Sporadic medullary thyroid carcinoma with a rare RET transmembrane domain mutation (A641R) that responds to...

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Medullary thyroid carcinoma (MTC) originates from C cells and is often driven by REarranged during Transfection (RET) proto-oncogene mutations.
• Activating RET mutations typically occur in extracellular or intracellular domains; transmembrane domain mutations are rare and poorly understood.
• Identifying actionable RET alterations is crucial for targeted therapy in MTC.

Purpose of the Study:

• To report a case of sporadic MTC with a rare RET transmembrane domain mutation (A641R).
• To evaluate the efficacy of selpercatinib in a patient with MTC harboring the RET A641R mutation.
• To emphasize the importance of comprehensive genomic profiling for detecting rare RET alterations.

Main Methods:

• Case report of a 59-year-old male with sporadic MTC and multiple recurrences.
• Genomic analysis using a next-generation sequencing panel to identify RET mutations.
• Treatment with selpercatinib, a selective RET inhibitor, and assessment of response via biochemical markers and radiological imaging.

Main Results:

• A rare RET A641R mutation in the transmembrane domain was identified via comprehensive genomic profiling, missed by companion diagnostics.
• The patient showed a rapid biochemical response (decreased CEA and calcitonin) and partial radiological response to selpercatinib.
• This is the first report demonstrating selpercatinib's efficacy for MTC with a RET A641R mutation.

Conclusions:

• The RET A641R mutation in the transmembrane domain is oncogenic and actionable.
• Comprehensive genomic profiling is essential for identifying rare, targetable RET alterations in MTC.
• Selpercatinib offers a potential therapeutic option for MTC patients with uncommon RET mutations, including those in the transmembrane domain.