To the Editor Ferrandino et al1 report clinical performance of plasma tumor tissue–modified viral (TTMV)-human papillomavirus (HPV) DNA in diagnosis and surveillance of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). The findings highlight the promise of liquid biopsies for improving patient care and the uncertainties around how to integrate these assays with imaging, clinical examinations, and conventional biopsy.2 The variable time points for plasma TTMV-HPV DNA monitoring limited estimates of lead time detection, suggesting an opportunity for further standardizing timing of liquid biopsy testing protocols. A key question is whether liquid biopsies have a role in HPV-negative OPSCC.