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Kinase Fusion–Related Thyroid Carcinomas: Towards Predictive Models for Advanced Actionable Diagnostics

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A Correction to this article was published on 21 November 2022

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Abstract

The past decade has brought significant advances in our understanding of the molecular mechanisms of thyroid carcinogenesis. Among thyroid carcinomas, the most successful class of targeted therapeutics appears to be selective kinase inhibitors. Actionable kinase fusions arise in around 10–15% of cases of thyroid cancer, a significant subset. A cohort of molecular testing platforms, both commercial and laboratory-derived, has been introduced into clinical practice to identify patients with targetable tumors, requiring pathologists to develop an integrative approach that utilizes traditional diagnostic cytopathology and histopathology, immunohistochemistry, and cutting-edge molecular assays for optimal diagnostic, prognostic, and therapeutic efficiency. Furthermore, there has been increasing scrutiny of the clinical behavior of kinase fusion–driven thyroid carcinoma (KFTC), still regarded as papillary thyroid carcinomas, and in characterizing molecular predictors of kinase inhibitor resistance with an aim to establish standardized, evidence-based treatment regimens. This review presents an overview of the current literature on the clinicopathologic and molecular features of KFTC as well as the latest investigational progress and encountered challenges for this unique subset of thyroid neoplasias.

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References

  1. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. The Journal of clinical endocrinology and metabolism. 2006;91:2892-9.

    Article  CAS  PubMed  Google Scholar 

  2. Ibrahimpasic T, Ghossein R, Carlson DL, Nixon I, Palmer FL, Shaha AR, et al. Outcomes in patients with poorly differentiated thyroid carcinoma. The Journal of clinical endocrinology and metabolism. 2014;99:1245-52.

    Article  CAS  PubMed  Google Scholar 

  3. Wong KS, Dong F, Telatar M, Lorch JH, Alexander EK, Marqusee E, et al. Papillary Thyroid Carcinoma with High-Grade Features Versus Poorly Differentiated Thyroid Carcinoma: An Analysis of Clinicopathologic and Molecular Features and Outcome. Thyroid : official journal of the American Thyroid Association. 2021;31:933-40.

    Article  CAS  PubMed  Google Scholar 

  4. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. The New England journal of medicine. 2015;372:621-30.

    Article  PubMed  Google Scholar 

  5. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet (London, England). 2014;384:319-28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Brose MS, Robinson B, Sherman SI, Krajewska J, Lin CC, Vaisman F, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2021;22:1126-38.

    Article  CAS  PubMed  Google Scholar 

  7. Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in Progressive Medullary Thyroid Cancer. Journal of Clinical Oncology. 2013;31:3639-46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jr SAW, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial. Journal of Clinical Oncology. 2012;30:134-41

  9. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Annals of oncology : official journal of the European Society for Medical Oncology. 2022;33:406-15.

    Article  CAS  PubMed  Google Scholar 

  10. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. The New England journal of medicine. 2020;383:825-35.

    Article  CAS  PubMed  Google Scholar 

  11. Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. The lancet Diabetes & endocrinology. 2021;9:491-501.

    Article  CAS  Google Scholar 

  12. Waguespack SG, Drilon A, Lin JJ, Brose MS, McDermott R, Almubarak M, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. European journal of endocrinology. 2022;186:631-43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. The Lancet Oncology. 2020;21:271-82.

    Article  CAS  PubMed  Google Scholar 

  14. Johnson DN, Sadow PM. Exploration of BRAFV600E as a diagnostic adjuvant in the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Human pathology. 2018;82:32-8.

    Article  CAS  PubMed  Google Scholar 

  15. Chu YH, Wirth LJ, Farahani AA, Nosé V, Faquin WC, Dias-Santagata D, et al. Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2020;33:2458-72.

  16. Pekova B, Sykorova V, Dvorakova S, Vaclavikova E, Moravcova J, Katra R, et al. RET, NTRK, ALK, BRAF, and MET Fusions in a Large Cohort of Pediatric Papillary Thyroid Carcinomas. Thyroid : official journal of the American Thyroid Association. 2020;30:1771-80.

    Article  CAS  PubMed  Google Scholar 

  17. Liang J, Cai W, Feng D, Teng H, Mao F, Jiang Y, et al. Genetic landscape of papillary thyroid carcinoma in the Chinese population. The Journal of pathology. 2018;244:215-26.

