Endocrine Abstracts

The rise of mutation-based systemic therapies for individuals with advanced thyroid cancer has underscored the significance of molecular profiling in patient care. Although next-generation sequencing (NGS) gene panels are accessible to clinicians, there is no consensus on the optimal approach to testing. This multicenter study investigates whether mutational profiling of advanced thyroid cancers can inform decisions about targeted therapies. Patients with advanced thyroid cancer from 10 different centers within an integrated Spanish Health Care Region are intended for inclusion in this study. We analyzed clinically derived molecular profiling using either NGS directly or a multistep testing approach. Data on clinicopathologic features and treatments were gathered by reviewing electronic medical records. The OncoKB framework served as the basis for categorizing molecular alterations according to their actionability levels. Patients with an actionable alteration by OncoKB framework who had treatment with a drug targeting the alteration were categorized as receiving ‘‘matched’’ therapy. Time-to-event data were analyzed using the Kaplan–Meier method. Our analysis focuses on the molecular profiling of the initial 103 patients with advanced thyroid cancer between 2018 and 2024, drawn from five centers. This initial cohort comprised 75 cases of radioactive iodine–refractory differentiated cancers (58 papillary, 12 follicular, and 5 oncocytic), 12 poorly differentiated/high-grade, 11 anaplastic, and 5 medullary thyroid cancers. Actionable alterations were identified in 83% patients, with 49% having at least one Level 1 alteration for which an FDA-approved drug is available. BRAFV600E (38%), Ret alterations (4%), NTRK fusions (3%), and ALK fusions (2%) comprised all Level 1 alterations. Most Level 3 and 4 alterations included mutations in NRAS/KRAS/HRAS (8%), alterations in PI3K/AKT/mTOR (8%), and BRAF non-V600E (1%). A matched therapeutic approach was employed in 29% of patients (e.g., BRAFV600E/dabrafenib +/- trametinib, RET fusion/pralsetinib, ALK fusion/Alectinib), with 11% receiving it as first-line therapy. Redifferentiation therapy was undertaken in 12% of cases, (e.g., BRAFV600E/dabrafenib +/- trametinib and NRAS/trametinib). Neoadjuvant systemic therapy was administered in 10 % of the cases, being 4% based on targeted therapies. This ongoing study examines the actionability and clinical use of molecular profiling in advanced thyroid cancer. Most patients had at least one potentially actionable mutation, with 49 % having at least one Level 1 alteration according to the OncokB framework. Our findings underscore the rationale for integrating routine NGS testing or reflex testing, encompassing BRAF, RAS, Ret alterations, NTRK and ALK fusions, into the management of patients with advanced thyroid cancer.