Exceptional and Durable Response to Selpercatinib in a Patient with Apparently RET -Negative, HRAS -, and NF1 -Mutated Metastatic Medullary Thyroid Carcinoma.
Ali S Alzahrani, Allianah Benito, Balgees Alghamdi et al.
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Case in brief
A 50-year-old woman presented with rapidly progressive medullary thyroid carcinoma (Ki-67 30%) and extensive liver and bone metastases. Selpercatinib was started urgently off-label before molecular results were available because of severe symptomatic progression. She improved rapidly, with marked declines in calcitonin and CEA and a radiographic partial response that persisted through the last follow-up at 29 months. Repeated germline and tumor analyses found no pathogenic or actionable RET alteration. The only identified somatic changes were HRAS p.G13S and truncating NF1 p.R2450*.
What made this case unusual
A durable response to selective RET inhibition occurred despite repeated testing showing no detectable RET alteration; the HRAS/NF1 co-alterations did not explain the drug sensitivity.
Diagnostic / clinical pearl
A response to selpercatinib does not itself establish a RET alteration: this case remained apparently RET-negative after extensive germline and tumor testing, and the mechanism of sensitivity was unresolved.
Why it matters
The observation is hypothesis generating and requires confirmation; it does not establish selpercatinib efficacy in RET-negative medullary thyroid carcinoma.