Cell-free HPV DNA as a complementary biomarker to imaging in HPV-associated oropharyngeal squamous cell carcinoma: a narrative synthesis of key studies.

INTRODUCTION: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) represents a biologically distinct disease entity with superior prognosis compared with HPV-negative head and neck cancers. While imaging-based strategies, particularly those monitoring hypoxia, have emerged as promising tools for response-guided de-escalation, they may not fully capture tumor biology or residual disease risk. Consequently, circulating tumor-derived HPV DNA (ctHPV-DNA) has gained attention as a minimally invasive biomarker with potential to complement imaging for treatment monitoring and surveillance.

AREAS COVERED: This review synthesizes data from studies published over the past decade that evaluated the clinical utility of ctHPV-DNA assessment. Evidence is summarized for pretreatment detection, on-treatment kinetics, postoperative minimal residual disease, and longitudinal surveillance, with emphasis on the complementarity between molecular and imaging markers.

EXPERT OPINION: Across cohorts, ctHPV-DNA mirrors tumor burden, clears with effective therapy, and often signals recurrence months before radiologic confirmation. Two consecutive positive tests may identify relapse and justify targeted imaging, whereas persistently negative serial tests provide strong reassurance. Although prognostic, the clinical benefit of ctHPV-DNA -guided management remains to be proven in prospective randomized trials. Standardization of assays and integration with imaging workflows will determine whether molecularly anchored surveillance becomes a quality benchmark in HPV-associated OPSCC care.