Table 1:

State-of-the-science and outstanding research questions on HPV positive oropharynx cancer

Area	State-of-the-science	Key research areas/questions
Burden	- OPC incidence rates of 5–10/100,000 - HPV established as the cause of rising incidence in men (age 50 to 60) in developed countries - Geographic variability in contemporary HPV attributable proportions (5%-80%), with higher proportions (>70%) in North America, northern Europe, and other countries - Emerging data on plateauing of rising incidence in young men in high income countries with now rising incidence in older ages, early signs of rising incidence in women, and rising incidence in additional countries.	- Is the rising incidence a phenomenon restricted to men (aged 50 to 60) in high income countries? - Have incidence rates in high income countries peaked? - Is HPV positive OPC increasing in low/middle income countries?
Epidemiology	- Oral HPV infection is primarily sexually transmitted - Prevalence follows a bimodal pattern with peaks at ages 25–30 and 55–60 years - Oral HPV prevalence and HPV positive OPC are more common in men - Presence of antibodies to HPV16E6 associated with a >100-fold increased risk of OPC - Association of traditional risk factors (tobacco and alcohol) and emerging OPC risk factors remains poorly quantified, as does interaction of HPV with these risk factors	- Identification of the reasons for the bimodal age-prevalence pattern as well as the male predominance of oral HPV infection/-associated OPC - Estimation of the main effects and interactions of established and emerging factors (oral health/microbiome) towards risk of HPV positive OPC - Characterization of the natural history of oral HPV infection - Absolute risk of future OPC development for oral HPV DNA detection by age
Genetics and genomics	- HPV positive OPC characterized by different somatic mutational profiles compared to HPV negative OPC - Risk of HPV positive OPC associated with the HLA haplotype DRB11301 - DQA10103 - DQB10603*	- Characterization of somatic changes in HPV positive OPC in large, representative studies - Further elucidation of the associations of host genetic polymorphisms with HPV positive OPC risk - Investigation of the role of viral genomics in risk of HPV positive OPC across geographic and ancestral backgrounds
Biology	- HPV16 causes over 90% of HPV positive OPC - HPV positive OPC arise from the specialized crypt epithelium in the lingual and palatine tonsils - High PD-L1 expression in the crypt epithelium provides immunological refuge for the infection/tumor - Natural history of oral HPV infection, encompassing establishment of infection and progression to cancer, remains poorly characterized	- Characterization of the natural history of HPV induced carcinogenesis in the oropharynx, including estimation of latency and identification of precancerous states - Discovering the reasons for the unique susceptibility of the tonsil crypt epithelium to HPV16-carcinogenesis - Development of model systems to study HPV induced carcinogenesis in the oropharynx - Elucidation of the postulated immune-evasion processes in the crypt epithelium and development of therapeutic strategies targeting them
Prevention	- Prophylactic HPV vaccination has high efficacy against oral HPV infection prevalence - Markers of HPV exposure, such as systemic HPV16 E6 antibodies and oral HPV16 DNA, are strongly associated with risk of HPV positive OPC - Secondary prevention and early detection through screening is not currently feasible due to lack of an identifiable HPV induced precancerous lesion, screening modalities, and risk-mitigation strategies	- Understanding the relevance of the second age-peak in oral HPV prevalence for risk of HPV positive OPC - Estimation of the effectiveness of an extended upper age-limit for catch-up HPV vaccination - Discovery of HPV induced precancer in the oropharynx and the identification and validation of screening methods and treatment strategies for secondary prevention and early detection
Clinical care	- HPV positive OPC patients have higher survival than HPV negative OPC patients - HPV testing through p16 immunohistochemistry is currently recommended for all newly-diagnosed OPC patients and patients with unknown head and neck primaries - Revised cTNM and pTNM staging of HPV positive OPC in the AJCC 8^th edition - Numerous investigations underway to determine optimal treatment de-escalation for HPV positive OPC patients	- Identification of markers to improve the accuracy of tumor HPV determination beyond p16 immunohistochemistry - Identification and incorporation of additional prognostic factors for improved staging of HPV positive OPC - Development and validation of prediction models to identify patients who could benefit from de-intensified treatments - Identification of optimal treatment protocols for HPV positive OPC patients that preserve disease control and reduce short-and-long-term treatment-related toxicities - Follow up biomarkers to detect recurrences in HPV driven OPC

OPC, oropharynx cancer