Postoperative ctDNA could potentially spare patients from unnecessary adjuvant therapy in HPV-negative head and neck squamous cell carcinoma: a meta-analysis

Abstract

Background The prognostic utility of circulating tumor DNA (ctDNA) for minimal residual disease detection in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains incompletely characterized. This meta-analysis evaluates the association between post-operative ctDNA and recurrence-free survival (RFS) in this population. Methods A systematic search of major databases through May 2026 identified studies evaluating post-operative ctDNA and RFS in HPV-negative HNSCC. Pooled hazard ratios (HRs) were calculated using a random-effects model. Results Eight studies (n=325) were included. Detectable post-operative ctDNA was associated with diminished RFS (HR = 10.07, 95% CI: 5.64–17.99) and overall survival (HR = 8.98, 95% CI: 2.93–27.58). However, sensitivity analyses substantially attenuated the pooled RFS estimate (HR range: 2.22–2.43), suggesting the primary effect magnitude may lack stability. Conclusions While preliminary evidence suggests an association between post-operative ctDNA and recurrence risk in HPV-negative HNSCC, these findings require cautious interpretation. The current literature is constrained by small sample sizes, heterogeneous detection methodologies, mixed-cohort inclusion, and potential confounding biases. Consequently, post-operative ctDNA remains an investigational biomarker in this setting. Clinical implementation necessitates further validation through large, prospective, multi-institutional studies employing standardized methodologies in strictly defined HPV-negative #146;populations.