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Endocrinology

Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid CarcinomasA Review

To identify the key insights or developments described in this article

1 Credit CME

JAMA Oncology

Published Online: June 8, 2023

Review

Article Information and Disclosures

Robert Haddad, MD¹;

Rossella Elisei, MD²;

Ana O. Hoff, MD³;

Zhiyan Liu, MD, PhD⁴;

Fabian Pitoia, MD, PhD⁵;

Giancarlo Pruneri, MD^6,7;

Peter M. Sadow, MD, PhD⁸;

Fernando Soares, MD, PhD⁹;

Andrew Turk, MD¹⁰;

Michelle D. Williams, MD¹¹;

Lori J. Wirth, MD^12,13;

Maria E. Cabanillas, MD¹⁴

Author Affiliations

¹Dana-Farber Cancer Institute, Boston, Massachusetts
²Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
³Instituto do Câncer do Estado de São Paulo, University of São Paulo and Vila Nova Star Hospital, Rede D’Or, São Paulo, Brazil
⁴Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁵Hospital de Clinicas, University of Buenos Aires, Buenos Aires, Argentina
⁶Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
⁷University of Milan, School of Medicine, Milan, Italy
⁸Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston
⁹Instituto D’Or de Pesquisa e Ensino, São Paulo, Brazil
¹⁰Department of Pathology and Cell Biology, Columbia University, New York, New York
¹¹Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston
¹²Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston
¹³Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
¹⁴Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston

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Abstract

Importance Thyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions.

Observations The relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy.

Conclusions and Relevance This review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.

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Article Information

Accepted for Publication: January 4, 2023.

Published Online: June 8, 2023. doi:10.1001/jamaoncol.2023.1379

Correction: This article was corrected on August 17, 2023, to fix affiliation errors and punctuation for sense.

Corresponding Author: Robert Haddad, MD, Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215 (robert_haddad@dfci.harvard.edu).

Conflict of Interest Disclosures: Dr Haddad reported receiving consulting fees from BMS, Merck, Celgene, Eisai, GSK, AstraZeneca, Boehringer Ingelheim, Genentech, Coherus, Pfizer, Loxo, Vaccinex, EMD Serono, Bayer, and Genmab during this review; grants from Merck, BMS, Pfizer, GSK, Merck Sorono, Eisai, Bayer, AstraZeneca, Kura, NCCN, Nanobiotix, ISA, and Mirati outside the submitted work; and participating in the data safety and monitoring boards of Nanobiotix, ISA Pharma, and Boehringer Ingelheim. Dr Elisei reported receiving consulting fees from Eisai, Ipsen, Lilly, Bayer, and Roche during preparation of this work. Dr Hoff reported receiving grants from Eli Lilly for a phase 3 trial on selpercatinib and grants from Exelixis for a phase 3 trial on cabozantinib; and consultant fees from Eli Lilly, Exelixis, and Bayer outside the submitted work. Dr Pitoia reported receiving speaking fees from Bayer outside the submitted work. Dr Pruneri reported receiving personal fees from Roche and Bayer during preparation of this work and personal fees from Foundation One outside the submitted work. Dr Sadow reported receiving grants from the National Institutes of Health of during preparation of this work. Dr Turk reported receiving personal fees from Bayer, Bristol Myers Squibb, Eli Lilly, Loxo Oncology, and Ventana/Roche outside the submitted work. Dr Williams reported receiving personal fees for consulting and serving on the scientific advisory board from Bayer outside the submitted work. Dr Wirth reported receiving personal fees from Bayer, Eisai, Exelixis, and Eli Lilly outside the submitted work. Dr Cabanillas reported receiving personal fees from Lilly, Bayer, and Blueprint during preparation of this work; and personal fees from Exelixis, grants from Genentech, and grants from Merck outside the submitted work. No other disclosures were reported.

Funding/Support: Bayer HealthCare Pharmaceuticals, Inc.

Role of the Funder/Sponsor: The funding organization had no role in the design and preparation of this work; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Medical writing support was provided by Charlotte Simpson, PhD, and Elizabeth Haygreen, PhD, and editorial support was provided by George Chappell, MSc, all of Scion, supported by Bayer HealthCare Pharmaceuticals, Inc according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460). No compensation outside of salary was provided.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.