Tumor-informed liquid biopsy for monitoring thyroid cancer: a proof-of-concept study.

Objective: This proof-of-concept, cross-sectional study assessed the feasibility and clinical relevance of detecting circulating tumor DNA (ctDNA) and RNA (ctRNA) in plasma of patients with thyroid cancer. The analysis was performed concurrently with clinical and biochemical assessment to explore its value as a complementary tool for postoperative surveillance. Methods: Thirty-four patients whose primary tumors had been molecularly profiled for key driver mutations and gene fusions were enrolled. Using a tumor-informed strategy, digital PCR assays were designed to detect patient-specific alterations in matched plasma ctDNA and ctRNA collected between 2021 and 2023. Molecular findings were correlated with treatment response categories according to the 2015 American Thyroid Association (ATA) guidelines. Results: ctDNA and/or ctRNA were detected in all patients with a structurally incomplete response, showing full concordance with imaging findings. In contrast, 91% of patients with an excellent response had undetectable ctDNA/ctRNA, consistent with remission. Among those with indeterminate and biochemical incomplete response group, results were variable: one patient with undetectable Tg exhibited an ETV6::NTRK3 fusion in cfRNA, while two of three with biochemical incomplete response tested negative for ctDNA/ctRNA. Conclusion: This cross-sectional analysis demonstrated that liquid biopsy accurately reflected disease activity and showed strong concordance with primary tumor alterations. These findings support its feasibility and clinical potential as an adjunct to conventional monitoring, particularly when Tg measurement or tumor tissue availability is limited. Prospective longitudinal studies are warranted to validate its role in personalized postoperative surveillance of thyroid cancer.