Circulating tumor DNA in human papillomavirus-associated oropharyngeal cancer management: A systematic review

Objective: Circulating tumor DNA (ctDNA) has emerged as a promising tool in the treatment of HPV-associated oropharyngeal squamous cell cancer (OPSCC). This systematic review sought to answer the question: what is the current role of ctDNA in the diagnosis, treatment, and surveillance of HPV-associated OPSCC? Data sources: Medline (Ovid), Embase (Ovid), Scopus. Review methods: Original articles studying the role of ctDNA in the diagnosis or surveillance of HPV-associated OPSCC were eligible for inclusion. Two authors independently reviewed studies for inclusion and abstracted data, including study design, characterization of liquid biopsy technology, and diagnostic outcomes. Results: After a preliminary screening of 441 studies, 23 were selected for inclusion. Ten studies were conducted retrospectively, and 13 were conducted prospectively. In these studies, diagnostic testing included plasma-based droplet digital polymerase chain reaction (ddPCR, n =13), quantitative PCR (qPCR, n = 4), digital PCR (dPCR, n = 3), next-generation sequencing (NGS) (n = 3), or a ctDNA detection kit (n = 1). Diagnostic outcomes were reported for pre-diagnosis (n =1), pre-treatment (n =17), during treatment (n = 6), and surveillance/recurrence (n = 11) timepoints. Test sensitivities ranged from 20.6 %-100 % pre-treatment and 72 %-100 % during surveillance, while test specificities ranged from 95 %-100 % pre-treatment and 87.2 %-100 % during surveillance. Conclusion: The majority of studied ctDNA technologies allow for detection of HPV-associated OPSCC with high diagnostic accuracy. However, heterogeneity is introduced by test type and assay used. These findings highlight the utility, as well as limitations, of ctDNA in the diagnosis, treatment monitoring, and surveillance of HPVassociated OPSCC. Future studies and clinical consensus will need to address acceptable diagnostic accuracy thresholds for clinical use.