SAT-364 - Clinical Response to Selpercatinib in Metastatic Medullary Thyroid Carcinoma with RABEP2-RET Fusion

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy derived from parafollicular C cells, comprising 1–2% of thyroid cancers. It is characteristically driven by RET point mutations rather than RET fusions. In contrast, RET fusions are typically seen in differentiated thyroid cancers, particularly papillary thyroid carcinoma. Nevertheless, the presence of a RET fusion in MTC, while rare, may still represent an actionable driver alteration. The development of highly selective RET inhibitors, such as selpercatinib and pralsetinib, has significantly improved outcomes for patients with advanced RET-altered thyroid malignancies. We describe a case of metastatic MTC with a RABEP2–RET fusion demonstrating a significant clinical and radiologic response to selpercatinib.

A 57-year-old female with metastatic MTC involving the lungs, liver, bones, and left kidney presented with progressive dyspnea, rib pain, hoarseness, and fatigue. She reported nausea, vomiting, diarrhea and weight loss. Baseline CT scan revealed innumerable pulmonary metastases, multiple hepatic lesions, periportal lymphadenopathy, osseous metastases, and left renal mass. A biopsy of a left supraclavicular node confirmed metastatic neuroendocrine neoplasm consistent with MTC. Next-generation sequencing identified a RABEP2-RET fusion with high RET expression, an uncommon alteration in MTC but consistent with the RET-driven oncogenic pathway.

Selpercatinib therapy was initiated, resulting in rapid clinical improvement with resolution of dyspnea and decreased oxygen supplementation. Laboratory results remained stable, with no cytopenias or persistent renal dysfunction. One month follow-up CT on therapy demonstrated a consistent radiographic response: the thyroid mass decreased from 2.8 cm to 2.0 cm, the left supraclavicular lymph node from 1.6 cm to 0.9 cm, pulmonary metastases were reduced by more than 50%, and hepatic lesions showed decreased size and enhancement. The previously enlarged portacaval lymph node reduced from 2.6 cm to 1.1 cm in short-axis diameter, indicating marked nodal response. Additionally, a cortical mass in the medial upper pole of the right kidney decreased from 3.0 cm × 2.4 cm to 2.7 × 2.0 cm, with no new renal abnormalities identified.

This case represents an uncommon presentation of MTC with a RABEP2–RET fusion demonstrating a pronounced response to selpercatinib, highlighting the importance of comprehensive genomic profiling in guiding targeted therapy. Although RET fusions are rare in MTC and more typical of differentiated thyroid cancers, their identification can guide effective targeted therapy. Selective RET inhibition yielded a meaningful clinical and radiologic response, emphasizing the transformative role of precision oncology in advanced thyroid cancer management.

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