HPV16 E6 Seropositivity and ctHPVDNA for Early Detection of Oropharyngeal Cancer

STRUCTURED TECHNICAL ABSTRACT Background: Human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is rapidly increasing; 85% of cases occur in men. There are no methods for early detection. A major barrier is the inability to identify men at high-risk. We demonstrated that HPV16 E6 seropositivity is an excellent risk biomarker and is present in ~90% of HPV-OPC patients and appears more than 10 years prior to diagnosis. Yet, not all seropositive men develop HPV-OPC. Thus, early detection biomarkers that indicate the presence of tumor need to be co-developed with HPV16 E6 antibodies. Circulating tumor HPV DNA (ctHPVDNA) detection is a promising non-invasive approach for detecting HPV-OPC cancer cells. ctHPVDNA is present in nearly all HPV-OPC patients, and can now be non-invasively detected in urine using our unique technology. Objectives/hypothesis: The objective of this study is to evaluate the accuracy of HPV16 E6 seropositivity and urine-based ctHPVDNA for the detection of HPV-OPC. We hypothesize that HPV16 E6 antibodies and ctHPVDNA combined will have a high positive predictive value (PPV >15%) for detecting HPV-OPC, which is comparable to other accepted cancer screening methods (range: 5% to 15%). Specific Aims: The aims are: (1) Identify factors associated with increased HPV16 E6 seroprevalence; (2) Evaluate the accuracy of HPV16 E6 antibodies and ctHPVDNA for the detection of HPV-OPC. Study Design: This study will be nested within the ongoing VOYAGER screening study which aims to recruit 3,000 healthy men aged 45+ from primary care clinics across Kentucky, including rural underserved Appalachia, to evaluate HPV16 E6 antibodies as a screening marker for HPV-OPC. A finger prick and blood spot card are collected for HPV16 E6 antibody testing along with an oral rinse for oral HPV testing and basic demographic and smoking data. All HPV16 E6 seropositive and a random subset of seronegative men will be invited for a one-time head and neck cancer screening exam to include urine-based ctHPVDNA testing as well as visual inspection of the oral cavity and neck, ultrasound imaging, laryngoscope exam, and a risk factor questionnaire. Seropositive men not diagnosed with HPV-OPC during the exam will undergo yearly ctHPVDNA monitoring using self-collected urine specimens; positives will be invited for a repeat clinical exam. Assuming 2% are HPV16 E6 seropositive and 90% consent, 54 seropositive and 79 seronegative men will undergo a one-time clinical exam. Assuming 8 HPV-OPCs are diagnosed among seropositives, 46 seropositive men will be longitudinally monitored for HPV-OPC using urine-based ctHPVDNA testing. This research is significant in that it may lead to methods for early detection of HPV-OPC and is particularly impactful given that Kentucky has a high and increasing incidence of OPC. This proposal is innovative by using novel biomarkers that can be assessed inexpensively using self-collected specimens. These methods could be rapidly scaled to increase screening accessibility for vulnerable populations across Kentucky by leveraging the full reach of our primary care networks.