Endocrine Abstracts

Introduction: Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have RAI-resistant disease, resulting in poor prognosis and high disease-related mortality. Current studies of individualized therapy with different MAPK inhibitors report restoring RAI-avidity in 50 – 70% of BRAF and RAS mutated and thyroid cancers with no detected driver mutation. Five recent case reports of rare NTRK and RET-PTC fusion-positive metastatic, RAI-resistant thyroid cancers described restoration of RAI-avidity during treatment with NTRK or RET inhibitors. However, the concurrent presence of TERT promoter mutation is associated with poor RAI-avidity in distant metastatic DTC. We report the outcome of two NTRK fusion-positive patients after treatment with the NTRK inhibitor Larotrectinib.

Case Reports: An 83-year-old male and a 31-year-old female presented with T4a tumours with RAI-resistant lung metastases. The female patient demonstrated a negative diagnostic I-123 whole body scan (WBS), whereas the male patient exhibited rising thyroglobulin (TG) 7 months after initial RAI treatment and a negative post-treatment I-131 WBS. The male presented with an ETV6-NTRK fusion-positive tumour harbouring an additional TERT promoter mutation c.1-124C>T. Larotrectinib 100 mg b.i.d resulted in a TG decrease from 5.6 to 1.9 ng/mL and a size reduction of pulmonary metastases 1 year post-treatment. However, diagnostic I-123 WBS at 3 and 12 months post-Larotrectinib were negative for reinduction of RAI-uptake. Alternatively, the female patient with a TRP-NTRK1 fusion-positive tumour (and negative for TERT promotor mutations) was treated with Larotrectinib 100 mg b.i.d, resulting in a TG decrease from 6.0 to 1.7ng/mL, and reduction in size and improvement in FDG/PET avidity of pulmonary metastases, 7 months post-treatment. Diagnostic I-123 WBS showed reinduction of RAI-avidity in the lung metastases, and she subsequently received 150 mCi I-131. The post-therapy scan showed prominent uptake in multiple lung metastases. Thyroid Differentiation Score derived from primary tumour RNAseq (mean of log2 of fold changes for mRNASeq read counts of 16 thyroid differentiation genes) was -0.287 for the TERT positive and -0.060 for the TERT negative tumour, respectively. The Apical Iodide Transporter (SLC5A8) and the Sodium-Iodide Symporter (SLC5A5) are characterized by a 2.5 fold and a 2.4 fold upregulation in the TERT negative compared to TERT positive tumour, respectively.

Conclusion: Similar to the association of RAI resistance with the co-occurrence of TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure, in addition to advanced age, male sex, and T stage.