Exceptional and Durable Response to Selpercatinib in a Patient with Apparently RET -Negative, HRAS -, and NF1 -Mutated Metastatic Medullary Thyroid Carcinoma

Background: Selpercatinib is approved for RET -mutated medullary thyroid carcinoma (MTC); its activity in tumors without detectable RET alterations is uncertain. Patient Findings: A 50-year-old woman developed rapidly progressive MTC (Ki-67 = 30%) with extensive liver and bone metastases. Because of severe symptomatic progression, selpercatinib was started urgently, off-label, before molecular testing results were available. She had rapid clinical improvement, marked calcitonin and CEA decline, and a remarkable and durable radiographic partial response until the last follow-up (29 months). Summary: Repeated germline and tumor testing [ RET Sanger sequencing, germline whole-exome sequencing, tumor DNA/RNA panel testing, RET Multiplex Ligation-Dependent Probe Amplification (MLPA), tumor whole-genome sequencing] identified no pathogenic or actionable RET variant, indel, copy-number alteration, or fusion. The only somatic alterations found were HRAS p.G13S and truncating NF1 p.R2450*. Conclusions: This remarkable response to selpercatinib in apparently RET -negative MTC is hypothesis generating and requires confirmation. HRAS / NF1 co-alteration supports RAS/MAPK activation but does not explain sensitivity to selective RET inhibition.