Context: Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported. Case presentation and results: We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of -0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. Conclusion: As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.
Iodine Radioisotopes , Thyroid Neoplasms , Humans , Iodine Radioisotopes/therapeutic use , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Neoplasms/radiotherapy , Male , Female , Adult , Aged, 80 and over , Pyrimidines/therapeutic use , Oncogene Proteins, Fusion/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/radiotherapy , Lung Neoplasms/secondary , Pyrazoles/therapeutic use , Receptor, trkA/genetics , Telomerase/genetics , Receptor, trkC/genetics , Receptor, trkC/metabolism , Repressor Proteins/genetics , Proto-Oncogene Proteins c-ets/genetics , Mutation , ETS Translocation Variant 6 Protein
