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Association of Oral Human Papillomavirus DNA Persistence With Cancer Progression After Primary Treatment for Oral Cavity and Oropharyngeal Squamous Cell Carcinoma

Key Points

Question  Is persistent detection of oral human papillomavirus (HPV) DNA after completion of primary therapy associated with recurrence and survival among patients with HPV-positive oral or oropharyngeal cancer?

Findings  In this cohort study of 396 patients, HPV DNA identical in type to that found in the tumor was detectable in oral rinses at diagnosis in 80% of patients with HPV-positive oropharyngeal cancer. Persistent detection of HPV DNA after completion of primary therapy was significantly associated with the increased risk of cancer recurrence and death.

Meaning  The findings suggest that presence of HPV DNA is associated with increased risk of recurrence and death from HPV-positive oral or oropharyngeal cancer.


Importance  Detection of persistent oral human papillomavirus (HPV) DNA may be associated with recurrence of HPV-positive head and neck squamous cell carcinoma (HNSCC).

Objective  To evaluate the dynamics of oral HPV DNA detection and associations with disease outcomes in patients with HPV-positive and HPV-negative HNSCC.

Design, Setting, and Participants  This prospective, 2-institution, tertiary referral center study of 396 patients with newly diagnosed oral cavity or oropharyngeal HNSCC was performed from July 11, 2011, to May 7, 2016. Oral rinse samples were prospectively collected at diagnosis and at completion of primary therapy. Weekly oral rinse samples were collected during radiotherapy. Purified tumor and oral rinse sample DNA were evaluated for 37 HPV types, and viral load was quantified by type-specific real-time polymerase chain reaction. Cancers were stratified by tumor HPV status, and HPV was classified as tumor type if identical to that detected in the tumor or nontumor type.

Main Outcomes and Measures  Prevalence of HPV DNA before, during, and after therapy. Associations between tumor-type and nontumor-type oral HPV DNA detection and recurrence-free and overall survival were evaluated.

Results  Of the 396 patients (median age, 59 years [range, 19-96 years]; 295 [74.5%] men; and 354 [89.4%] white race/ethnicity), 217 had oropharyngeal cancer; 170, oral cavity cancer; and 9, unknown primary HNSCC. The prevalence of oral HPV detection at diagnosis was higher among patients with HPV-positive compared with HPV-negative HNSCC (24 of 194 [84.2%] vs 170 of 202 [12.4%]; P < .001). Oral HPV-16 DNA had an 81% sensitivity and 100% specificity for HPV-16–positive HNSCC. The prevalence and load of tumor-type HPV decreased significantly during primary therapy with odds ratio for probability of infection with each increasing month after diagnosis (0.41; 95% CI, 0.33-0.52; P < .001), whereas those of nontumor types did not (1.01; 95% CI, 0.97-1.06; P = .62). Current smoking was significantly associated with a reduced clearance of tumor-type HPV DNA (hazard ratio [HR], 0.54; 95% CI, 0.32-0.93). Two-year overall survival was significantly lower among the HPV-positive patients with persistent detection of tumor-type HPV after therapy than among those without detectable tumor-type DNA after therapy (68% vs 95%; adjusted HR, 6.61; 95% CI, 1.86-23.44; P = .003), as was recurrence-free survival (55% vs 88%; adjusted HR, 3.72; 95% CI, 1.71-8.09; P < .001). No associations were observed for nontumor type HPV DNA among patients with HPV-positive or HPV-negative HNSCC.

Conclusions and Relevance  Prevalence and viral load of tumor-type HPV DNA decreased rapidly with therapy, and persistent detection was associated with increased risk of recurrence and death. Analysis of tumor type HPV DNA has considerable promise as a biomarker for treatment response and risk of progression.