The potential impact of prophylactic human papillomavirus vaccination on oropharyngeal cancer

Abstract

The incidence of oropharyngeal cancer (OPC) is significantly increasing in the United States. Given that these epidemiologic trends are driven by human papillomavirus (HPV), the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest. The primary evidence supporting the approval of current prophylactic HPV vaccines is from large phase 3 clinical trials focused on the prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported vaccine efficacy rates of 89% to 98% for the prevention of both premalignant lesions and persistent genital infections. However, these trials were designed before the etiologic relationship between HPV and OPC was established. There are differences in the epidemiology of oral and genital HPV infection, such as differences in age and sex distributions, which suggest that the vaccine efficacy observed in genital cancers may not be directly translatable to the cancers of the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx because no premalignant lesion analogous to cervical intraepithelial neoplasia in cervical cancer has yet been identified. To truly investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. Cancer 2016;122:2313-2323. © 2016 American Cancer Society.

Keywords: cancer vaccines; human papillomavirus (HPV); human papillomavirus vaccines; oropharyngeal neoplasms; squamous cell carcinoma of the head and neck.

Figure 1. HPV infection prevalence in oral and cervical samples by age

Prevalence of oral HPV infection using NHANES 2009-2012 on men and women ages 14-69. Cervical prevalence rates are adapted from adjusted NHANES data from women ages 14-59 in 2003-2004.

Figure 2. Distribution of type-specific HPV infections found in cervical cancer and oropharyngeal cancers

Oropharyngeal cancer data is pooled from studies with type-specific HPV detection performed.^, For cervical cancer, data is adapted from Munoz et al. for tumors with a single HPV infection.

Figure 3. Schematic diagram to compare known and unknown vaccination related endpoints for the progression from HPV infection to malignancy in the cervix and oropharynx

After vaccination, the first potential endpoint would be antibody response. Antibody titers necessary for prevention of cervical HPV infection have been established, but remain unknown in the oropharynx. In the cervix, peak age of HPV infection is earlier (20-24 years). The average age of CIN2+, the precancer disease surrogate endpoint used in vaccine trials in the cervix, is approximately 10 years later, at median age of 34 years. The progression of CIN2+ to invasive cancer occurs in 30-50% of cases. Median age of invasive cervical carcinoma is 48 years, with a latency of greater than 10 years from CIN2+. In comparison, oral HPV infection has a bimodal age distribution. The first peak is 30-34 years of age and the second peak is 60-64 years of age. While persistent oral HPV infection has not been shown to be a viral endpoint predating oropharyngeal cancer, it is expected to have analogous role as in the cervical HPV to cervical cancer progression model. No precursor lesion has been identified as of yet, but the median age of oropharynx cancer is later than cervical cancer at 58 years. Based on our current knowledge, potential vaccination related endpoints for oral HPV infection and oropharyngeal cancer include antibody response (immunogenicity endpoint), persistent HPV infection (viral endpoint), precancer (disease surrogate endpoint) and invasive cancer (disease endpoint). Unknowns are depicted in grey color.