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

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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 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.

Related collections

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The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma. A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses. Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not. (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.

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Author and article information

Journal

Journal ID (nlm-ta): Eur Thyroid J

Journal ID (iso-abbrev): Eur Thyroid J

Journal ID (publisher-id): ETJ

Title: European Thyroid Journal

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 2235-0640

ISSN (Electronic): 2235-0802

Publication date (Electronic): 09 May 2024

Publication date (Electronic preprint): 18 April 2024

Publication date Collection: 01 June 2024

Volume: 13

Issue: 3

Electronic Location Identifier: e230227

Affiliations

[1 ]University of Calgary , Calgary, Alberta, Canada

[2 ]Arnie Charbonneau Cancer Institute , Cumming School of Medicine, University of Calgary, Alberta, Canada

[3 ]Alberta Precision Laboratories , Molecular Pathology Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

[4 ]Precision Oncology Hub Laboratory , Tom Baker Cancer Centre, Calgary, Alberta, Canada

[5 ]Department of Radiology , Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada

[6 ]Arnie Charbonneau Cancer Institute , Department of Medicine, Section of Endocrinology, University of Calgary, Calgary, Alberta, Canada

[7 ]Department of Oncology , Cumming School of Medicine, and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada

[8 ]Departments 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

Author notes

Correspondence should be addressed to R Paschke: Ralf.paschke@ 123456ucalgary.ca

Author information

Abdul Rehman Syed http://orcid.org/0000-0002-1023-6039

Markus Eszlinger http://orcid.org/0000-0002-4732-2934

Ralf Paschke http://orcid.org/0000-0003-1470-268X

Article

Publisher ID: ETJ-23-0227

DOI: 10.1530/ETJ-23-0227

PMC ID: 11103761

PubMed ID: 38642578

SO-VID: d756bd35-6d06-4fb0-b2a1-7623bc66f689

License:

This work is licensed under a Creative Commons Attribution 4.0 International License.

History

Date received : 01 November 2023

Date accepted : 18 April 2024

Funding

Funded by: Bayer, doi http://dx.doi.org/10.13039/100004326;

Custom metadata

ifp:collection ETJ-cancer-basic-translational

Keywords: radioiodine uptake reinduction,radioiodine avidity restoration,ntrk fusion gene thyroid cancer,radioiodine resistance,larotrectinib

Data availability:

Keywords: radioiodine uptake reinduction, radioiodine avidity restoration, ntrk fusion gene thyroid cancer, radioiodine resistance, larotrectinib

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