The role of liquid biopsy in the molecular characterization of HPV-related cancers

Human papillomavirus (HPV)-related cancers represent a significant and growing global health burden, encompassing cervical, anogenital, and an increasing proportion of head and neck squamous cell carcinomas, particularly oropharyngeal cancer. While tissue biopsy remains the cornerstone of diagnosis and initial molecular characterization, its invasive nature and inability to capture tumor heterogeneity or dynamic molecular changes limit its utility for longitudinal disease monitoring. Liquid biopsy has emerged as a powerful, minimally invasive approach that enables real-time assessment of tumor- and virus-derived biomarkers from blood, saliva, and other body fluids. Among these, circulating tumor HPV DNA (ctHPV-DNA) has demonstrated exceptional specificity and sensitivity, in HPV-driven malignancies, where viral DNA serves as a highly tumor-specific marker. Advances in analytical platforms, including droplet digital PCR and next-generation sequencing, have markedly improved the detection of low-abundance circulating biomarkers, enabling applications ranging from early detection and treatment response monitoring to minimal residual disease assessment and early identification of recurrence. This review provides a comprehensive overview of the current landscape of liquid biopsy in HPV-related cancers.