Prospective Trial of Biomarker-Guided Surveillance for HPV-positive Oropharynx Cancer Using Plasma Tumor Tissue Modified Viral HPV DNA

Abstract Background: Observational studies suggest circulating tumor HPV DNA may facilitate early detection of recurrent HPV-positive oropharynx cancer (OPC). We prospectively investigated whether biomarker-guided surveillance detects recurrence sooner than standard-of-care. Patients and Methods: We enrolled patients evaluated for HPV-positive OPC at a single center 11/2020-4/2023 undergoing curative-intent treatment in a single-arm cohort study. Pretreatment plasma and/or tumor tissue were tested for tumor tissue modified viral HPV DNA (‘TTMV’) from HPV subtypes 16/18/31/33/35 using a ddPCR-based commercial assay. Post-treatment plasma TTMV was assessed periodically. Detectable/indeterminate tests prompted imaging. Primary outcome was proportion of recurrences first detected by TTMV. Results: Median follow-up was 23 months, with median 6 post-treatment TTMV tests for 155 subjects. Fifteen subjects (9%) recurred. Among these, 6 (40%, 95%CI=16%-68%) were ‘early true-positives’, for whom TTMV detection predated and prompted the imaging and clinical workup that diagnosed recurrence (median lead-time=132 days; range=47-280). Another 5 subjects (33%) were ‘confirmatory true-positives’, for whom detectable TTMV confirmed suspicious standard-of-care imaging findings. Finally, 4 subjects (27%) with recurrence had undetectable TTMV at diagnosis (‘false-negatives’). False-negatives had low or undetectable pretreatment TTMV, and 2/4 had non-HPV16 genotypes. Finally, 3 subjects had prolonged detectable TTMV without disease (‘false-positives’); all had immunologic comorbidities. Overall, sensitivity of TTMV for recurrence was 73% (95%CI=45-92%). Among 117 subjects with HPV16 and detectable pretreatment TTMV, sensitivity was higher (91%, 95%CI=59-100%) Conclusions: TTMV-guided surveillance facilitates early detection of many HPV-positive OPC recurrences, with highest sensitivity for HPV16 and detectable pretreatment TTMV. Clinical implementation should be carefully informed by the limitations described herein.