Abstract Purpose: Detecting minimal residual disease (MRD) has emerged as a key strategy in oncology for identifying those at high risk of relapse. Circulating tumor tissue modified viral (TTMV)-HPV DNA has emerged as a promising biomarker in HPV-driven oropharyngeal cancer. Prior studies have largely focused on detection beyond three months post-treatment. This study evaluated the ability of TTMV-HPV DNA to detect MRD immediately after initial or salvage treatment. Patients and Methods: This IRB-approved, retrospective cohort study included 171 patients across eight U.S. centers who had pathologically confirmed HPV-driven oropharyngeal cancer. Patients received at least one TTMV-HPV DNA test (NavDx®, Naveris, Inc.) done between zero and three months of treatment between February 2020 and April 2022. Minimum four months of follow-up was required for patient inclusion. Test results were correlated with physician-reported exams, imaging studies, and biopsies. Results: Patients were primarily White (94%) and male (86%) and were a median age at diagnosis of 60 years (range: 31 - 81). Primary tumors were located in the tonsil or base of tongue (94%) and were mostly T1-T2 (77%), N1 (66%), and M0 (98%). Patients had a median follow-up of 17 months after the completion of initial definitive treatment (range: 4-96 months). In this cohort, 198 tests conducted in 171 patients were evaluable. A total of 14 patients had both biopsy-confirmed pathologic recurrences and relevant post-treatment testing data in relation to the recurrence, with a median disease-free interval of three months (range: 1-16). Within this cohort, TTMV-HPV DNA testing demonstrated a per-patient sensitivity of 85.7% (12/14, 95% CI: 67-100). The positive predictive value (PPV) of a single TTMV-HPV DNA test within the first three months following treatment was 86.7% (13/15, 95% CI: 69.5-100). Six of the positive tests (46.2%) preceded clinical recurrence detection by a median lead-time of 36 days (range: 21-97). Test positivity following initial definitive treatment was significantly associated with worse recurrence-free survival (log-rank test, p&amp;lt;0.0001; hazard ratio: 21). The two patients with false positive test results had their TTMV-HPV DNA testing performed just four days after completing CRT. Their test scores returned to negative on the subsequent test, and both patients have remained disease-free. Of the 157 patients who remained TTMV-HPV DNA negative throughout the duration of follow-up, only two (1.3%) had biopsy-confirmed, HPV-positive recurrence before or within three months of a negative test. The specificity and negative predictive value (NPV) per-test were each 98.9% (181/183, 95% CI: 97.4-100). Conclusion: TTMV-HPV DNA demonstrates strong potential as a prognostic biomarker for detecting MRD in the immediate post-treatment setting, with a high PPV and NPV for recurrence. These findings support the integration of TTMV-HPV DNA into routine surveillance protocols to enhance early detection of recurrence and guide timely interventions. Citation Format: Scott A Roof, James Jabalee, Eleni M Rettig, Rocco Ferrandino, Sida Chen, Marshall R Posner, Krzysztof J Misiukiewicz, Eric M Gender, Raymond L Chai, John Sims, Elaine Thrash, Scott J Stern, Noah S Kalman, Sreenija Yarlagadda, Adam Raben, Lydia Clements, Abie Mendelsohn, John M Kaczmar, Yadav Pandey, Mihir Bhayani, Catherine DV Fitz, Glenn J Hanna. Immediate post-treatment detection of minimal residual disease in HPV-Driven oropharyngeal cancer is associated with high risk of recurrence [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B022.

Abstract B022: Immediate post-treatment detection of minimal residual disease in HPV-Driven oropharyngeal cancer is associated with high risk of recurrence