Predictors of radioiodine (RAI)-avidity restoration for NTRK fusion-positive RAI-resistant metastatic thyroid cancers

Eur Thyroid J. 2024 May 9;13(3):e230227. doi: 10.1530/ETJ-23-0227. Print 2024 Jun 1.


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.

Keywords: NTRK fusion gene thyroid cancer; larotrectinib; radioiodine avidity restoration; radioiodine resistance; radioiodine uptake reinduction.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Aged, 80 and over
  • ETS Translocation Variant 6 Protein
  • Female
  • Humans
  • Iodine Radioisotopes* / therapeutic use
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / radiotherapy
  • Lung Neoplasms / secondary
  • Male
  • Mutation
  • Oncogene Proteins, Fusion / genetics
  • Proto-Oncogene Proteins c-ets / genetics
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • Receptor, trkA / genetics
  • Receptor, trkC / genetics
  • Receptor, trkC / metabolism
  • Repressor Proteins / genetics
  • Telomerase / genetics
  • Thyroid Neoplasms* / genetics
  • Thyroid Neoplasms* / pathology
  • Thyroid Neoplasms* / radiotherapy


  • Iodine Radioisotopes
  • larotrectinib
  • Pyrimidines
  • Oncogene Proteins, Fusion
  • Pyrazoles
  • Receptor, trkA
  • NTRK1 protein, human
  • Telomerase
  • TERT protein, human
  • Receptor, trkC
  • NTRK3 protein, human
  • Repressor Proteins
  • Proto-Oncogene Proteins c-ets
  • ETS Translocation Variant 6 Protein