    Article  CAS  PubMed  Google Scholar 

  18. Franco AT, Ricarte-Filho JC, Isaza A, Jones Z, Jain N, Mostoufi-Moab S, et al. Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;40:1081-90.

    Article  CAS  PubMed  Google Scholar 

  19. Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. The Journal of clinical investigation. 2021;131.

  20. Alzahrani AS, Alswailem M, Alswailem AA, Al-Hindi H, Goljan E, Alsudairy N, et al. Genetic Alterations in Pediatric Thyroid Cancer Using a Comprehensive Childhood Cancer Gene Panel. The Journal of clinical endocrinology and metabolism. 2020;105.

  21. Bounacer A, Schlumberger M, Wicker R, Du-Villard JA, Caillou B, Sarasin A, et al. Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation. British journal of cancer. 2000;82:308-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, Höög A, Larsson C, et al. Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma. European journal of endocrinology. 2012;166:1049-60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clinical cancer research : an official journal of the American Association for Cancer Research. 2000;6:1093-103.

    CAS  PubMed  Google Scholar 

  24. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, Tuttle RM. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. The Journal of clinical endocrinology and metabolism. 2000;85:1170-5.

    CAS  PubMed  Google Scholar 

  25. Ricarte-Filho JC, Halada S, O'Neill A, Casado-Medrano V, Laetsch TW, Franco AT, et al. The clinical aspect of NTRK-fusions in pediatric papillary thyroid cancer. Cancer genetics. 2022;262-263:57-63.

    Article  PubMed  Google Scholar 

  26. Musholt TJ, Musholt PB, Khaladj N, Schulz D, Scheumann GF, Klempnauer J. Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery. 2000;128:984-93.

    Article  CAS  PubMed  Google Scholar 

  27. Brzeziańska E, Karbownik M, Migdalska-Sek M, Pastuszak-Lewandoska D, Włoch J, Lewiński A. Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population. Mutation research. 2006;599:26-35.

    Article  PubMed  Google Scholar 

  28. Lee YC, Hsu CY, Lai CR, Hang JF. NTRK-rearranged papillary thyroid carcinoma demonstrates frequent subtle nuclear features and indeterminate cytologic diagnoses. Cancer cytopathology. 2022;130:136-43.

    Article  CAS  PubMed  Google Scholar 

  29. Kong Y, Bu R, Parvathareddy SK, Siraj AK, Siraj N, Al-Sobhi SS, et al. NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC. European journal of endocrinology. 2021;184:503-11.

    Article  CAS  PubMed  Google Scholar 

  30. Panebianco F, Nikitski AV, Nikiforova MN, Kaya C, Yip L, Condello V, et al. Characterization of thyroid cancer driven by known and novel ALK fusions. Endocrine-related cancer. 2019;26:803-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chou A, Fraser S, Toon CW, Clarkson A, Sioson L, Farzin M, et al. A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma. The American journal of surgical pathology. 2015;39:652-9.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Park G, Kim TH, Lee HO, Lim JA, Won JK, Min HS, et al. Standard immunohistochemistry efficiently screens for anaplastic lymphoma kinase rearrangements in differentiated thyroid cancer. Endocrine-related cancer. 2015;22:55-63.

    Article  CAS  PubMed  Google Scholar 

  33. Nozaki Y, Yamamoto H, Iwasaki T, Sato M, Jiromaru R, Hongo T, et al. Clinicopathological features and immunohistochemical utility of NTRK-, ALK-, and ROS1-rearranged papillary thyroid carcinomas and anaplastic thyroid carcinomas. Human pathology. 2020;106:82-92.

    Article  CAS  PubMed  Google Scholar 

  34. Sisdelli L, Cordioli M, Vaisman F, Moraes L, Colozza-Gama GA, Alves PAG, Jr., et al. AGK-BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma. Pediatric blood & cancer. 2019;66:e27707.

    Article  Google Scholar 

  35. Efanov AA, Brenner AV, Bogdanova TI, Kelly LM, Liu P, Little MP, et al. Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer. Journal of the National Cancer Institute. 2018;110:371-8.

