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

Observational studies suggest circulating tumor human papillomavirus (HPV) DNA may facilitate early detection of recurrent HPV-positive oropharynx cancer. We prospectively investigated whether biomarker-guided surveillance detects recurrence earlier than the standard-of-care methods.

We enrolled patients evaluated for HPV-positive oropharynx cancer at a single center from November, 2020, to April, 2023, undergoing curative-intent treatment in a single-arm cohort study. Pretreatment plasma and/or tumor tissue were tested for tumor tissue–modified viral (TTMV) HPV DNA from HPV subtypes 16/18/31/33/35 using a droplet digital PCR–based commercial assay. Posttreatment plasma TTMV was assessed periodically. Detectable/indeterminate tests prompted imaging. The primary outcome was the proportion of recurrences first detected by TTMV.

Median follow-up was 23 months, with median six posttreatment TTMV tests for 155 subjects. Fifteen subjects (9%) experienced recurrence. Among these, six [40%, 95% confidence interval (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 five subjects (33%) were “confirmatory true-positives,” for whom detectable TTMV confirmed suspicious standard-of-care imaging findings. Finally, four 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, three subjects had prolonged detectable TTMV without disease (“false-positives”); all had immunologic comorbidities. Overall, the 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%).

TTMV-guided surveillance facilitates early detection of many HPV-positive oropharynx cancer recurrences, with the highest sensitivity for HPV16 and detectable pretreatment TTMV. Clinical implementation should be carefully informed by the limitations described in this study.