The Role of Circulating Tumor DNA (ctDNA) in the Treatment of Human Papilloma Virus-positive (HPV+) Oropharyngeal Squamous Cell Carcinoma.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) presents a favorable prognosis compared with its HPV-negative counterpart, prompting interest in treatment de-escalation to reduce toxicity. However, attempts using risk factors, stage, and HPV status alone have not proven sufficient. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker to personalize treatment by detecting tumor burden, monitoring minimal residual disease (MRD), and guiding response-adaptive therapy. This review evaluates the role of ctDNA across the clinical course-from diagnosis to mid-treatment monitoring to post-treatment surveillance. It highlights ctDNA's potential to enhance diagnostic accuracy, guide treatment deintensification, and detect recurrence through a summary of recent and ongoing clinical trials. However, limitations in assay sensitivity and the need for prospective validation restrict its current clinical utility. Ongoing clinical trials will be pivotal in determining whether ctDNA can reliably support personalized de-escalation strategies in HPV+ OPSCC.