Background: Liquid biopsy is emerging as a non-invasive tool that provides a personalized snapshot of primary and metastatic tumors. It aids in detecting early metastasis, recurrence, or resistance to the disease. We aimed to assess the role of circulating tumour cells (CTCs) as a predictive biomarker in recurrent or metastatic head and neck cancer, specifically head and neck squamous cell carcinoma (HNSCC).

Methodology: Thirty-five patients receiving palliative chemotherapy underwent blood sampling (2 mL in an ethylenediaminetetraacetic acid (EDTA) vial) at baseline and at 3-month intervals. The CTCs were isolated and evaluated using anti-epithelial cell adhesion molecule antibody-based enrichment with the OncoDiscover platform.

Results: CTCs were isolated from 80% of patients (n = 28), showing sensitivity of cell detection at baseline and at 3-month intervals. The median CTC count was 1 per 1.5 mL of blood, and the concordance with clinicoradiological outcomes was 51.4%. The median CTC count declined at 3 months in responders (1 (range: 0–4) to 0 (range: 0–1)), while non-responders showed an increase in levels (0 (range: 0–2) to 1 (range: 0–3)). Although CTCs positively correlated with progression-free survival (PFS) and overall survival (OS), the association did not show a significant difference between CTC-positive and CTC-negative patients at 3 months (PFS: 6 months versus 4 months; hazard ratio: 0.68; 95% confidence interval (CI): 0.29–1.58, p = 0.323; OS: 10 months versus 8 months; hazard ratio: 0.54; 95% CI: 0.18–1.57; p = 0.216).

Conclusion: This study highlights the utility of CTCs as a disease progression monitoring tool in recurrent HNSCC patients. Our findings suggest the potential clinical utility of CTCs and the need for further exploration in upfront settings of the disease as well (NCT: CTRL/2020/02/023378).