Minimal Residual Disease in Head and Neck Cancer: Molecular Surveillance and Clinical Action.

PURPOSE OF REVIEW: Recurrence following curative-intent treatment for head and neck squamous cell carcinoma (HNSCC) approaches 50% in locally advanced disease, yet conventional surveillance detects relapse only after anatomical or metabolic thresholds are reached. Minimal residual disease (MRD) monitoring, using circulating tumor DNA (ctDNA) and viral DNA biomarkers, offers an earlier, molecularly informed framework for post-treatment surveillance. This structured narrative review synthesizes contemporary evidence on MRD in HNSCC, drawing on a search of PubMed and Scopus covering January 2020 to March 2026, and defines its role as a clinical instrument for risk-adapted surveillance and decision-making. RECENT FINDINGS: Across prospective cohorts and platform-validation studies, MRD positivity is independently associated with recurrence risk, with hazard ratios ranging from 3- to tenfold across tumor-informed ctDNA platforms, and molecular relapse frequently precedes radiologic detection by months. Viral DNA assays demonstrate specificities exceeding 95% in virally mediated subtypes. Early interventional data suggest potential for MRD-guided treatment adaptation, but results have been mixed: a recent HPV ctDNA-guided de-escalation trial closed early due to an unacceptable recurrence rate, underscoring that standardized thresholds, optimal testing intervals, and definitive evidence of clinical utility remain unresolved. MRD should currently be integrated as an adjunct to established surveillance modalities rather than a standalone trigger for intervention. Results are best interpreted longitudinally, and an early post-treatment molecular checkpoint at 2-6 weeks represents a high-yield decision point where confirmed positivity may justify intensified evaluation and multidisciplinary review.