The objective of our study is to demonstrate that it is possible to detect and treat human papilloma virus (HPV)-related oropharyngeal cancers (OPC) early using simple blood tests. The success of this strategy will be evaluated by the number of participants positive for both HPV16-E6 serology and HPV circulating tumor DNA (ctDNA) whose early management has allowed the detection of a cancerous lesion and/or whose HPV ctDNA results have normalized after surgical intervention. If this study is conclusive, it could pave the way for the implementation of a national screening strategy for HPV-related OPC.

OPC caused by HPV are the most common head and neck cancers and are expected to increase in the future, especially since HPV vaccines are not widely used. Currently, there are no screening strategy available for these cancers, but developing such approaches could enable the earlier management of patients and thus improve prognosis while reducing treatment related toxicities.

Traditional screening methods like imaging or examination are not effective for OPC because early lesions are undetectable. However, studies suggest that using certain blood tests to detect HPV-related OPC early might be efficient:

• Antibodies directed against a specific protein of HPV called HPV16-E6 are present in most cases of HPV-related OPC and it has been shown that they can, be detected several years before the cancer diagnosis.
• HPV ctDNA can be found in the blood of almost all patients with HPV-related cancers. After treatment, HPV ctDNA can detect relapses before they are visible on imaging tests (microscopic disease) We propose to test the use of these two blood tests to identify individuals at high risk of developing OPC and offer them appropriate medical follow-up. HPV16-E6 serology will be conducted on 10,000 men over 50 years of age without symptoms who have consented to participate in the project. These participants will be included during routine visits to the biomedical analysis laboratory.

Individuals positive for HPV16-E6 test will be contacted (approximately 100 participants). They will be offered to continue the study to receive an initial assessment and regular monitoring for 5 years (HPV ctDNA test, regular clinical examinations, imaging examinations if needed). In case of identification of suspicious lesions, appropriate management will be proposed according to the standard recommendations. If no lesion is detected but HPV ctDNA remains positive, preventive surgery may be considered.

Inclusion Criteria:

• Aged ≥50 years from the general population
• Man
• No previous history of HPV-driven cancer or head neck cancer
• Willingness to complete follow up visits

Exclusion Criteria:

• Aged < 50 years
• Woman
• History of HPV-driven cancer or head and neck cancer
• Psychiatric conditions
• Inability to complete follow up visits
• Severe medical condition (life expectancy <5 years)
• Previous prophylactic HPV vaccination

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.