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IMPORTANCE: Recurrence rates for locally advanced HPV-independent (HPV-) 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- HNSCC remains understudied.OBJECTIVE: To evaluate the performance of a tumor-informed ctDNA-based MRD assay (PredicineBEACON) in patients with newly diagnosed, locally advanced HNSCC (LA-HNSCC).DESIGN: Between 12/2020 and 3/2022 ctDNA was assessed before surgery, before the start of adjuvant treatment (MRD-E), within six weeks of completion of treatment (MRD-TC), and during surveillance (MRD-S). Patients were followed for at least 12 months after treatment completion. We used Kaplan-Meier survival analyses to compare recurrence-free survival (RFS) and overall survival (OS) between patients who were MRD positive 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.SETTING: This was a prospective cohort study of patients treated at a large referral center specializing in treatment of HNSCC.PARTICIPANTS: Forty patients with newly diagnosed, LA-HNSCC treated with surgery followed by risk-adjusted adjuvant treatment.INTERVENTION: Tumor-informed ctDNA-based MRD testing.MAIN OUTCOMES AND MEASURES: Recurrence-free survival (RFS) and overall survival (OS).RESULTS: We processed 142 samples from 40 patients. The median age was 63, 27% were female, 87% were Caucasian, and 95% had HPV- disease. Fifty percent (20/40) of patients experienced recurrence. The pre-surgery ctDNA detection rate was 97% (35/36). MRD-TC positivity was associated with worse OS (HR= 7.15; 95% CI: 1.44-35.3) and RFS (HR= 5.39; 95% CI: 1.98-21.07). MRD-S positivity was associated with worse RFS (HR=8.2; 95% CI: 2.06-33.6). The median time from first MRD detection to clinical detection of recurrence was 5 months (range 0.2-21.6). In multivariable analyses, MRD positivity was associated with worse RFS (HR 13.8; 95% CI 2.92-65.7) and worse OS (HR 18.9; 95% CI 2.27-158).CONCLUSIONS AND RELEVANCE: Tumor-informed ctDNA MRD positivity was associated with worse RFS and OS in patients with HNSCC. MRD testing could serve as a non-invasive, prognostic biomarker in HPV- HNSCC patients.