Liquid Biopsies for Head and Neck Cancers—Any Hope for Human Papillomavirus–Negative Disease?

Abstract

To the Editor Ferrandino et al 1 report clinical performance of plasma tumor tissue-modified viral (TTMV)-human papillomavirus (HPV) DNA in diagnosis and surveillance of HPVassociated 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.Whereas plasma TTMV-HPV DNA assays detect viral DNA shed from the primary tumor or metastatic deposits, HPVnegative head and neck squamous cell carcinoma (HNSCC) lacks this viral fingerprint. Biomarkers for HPV-negative HNSCC are thus more nuanced, relying on detection of genomic and/or proteomic signatures of the parent tumor. These assays can use saliva, urine, or plasma-based biomarkers to improve diagnosis, treatment, and surveillance paradigms, but progress in developing robust and reliable liquid biopsy techniques for patients with HPV-negative HNSCC is more arduous. Nonetheless, preclinical and translational efforts are advancing liquid biopsy techniques for patients with HPV-negative tumors. 3 Recently, plasma tumor-derived extracellular vesicles (TDEVs), also known as exosomes, have emerged as a promising alternative to the circulating tumor DNA techniques. TDEVs are small (30 nm-200 nm), lipid-bilayer bound particles that are constitutively released by malignant cells harboring diverse DNA, RNA, and protein cargo. These particles are abundant in saliva, urine, and plasma of patients with HPVnegative HNSCC and can be readily isolated before, during, and after treatment. TDEVs have been studied in multiple cancers, including HPV-negative HNSCC. 4 Plasma TDEV kinetics and protein cargo (eg, surface programmed cell death ligand 1 [PD-L1] expression) can predict disease recurrence and treatment response in certain HPV-negative HNSCC populations. 5 The study by Ferrandino et al 1 underscores the need for further investigation of liquid biopsy, encompassing the implications for de-escalating therapy and improving patient out-