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Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is an aggressive disease with limited predictive biomarkers, often leading to ineffective treatments and unnecessary toxicity. Circulating tumor DNA (ctDNA) provides a promising real-time, non-invasive tool for monitoring disease activity. In this study, we analyzed 137 plasma samples from 16 patients with R/M HNSCC receiving immune checkpoint blockade (ICB), using a tumor-informed, highly sensitive next-generation sequencing assay (RaDaR, NeoGenomics). Serial ctDNA monitoring was performed at baseline and throughout treatment, and its association with clinical outcomes, including disease control, three-year overall survival (OS), and progression-free survival (PFS), was evaluated through univariable and multivariable analyses. ctDNA negativity during treatment was significantly associated with improved disease control (OR 21.7, 95% CI 1.86-754.88, p = 0.0317), three-year OS (HR 0.04, 95% CI 0.00-0.47, p = 0.0103), and PFS (HR 0.03, 95% CI 0.00-0.37, p = 0.0057). Early increases in ctDNA levels correlated with disease progression. Our findings suggest that ctDNA negativity, regardless of PD-L1 expression, ICB regimen, or line of therapy, is a strong predictor of favorable outcomes in R/M HNSCC.