Although there are no drugs that target HPV oncoproteins directly, plasma ctDNA profiling enables indirect precision matching in HPV-positive HNSCC: detection of actionable co-alterations (e.g., PIK3CA) can support PI3K-pathway trials when tissue is limited; emerging resistance variants (e.g., NOTCH1) can prompt radiosensitizer use or systemic switches; and mutations such as CTNNB1 may stratify response to immunotherapy [17]. Here, PIK3CA is linked to head and neck squamous cell carcinoma.