Fatal tracheal perforation following Dabrafenib-Trametinib therapy in BRAF V600E-mutant mixed anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC), pure or mixed, is the most aggressive form of thyroid cancer that leads to rapid death if left untreated. BRAF V600E is the most frequent pathogenic variant of ATC. Dabrafenib and Trametinib (D+T) have shown promising efficacy and are approved as first-line therapy for unresectable BRAF-mutant ATC. We report a case of fatal aero-digestive perforation in a patient treated with D+T. A 56-year-old man presented with an enlarging cervical mass and airway compromise. BRAF V600E-mutant high-grade papillary thyroid carcinoma with an anaplastic component and tracheal invasion was diagnosed. Due to unresectable disease, D+T therapy was initiated. The patient showed rapid clinical improvement and tumor shrinkage. However, he developed acute respiratory failure after a few days. Imaging revealed a large tracheal perforation and subcutaneous emphysema. D+T was discontinued, but the patient died soon from massive hemorrhage. Aero-digestive perforations have been described with antiangiogenic multikinase inhibitors, but never reported with D+T. In this case, rapid tumor shrinkage likely caused weakening and rupture of the trachea, leading to a fatal perforation. This highlights a potential risk of D+T in cases with extensive invasion of vital structures.