Abstract
BACKGROUND: Human papillomavirus (HPV) type 16 E6 protein seropositivity accurately predicts oropharyngeal squamous cell carcinoma risk decades before diagnosis; but the biomarker's translational potential is unknown. To inform considerations for oropharyngeal squamous cell carcinoma screening, we described HPV-16 E6 seroprevalence, predictors, and kinetics among cancer-free men. METHODS: In a cohort study in Brazil, Mexico, and the United States, we calculated HPV-16 E6 seropositivity (median fluorescence intensity > 1000), measured by multiplex serology, in cancer-free men. We assessed HPV-16 E6 seropositivity predictors using logistic regression, adjusting for country, age, sexual orientation, and lifetime number of sexual partners. Among HPV-16 E6 seropositive men, we retrieved all available retrospective serum samples and described temporal HPV-16 E6 antibody patterns. RESULTS: Of 3997 men, 14 had HPV-16 E6 antibodies detected (seroprevalence = 0.35%, 95% CI = 0.19% to 0.59%; median fluorescence intensity = 2407 [IQR = 1325-5986]). Older age was associated with increased odds of HPV-16 E6 seropositivity (50-84 years vs 18-29 years odds ratio = 16.61, 95% CI = 2.20 to 417.03). Serum from 11 of the 14 seropositive men retested positive; 6 men had median fluorescence intensity above 5000, of whom 2 had median fluorescence intensity greater than 10 000. Seven men had 3 or more years of follow-up; all were persistently seropositive for 3 years. One man was seropositive for 9 years but seroreverted at his exit visit. Oral HPV-16 DNA (prevalence = 1.13%) was associated with HPV-16 E6 seropositivity (odds ratio = 16.87, 95% CI = 3.35 to 69.55), but oral HPV-16 DNA positivity was not persistent over follow-up, even when HPV-16 E6 antibodies were persistently detected. CONCLUSION: Although HPV-16 E6 seropositivity is rare, it is generally stable once detected; thus, HPV-16 E6 antibodies may be an informative biomarker of HPV-driven oropharyngeal squamous cell carcinoma. Few men seroreverted following HPV-16 E6 seropositivity but remained close to the seropositivity cutoff; thus, cancer risk among these men is less clear.