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Longitudinal Circulating Tumor DNA Profiling as a Biomarker for Response and Resistance in Platinum-Refractory Head and Neck Squamous Cell Carcinoma

Year: 2025

Type: article

Abstract: Purpose: Immune checkpoint inhibitors (ICIs) are the standard treatment for platinum-refractory head and neck squamous cell carcinoma (HNSCC). This study aimed to characterize genomic alterations, monitor dynamic changes in circulating tumor DNA (ctDNA) associated with treatment response, and identify novel alterations linked to resistance through serial ctDNA profiling. Materials and Methods: Patients with platinum-refractory HNSCC receiving nivolumab were enrolled. ctDNA was analyzed using FoundationOne Liquid CDx at baseline, 6 weeks after treatment, and at disease progression. Results: A total of 36 patients were enrolled, and 33 were evaluable for ctDNA. The most frequent baseline alterations were TP53 (75.8%), followed by TERT (27.3%), NOTCH1 (24.2%), CDKN2A (12.1%), and CCND1 (12.1%). Of 27 patients with measurable lesions, 5 achieved a partial response with a response rate of 18.5%. Dynamic ctDNA profiling revealed all responders had marked reductions in both the sum of variant allele frequencies (sumVAF) and the maximum variant allele frequencies (maxVAF) across detected mutations. A decrease in sumVAF or maxVAF correlated with longer treatment durations, and patients with a >50% decrease in either sumVAF or maxVAF showed significantly longer progression-free survival. Additionally, serial profiling identified de novo mutations in 17 patients, detected during stable disease or progression. Conclusion: Serial ctDNA analysis provides a noninvasive tool for monitoring treatment response and detecting emerging resistance in HNSCC treated with ICIs. A significant reduction in ctDNA at 6 weeks was associated with improved clinical outcomes and warrants validation in larger, prospective studies to define its role as a predictive biomarker in HNSCC.

Source: Cancer Research and Treatment

DOI: 10.4143/crt.2025.1089