Clinical actionability of molecular testing in advanced thyroid cancer: a real-world cohort study.

Objectives: Molecular testing is increasingly used in thyroid cancer (TC) to complement diagnostics and guide systemic therapy choices. However, real-world data on its clinical impact remain limited. We evaluated the molecular landscape, clinical actionability, and outcomes of matched therapy in patients with advanced TC. Methods: We retrospectively assessed 103 patients with advanced TC who underwent panel-based molecular testing with potential treatment consequences at Radboud University Medical Center, Nijmegen, the Netherlands, between 2014 and 2024. Alterations were classified using the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT), and details on matched treatment and follow-up were collected. Results: Molecular testing was performed at diagnosis (51.5%; primarily anaplastic TC) or upon disease progression (48.5%; primarily differentiated and medullary TC). Most frequent alterations were TP53 (39.8%), NRAS (17.5%), BRAF (16.5%), PTEN (16.5%), and RET (11.7%). Potential targetable alterations (ESCAT level I-III) were detected in 62.1% of patients, and 32.0% harbored ESCAT level I or II alterations considered clinically actionable. Matched systemic therapy was initiated in 16 patients and demonstrated an objective response rate of 56.3% and a disease control rate of 68.8%. Durable responses were predominantly observed in patients with ESCAT level I or II alterations (BRAF, RET, and NTRK). Matched therapy was associated with a trend toward longer overall survival (123.0 vs 57.0 months; P = 0.058). Conclusion: Molecular testing frequently revealed targetable alterations in patients with advanced TC, and matched therapies yielded meaningful clinical benefit. These findings underscore the value of precision medicine in TC and support broader implementation of molecular-guided treatment strategies.