Circulating tumor DNA in human papilloma virus negative head and neck squamous cell carcinoma

Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging disease with poor prognosis. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker to improve risk stratification, detect minimal residual disease (MRD), and guide treatment adaptation. This review synthesizes recent advances in ctDNA technologies and their clinical relevance for HPV-negative HNSCC.

Technical progress has significantly improved ctDNA detection, with tumor-informed assays achieving limits of detection near 0.01% VAF and tumor-agnostic strategies offering broader applicability. Across studies, ctDNA is detectable in approximately 80% of HNSCC patients, though performance varies with tumor burden and assay sensitivity. In the postcurative setting, ctDNA positivity consistently identifies patients at high risk for relapse, often months before radiologic detection. Early data suggest that ctDNA kinetics may reflect treatment response. In R/M HNSCC, baseline ctDNA detection exceeds 90%, and on-treatment ctDNA decrease correlates with improved survival. Interventional studies, including ctDNA-guided adjuvant (de-)escalation approaches are ongoing.

ctDNA represents a potential biomarker for MRD detection and response monitoring in HPV-negative HNSCC. Despite encouraging pilot studies, clinical utility remains to be proven. Well powered, prospective, ctDNA-driven trials are essential to validate how ctDNA can guide therapeutic intensification, de-escalation, and personalized treatment strategies in HNSCC.