PROJECT SUMMARY HPV mediated Oropharyngeal Squamous Cell Carcinoma (HPVmOPSCC) is increasing in prevalence, surpassing cervical cancer as the most common HPV mediated malignancy in the United States. Current treatment approaches for HPVmOPSCC result in significant long-term morbidity and decreased quality of life. As HPVmOPSCC patients are more responsive to treatment than “traditional” carcinogen induced OPSCC, and thus experience longer life expectancy after cure, interest is focused on de-intensifying treatment to improve functional outcomes, including the use of surgery as a single modality approach. A major barrier to treatment de-intensification is the imprecise nature of current methods for diagnosing and monitoring disease which: 1) cannot be performed longitudinally without significant inconvenience to the patient, 2) are user dependent resulting in variable sensitivity and specificity, 3) have high costs, and 4) can be invasive. Further, all existing approaches are unable to determine the presence of microscopic residual disease and have poor individualized prognostic capacity in the post-operative period. Liquid biopsy approaches allow non-invasive, rapid, longitudinal monitoring of analytes and hold enormous potential in the pre-, post- and diagnostic cancer settings. In this proposal we will test the hypothesis that circulating tumor HPV DNA (ctHPVDNA) can be used to accurately predict disease status at the time of diagnosis and in the immediate post-operative period. To test this hypothesis, we have established a multi-institutional collaboration of HPVmOPSCC biorepositories as well as ongoing prospective collection. We will: (1) determine the clinical utility of ctHPVDNA at the time of diagnosis with HPVmOPSCC compared to the gold standard and 2) determine the kinetics of ctHPVDNA in the surgical setting and define the relationship between ctHPVDNA and clinicopathologic risk factors for recurrence. In doing so, we will fill critical gaps in the field, build necessary collaborative infrastructure, and generate preliminary data needed to launch a prospective evaluation of ctHPVDNA as a decision-making tool following surgery in a subsequent R01 application. Such an advance would lead to a paradigm shift in the management of HPVmOPSCC by enabling personalized treatment de-intensification, with significant benefit to patients suffering from this disease.