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.