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

Sep 21, 2026

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Two-thirds of metastatic differentiated thyroid cancer (DTC) patients develop radioiodine (RAI)-resistant disease, driving poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, limited and variable re-induction of RAI avidity has been reported with NTRK/RET inhibitors. Two cases with larotrectinib showed unsuccessful I-123 uptake restoration in a TERT-positive tumor, while a TERT-negative tumor achieved I-131 reuptake, indicating co-occurrence of TERT mutations and NTRK fusions may impair re-sensitization.

LanguageEnglish

CategoryHealthcare

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Pages10

Reading Time25 min

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Abstract

Introduction

Case presentation and results

Conclusion

European Thyroid Journal (2024) 13 e230227 [https://doi.org/10.1530/ETJ-23-0227](https://doi.org/10.1530/ETJ-23-0227) RESEARCH Received 1 November 2023 Accepted 18 April 2024 Available online 18 April 2024 Version of Record published 9 May 2024 | Predictors of radioiodine (RAI)-avidity restoration for NTRK fusion-positive RAI-resistant metastatic thyroid cancers
Abdul Rehman Syed1, Aakash Gorana2, Erik Nohr3, Xiaoli-Kat Yuan4, Parthiv Amin MASc5, Sana Ghaznavi6, Debbie Lamb2, John McIntyre4, Markus Eszlinger7 and Ralf Paschke8
1University of Calgary, Calgary, Alberta, Canada
2Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada
3Alberta Precision Laboratories, Molecular Pathology Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
4Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
5Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada
6Arnie Charbonneau Cancer Institute, Department of Medicine, Section of Endocrinology, University of Calgary, Calgary, Alberta, Canada
7Department of Oncology, Cumming School of Medicine, and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
8Departments of Medicine, Section of Endocrinology, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Correspondence should be addressed to R Paschke: Ralf.paschke@ucalgary.ca | | --- | | Abstract
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 TERTnegative tumor exhibited successful I-131 reuptake with a TDS of −0.060.
Conclusion: As observed for RAI-resistance associated with concurrent TERTand BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.
Keywords: radioiodine uptake reinduction; radioiodine avidity restoration; NTRK fusion gene thyroid cancer; radioiodine resistance; larotrectinib | Published by Bioscientifica Ltd. [https://etj.bioscientifica.com](https://etj.bioscientifica.com) © 2024 the author(s) This work is licensed under a Creative Commons Attribution 4.0 International License. A R Syed et al. European Thyroid Journal (2024) 13 e230227 [https://doi.org/10.1530/ETJ-23-0227](https://doi.org/10.1530/ETJ-23-0227) Graphical abstract A R Syed et al. European Thyroid Journal (2024) 13 e230227 [https://doi.org/10.1530/ETJ-23-0227](https://doi.org/10.1530/ETJ-23-0227) Introduction Papillary thyroid carcinoma (PTC) typically has an excellent clinical prognosis. However, 10% of cases of differentiated thyroid cancers (DTC) will progress to a metastatic stage after receiving initial treatment (1) . Two-thirds of metastatic DTCs lose their ability to uptake radioiodine (RAI) due to oncogene driver mutations silencing thyroid iodide-metabolizing genes, causing them to be RAI-resistant or refractory (1, 2, 3) . Patients w

FAQs

Why is radioiodine (RAI) avidity restoration clinically important in metastatic differentiated thyroid cancer?

Many metastatic DTC patients become RAI-resistant, resulting in poor prognosis. Restoring RAI uptake can enable renewed effectiveness of RAI-based therapy.

What did the two reported larotrectinib cases show regarding RAI uptake?

The TERT-positive ETV6::NTRK3 tumor failed to show successful re-induction on diagnostic I-123 scanning, whereas the TERT-negative TPR::NTRK1 tumor exhibited successful I-131 reuptake.

How might TERT mutations influence RAI re-sensitization in NTRK fusion-positive disease?

The report concludes that, similar to RAI resistance linked with concurrent TERT and BRAF mutations, co-occurring TERT mutations and NTRK fusions may contribute to failure of re-sensitization.

Sep 21, 2026

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