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IMPORTANCE: Recurrence rates for locally advanced human papillomavirus (HPV)-independent head and neck squamous cell carcinoma (HNSCC) are high. Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assays have shown promise to improve management and surveillance in several tumor types, but their clinical utility in HPV-independent HNSCC remains understudied.OBJECTIVE: To evaluate the performance of a tumor-informed ctDNA-based MRD assay in patients with newly diagnosed locally advanced HNSCC.DESIGN, SETTING, AND PARTICIPANTS: Between December 2020 and March 2022, among patients newly diagnosed with locally advanced HNSCC treated with surgery followed by risk-adjusted adjuvant treatment at a large referral center specializing in treatment of HNSCC, ctDNA was assessed before surgery, before the start of adjuvant treatment, within 6 weeks of completion of treatment, and during surveillance. Patients were followed up for at least 12 months after treatment completion. Kaplan-Meier survival analyses were used to compare recurrence-free survival (RFS) and overall survival (OS) between patients who were MRD positive and those who were MRD negative during each time window. Multivariable Cox hazard regressions were used to assess the association between MRD status and outcomes while controlling for established risk factors. Data were analyzed from August 2024 to March 2025.INTERVENTION: Tumor-informed ctDNA-based MRD testing.MAIN OUTCOMES AND MEASURES: RFS and OS.RESULTS: Of 40 included patients, 29 (73%) were male, 38 (95%) had HPV-independent disease, and the median (IQR) age at diagnosis was 63 (28-85) years. A total of 142 samples from 40 patients. A total of 20 patients (50%) experienced recurrence. The presurgery ctDNA detection rate was 97% (35 of 36). MRD positivity within 6 weeks of completion of treatment was associated with worse OS (hazard ratio [HR], 7.15; 95% CI, 1.44-35.34) and RFS (HR, 5.39; 95% CI, 1.98-21.07). MRD positivity during surveillance was associated with worse RFS (HR, 8.27; 95% CI, 2.03-33.64). The median (range) time from first MRD detection to clinical detection of recurrence was 5 (0.2-21.6) months. In multivariable analyses, MRD positivity was associated with worse RFS (HR, 13.84; 95% CI, 2.92-65.68) and worse OS (HR, 18.93; 95% CI, 2.27-157.70).CONCLUSIONS AND RELEVANCE: In this study, tumor-informed ctDNA MRD positivity was associated with worse RFS and OS in patients with HNSCC. MRD testing could serve as a noninvasive, prognostic biomarker in patients with HPV-independent HNSCC.