Integrating minimal residual disease into postoperative treatment selection for head and neck cancer.

Postoperative treatment selection for head and neck squamous cell carcinoma remains largely anchored to static pathological risk factors, particularly extranodal extension and positive surgical margins. Although these features identify patients at increased risk of recurrence, they do not directly determine whether residual disease persists after surgery. Circulating tumor DNA-based minimal residual disease (MRD) assessment may help bridge this gap by providing a dynamic molecular measure of residual disease burden. Emerging evidence supports the prognostic value of postoperative MRD detection and longitudinal monitoring in head and neck cancer, creating opportunities to refine surveillance and explore risk-adapted treatment strategies. However, residual disease burden alone may not identify which therapy is most likely to be effective, particularly as immune checkpoint blockade becomes integrated into perioperative and postoperative treatment. In this Perspective, we propose a framework that combines longitudinal MRD assessment with clinicopathological risk factors and complementary tumor and immune profiling. Such an approach could shift postoperative decision-making from static recurrence-risk classification toward dynamic, biology-informed treatment selection. Prospective interventional trials will be essential to determine whether MRD-guided strategies can improve outcomes while limiting unnecessary treatment.