Circulating Human Papillomavirus DNA—Liquid Biopsy in Head and Neck Cancers

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is clinically and biologically distinct from HPV-negative counterparts, differing in prognosis, failure patterns, and patient demographics. Although outcomes are generally favorable for HPV-OPSCC, large randomized trials have not confirmed the safety or efficacy of treatment de-escalation. Liquid biopsy approaches, particularly those measuring circulating tumor HPV DNA (ctHPVDNA), have emerged as promising tools for risk stratification, treatment response monitoring, and early recurrence detection. Technologies such as droplet digital PCR and next-generation sequencing offer high sensitivity and specificity in detecting ctHPVDNA, supporting their potential utility in clinical management. Baseline ctHPVDNA levels correlate with tumor burden, HPV integration status, and clinical outcomes. Notably, rapid clearance of ctHPVDNA during radiation therapy is a strong predictor of disease control, whereas persistent or detectable ctHPVDNA after surgery is associated with a heightened risk of recurrence. For surveillance, ctHPVDNA demonstrates high positive and negative predictive values, in some studies surpassing the performance of conventional imaging modalities. Despite these encouraging findings, standardization of assay methodologies and further clinical validation are essential before ctHPVDNA can be fully incorporated into personalized treatment algorithms for HPV-OPSCC.