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Ref Type Journal Article
PMID (40638225)
Authors Fukuda N, Toda K, Chiba T, Fukada I, Mori S, Tonooka A, Toda E, Yoshida J, Wang X, Oki R, Nakao T, Urasaki T, Nakano K, Ono M, Tomomatsu J, Takeuchi K, Takahashi S, Miura Y
Title Sporadic medullary thyroid carcinoma with a rare RET transmembrane domain mutation (A641R) that responds to selpercatinib.
Journal Vol Issue Date Pages Journal Short Title
The oncologist 30 9 2025 Sep 01 Oncologist
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET A641R medullary thyroid carcinoma predicted - sensitive Selpercatinib Case Reports/Case Series Actionable In a clinical case study, Retevmo (selpercatinib) treatment resulted in a partial response in a patient with metastatic medullary thyroid carcinoma harboring RET A641R (PMID: 40638225). 40638225