Liquid Biopsy in Head and Neck Cancer: Current Evidence and Clinical Applications

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous malignancy with substantial morbidity and high rates of locoregional recurrence despite advances in surgery, radiotherapy, and systemic therapy. Conventional
diagnostic and surveillance approaches rely on tissue biopsy and imaging, which are invasive, spatially limited, and often insufficiently sensitive for detecting minimal residual disease or early relapse. Liquid biopsy has emerged as a minimally invasive strategy that enables real-time assessment of tumor burden and molecular dynamics through analysis of tumor-derived material in body fluids.
Objective: This review summarizes current liquid biopsy strategies in head and neck cancer, highlighting their biological foundations, analytical methodologies, and clinical applications across the disease continuum.
Methods: A narrative review of the literature was conducted, focusing on circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) with biological basis of liquid biopsy. Evidence from translational studies, clinical cohorts, and emerging prospective trials was critically evaluated.
Results: Among liquid biopsy modalities, ctDNA represents the most clinically mature approach, demonstrating utility in treatment response assessment, detection of minimal residual disease, and early identification of recurrence. Viral ctDNA, particularly human papillomavirus (HPV) DNA in oropharyngeal cancer, offers exceptional specificity and prognostic value. Circulating tumor cells provide complementary cellular and functional insights into tumor heterogeneity, metastatic potential, and treatment resistance, although technical challenges limit their routine use. Extracellular vesicles and non-coding RNAs show promise as diagnostic and prognostic biomarkers but require further standardization and validation. Saliva-based assays represent an attractive proximal sampling strategy, especially for HPV-associated disease.
Conclusion: Liquid biopsy strategies offer transformative potential in the management of head and neck cancer by enabling non-invasive, dynamic monitoring of disease biology. While ctDNA and viral biomarkers are closest to clinical integration, emerging multi-analyte approaches incorporating CTCs and extracellular vesicles may further enhance precision oncology. Prospective trials demonstrating clinical utility and outcome benefit are essential to establish liquid biopsy as a routine component of head and neck cancer care.