  • 3Research Program Infection and Cancer, German Cancer Research Center, DKFZ, Heidelberg, Germany
  • 4Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts
  • 5Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts
  • 6Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 7Department of Epidemiology, Brown University, Providence, Rhode Island
  • 8Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
JAMA Oncol. 2017;3(2):178-185. doi:10.1001/jamaoncol.2016.4500
Key Points

Question  Does immune response to human papillomavirus (HPV) E6 and E7 proteins predict patient outcomes for head and neck cancer?

Findings  Using a large, population-based study of patients with head and neck cancer, we investigated the relationship between patient titers for HPV E6 and E7 proteins at the time of diagnosis and patient survival. Any positive seroresponse, irrespective of level, was associated with a significantly improved outcome for all forms of head and neck cancer (oropharyngeal, oral cavity, and larynx.

Meaning  Seropositivity to HPV E6 and E7 proteins may be a useful alternative or adjunct to pathology-based testing for HPV in head and neck cancers, particularly for tumors outside of the oropharynx.


Importance  Pathology-based measures of human papillomavirus (HPV) status are routinely obtained in the care of head and neck cancer and are clearly associated with patient outcome for cancers of the oropharynx. However, it is unclear if HPV status is of high value for cancers of the larynx and oral cavity. In addition, it is possible to assess HPV infection using serology-based methods; however, the suitability of this pathology-independent measure for predicting patient outcome in head and neck cancer is unknown.

Objective  To investigate whether immunologic response to HPV16 is associated with patient survival across anatomic sites, independent of smoking and drinking history.

Design, Setting, and Participants  This was a population-based study of 1054 patients with head and neck cancer in the greater Boston, Massachusetts, area (1999-2003, 2006-2011).

Main Outcomes and Measures  All-cause survival in relation to HPV16 E6 and E7 seropositivity.

Results  The 1054 patients reflected the demographics of those treated in this timeframe (75% male; mean age, 59 years). Seropositivity was very strongly associated with improved survival overall (hazard ratio HR], 0.33; 95% CI, 0.24-0.45; P < .001), with no evidence that the magnitude of immune response, as assessed by titer levels, effected outcome. Seropositivity was associated with improved patient survival across all head and neck cancer sites: HR for oropharynx cancer, 0.26; 95% CI, 0.18-0.39; for oral cavity cancer, 0.45; 95% CI, 0.18-0.80; and for larynx cancer, 0.29; 95% CI, 0.10-0.85. In addition, the associations with seropositivity were similar across smoking and/or drinking exposure groups: HRfor low exposure, 0.52; 95% CI, 0.20-1.36; for moderate exposure, 0.42; 95% CI, 0.25-0.70; for heavy exposure, 0.51; 95% CI, 0.36-0.73. In a subset of 162 patients with both HPV serology and p16 immunohistochemical (IHC) measures available, both measures were similarly associated with survival in the oropharynx (HR for serology, 0.16; 95% CI, 0.03-0.47; for p16 measures, 0.16; 95% CI, 0.03-0.46), whereas only serology was associated with outcome when considering all head and neck cancer cases (HR for serology,0.49; 95% CI, 0.23-1.04; for p16, 0.65; 95% CI, 0.30-1.42).

Conclusions and Relevance  Collectively, these data suggest that a positive serologic response to HPV16 oncoproteins may be the best approach to assess HPV-disease for clinical outcome because it is associated with survival for all types of disease and is a marker that is not dependent on pathology material.