Anaplastic Thyroid Cancer

Maria E. CabanillasUnited States Speaker Genomic Alterations in Thyroid Cancer: Biological and Clinical InsightsGenomic alterations play a central role in the initiation, progression, and clinical behavior of thyroid cancers, offering critical insights into their underlying biology and therapeutic vulnerabilities. Follicular cell derived thyroid tumors commonly harbor driver mutations that constitutively activate the MAPK signaling pathway, most notably BRAFV600E and RAS mutations. These early events define major molecular subtypes and strongly influence differentiation status, tumor phenotype, and response to therapy. Progression toward aggressive or dedifferentiated forms, such as poorly differentiated and anaplastic thyroid carcinomas, is driven by additional alterations in key genes regulating chromatin remodeling, cell cycle control, and genomic stability, including TERT promoter mutations, TP53, PIK3CA, and EIF1AX. Actionable genomic alterations are increasingly leveraged to personalize treatment strategies in thyroid cancer and underscore the importance of genomic characterization in improving outcomes in thyroid cancer. Anaplastic Thyroid CancerAnaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, characterized by rapid local invasion, early metastasis, and near‑universal disease‑specific mortality and is considered a medical emergency. Current treatment strategies prioritize rapid assessment of resectability, with surgery pursued only when complete or near‑complete tumor removal is feasible, as partial debulking offers limited benefit. For unresectable disease, localized disease, combined modality therapy—typically external‑beam radiation with concurrent systemic therapy—remains the cornerstone of local control. Recent advances in molecular profiling have transformed systemic management, enabling targeted therapies for tumors harboring BRAFV600E mutations. These agents have demonstrated meaningful responses and, in select cases, have converted unresectable tumors to operable ones, expanding the role of surgery in modern care. However, due to the high risk of relapses, immunotherapy has been added to the treatment strategy. Patients with distant metastatic disease without a BRAFV600E mutation have a more complicated treatment regimen which is still under investigation but require systemic therapy combination strategies involving immunotherapy. These evolving strategies reflect a shift toward precision‑based, time‑critical management aimed at improving outcomes in this highly lethal cancer.