SAT-328 Favorable Response of a rare BRAF G469A-Mutated Medullary Thyroid Carcinoma to Dabrafenib and Trametinib Combination Therapy

Abstract Disclosure: A. Razzeto: None. C.V. Villabona: None. J. Mark: None. Introduction: Medullary thyroid carcinoma (MTC), a rare malignancy originating from parafollicular C cells, accounts for 2-3% of all thyroid cancers. While primarily driven by RET mutations in hereditary cases and RET or RAS alterations in sporadic cases, other genetic drivers are infrequent. This report describes the therapeutic response to the combination of a BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) in a patient with aggressive MTC harboring a very rare BRAF p.G469A mutation. Case Presentation: A 71-year-old female with a history of multinodular goiter presented with a suspicious right thyroid mass. Ultrasound-guided fine-needle aspiration confirmed medullary thyroid carcinoma (MTC). Presurgical evaluation revealed an enlarged right thyroid gland with multiple enlarged cervical lymph nodes. Plasma metanephrines and calcium levels were normal. She underwent thyroidectomy with right-sided neck dissection at an outside facility, but the surgery was complicated and aborted after sacrificing the innervation to the right true vocal cord, as well as the 11th cranial nerve and the jugular vein due to tumor invasion. The tumor also invaded the spine and esophagus. Pathology demonstrated MTC in 24 of 28 lymph nodes with extranodal extension. Next-generation sequencing (NGS) revealed a somatic BRAF G469A mutation and was negative for RET mutations. Postoperatively, calcitonin was elevated at 5846 pg/mL, with a CEA of 14.9 ng/mL. Follow-up imaging demonstrated a 4 x 2.9 cm mass with coarse calcifications, invading the right prevertebral muscles and esophagus and deviating the trachea to the left. Due to the high risk of repeat surgery, and significant esophageal invasion posing a bleeding risk with other tyrosine kinase inhibitors, systemic therapy with dabrafenib 150 mg BID and trametinib 2 mg daily was initiated, based on previous reports suggesting sensitivity in Non-Small Cell Lung Cancer with the BRAF G469A mutation. After two months of treatment, the patient reported no adverse events and imaging revealed a slight reduction in the primary tumor size to 3.2 x 2.6 cm and calcitonin decreased to 3338 pg/mL. After four months, calcitonin decreased further to 1809 pg/mL and CEA to 14.4 ng/mL. Conclusion: This case highlights a very rare BRAF G469A mutation in a patient with MTC. The observed response to dabrafenib/trametinib, similar to responses seen in reports of non-small cell lung cancer with the same mutation, suggests a potential therapeutic role for this combination in this specific molecular subtype of MTC. Further investigation is needed to determine the durability of response and underlying mechanisms of action. To our knowledge, this is the first report documenting the clinical utilization of dabrafenib and trametinib in an MTC patient harboring the BRAF G469A mutation; only one prior case report has described the presence of this specific mutation in MTC. Presentation: Saturday, July 12, 2025