Tumor-Informed Circulating Tumor DNA Monitoring for Predicting Outcomes in Patients With Head and Neck Squamous Cell Carcinoma

Purpose Despite advances in treatments, nearly half of the patients with head and neck squamous cell carcinoma (HNSCC) experience recurrence. Early recurrence detection is critical for enabling timely curative interventions and improving survival outcomes. Here, we evaluated circulating tumor DNA (ctDNA) testing post-definitive treatment to detect molecular residual disease (MRD) and predict outcomes in patients with HNSCC. Methods and Materials This retrospective study included a real-world cohort of 97 patients with stage I to IV HNSCC undergoing ctDNA testing using a personalized, tumor-informed assay (Signatera, Natera, Inc). Longitudinal plasma samples (n = 500) were collected pretreatment, in the early postdefinitive local treatment setting (within 3 months of completing definitive local treatment, before adjuvant treatment), and during postdefinitive treatment surveillance (after adjuvant therapy [if given] or postcompletion of definitive local treatment until recurrence). Results Median patient follow-up was 22 (2-56) months. ctDNA-based MRD positivity in the early postdefinitive local treatment setting was significantly associated with inferior progression-free survival (PFS) (hazard ratio [HR], 6.39; P = .0002) and overall survival (OS) (HR, 25.72; P = .003). Longitudinally, MRD positivity during the postdefinitive treatment surveillance window was associated with significantly shorter PFS (HR, 38.87; P < .0001) and OS (HR, 14.37; P = .014) and preceded radiographic progression by a median of 4.3 (0.62-21.91) months. The increased risk of recurrence for patients who were MRD-positive was observed across all pathologic stages, regardless of p16 status. In multivariate analysis, MRD positivity postdefinitive treatment was the only clinicopathologic factor significantly associated with PFS (HR, 38.29; P < .001). Conclusions In patients with stage I to IV HNSCC, ctDNA-based MRD positivity after definitive local therapy and adjuvant treatment is associated with disease recurrence and poor survival outcomes.