Abstract
Medullary thyroid carcinoma is a rare thyroid malignancy derived from parafollicular C cells that is frequently driven by activating mutations in the REarranged during Transfection (RET) proto-oncogene. While most actionable RET mutations are located in the extracellular cysteine-rich or intracellular tyrosine kinase domains, mutations in the transmembrane domain are exceedingly rare and their oncogenic significance remains unclear. We report a case of a 59-year-old male with sporadic medullary thyroid carcinoma harboring a rare RET A641R mutation in the transmembrane domain. The patient experienced multiple locoregional recurrences after four surgical resections. While the companion diagnostic test did not identify RET mutations, comprehensive genomic profiling using a next-generation sequencing panel revealed the RET A641R mutation. Following administration of selpercatinib, a selective RET inhibitor, a rapid biochemical response with decreased serum carcinoembryonic antigen and calcitonin levels was observed, and radiological assessment showed partial response. This is the first report demonstrating the clinical efficacy of selpercatinib in a patient with medullary thyroid carcinoma harboring a RET A641R mutation, supporting the oncogenic potential of this rare variant. This case also emphasizes the importance of comprehensive genomic profiling in identifying rare but actionable RET alterations that are undetectable by targeted sequencing companion diagnostic tests. Selpercatinib may represent an effective therapeutic option for patients with medullary thyroid carcinoma driven by uncommon RET mutations, including mutations in the transmembrane domain.