    Article  CAS  PubMed  Google Scholar 

  36. Macerola E, Proietti A, Poma AM, Ugolini C, Torregrossa L, Vignali P, et al. Molecular Alterations in Relation to Histopathological Characteristics in a Large Series of Pediatric Papillary Thyroid Carcinoma from a Single Institution. Cancers. 2021;13.

  37. Bastos AU, de Jesus AC, Cerutti JM. ETV6-NTRK3 and STRN-ALK kinase fusions are recurrent events in papillary thyroid cancer of adult population. European journal of endocrinology. 2018;178:83-91.

    Article  CAS  PubMed  Google Scholar 

  38. Prasad ML, Vyas M, Horne MJ, Virk RK, Morotti R, Liu Z, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122:1097-107.

    Article  CAS  PubMed  Google Scholar 

  39. Duan H, Li Y, Hu P, Gao J, Ying J, Xu W, et al. Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing. Histopathology. 2019;75:890-9.

    Article  PubMed  Google Scholar 

  40. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. The Journal of clinical investigation. 2016;126:1052-66.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Pekova B, Sykorova V, Mastnikova K, Vaclavikova E, Moravcova J, Vlcek P, et al. NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis. Cancers. 2021;13.

  42. Xu B, Fuchs T, Dogan S, Landa I, Katabi N, Fagin JA, et al. Dissecting Anaplastic Thyroid Carcinoma: A Comprehensive Clinical, Histologic, Immunophenotypic, and Molecular Study of 360 Cases. Thyroid : official journal of the American Thyroid Association. 2020;30:1505-17.

    Article  CAS  PubMed  Google Scholar 

  43. Agarwal S, Bychkov A, Jung C-K. Emerging Biomarkers in Thyroid Practice and Research. Cancers. 2022;14:204.

    Article  CAS  Google Scholar 

  44. Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, et al. Overview of the 2022 WHO Classification of Thyroid Neoplasms. Endocr Pathol. 2022 Mar;33(1):27-63.

    Article  PubMed  Google Scholar 

  45. Allison DB, Rueckert J, Cornea V, Lee CY, Dueber J, Bocklage T. Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production. Endocr Pathol. 2022 Jun;33(2):315-326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barletta JA, Gilday SD, Afkhami M, Bell D, Bocklage T, Boisselier P, et al. NUTM1-rearranged Carcinoma of the Thyroid: A Distinct Subset of NUT Carcinoma Characterized by Frequent NSD3-NUTM1 Fusions. Am J Surg Pathol. 2022 Aug 29. https://doi.org/10.1097/PAS.0000000000001967.

    Article  PubMed  Google Scholar 

  47. Grubbs EG, Ng PK, Bui J, Busaidy NL, Chen K, Lee JE, et al. RET fusion as a novel driver of medullary thyroid carcinoma. The Journal of clinical endocrinology and metabolism. 2015;100:788-93.

    Article  CAS  PubMed  Google Scholar 

  48. Hillier K, Hughes A, Shamberger RC, Shusterman S, Perez-Atayde AR, Wassner AJ, et al. A Novel ALK Fusion in Pediatric Medullary Thyroid Carcinoma. Thyroid : official journal of the American Thyroid Association. 2019;29:1704-7.

    Article  CAS  PubMed  Google Scholar 

  49. Ji JH, Oh YL, Hong M, Yun JW, Lee HW, Kim D, et al. Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer. PLoS genetics. 2015;11:e1005467.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kasaian K, Wiseman SM, Walker BA, Schein JE, Hirst M, Moore RA, et al. Putative BRAF activating fusion in a medullary thyroid cancer. Cold Spring Harbor molecular case studies. 2016;2:a000729.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Dar AC, Shokat KM. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annual review of biochemistry. 2011;80:769-95.

    Article  CAS  PubMed  Google Scholar 

  52. Sciacchitano S, Lavra L, Ulivieri A, Magi F, De Francesco GP, Bellotti C, et al. Comparative analysis of diagnostic performance, feasibility and cost of different test-methods for thyroid nodules with indeterminate cytology. Oncotarget. 2017;8:49421-42.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rajab M, Payne RJ, Forest VI, Pusztaszeri M. Molecular Testing for Thyroid Nodules: The Experience at McGill University Teaching Hospitals in Canada. Cancers. 2022;14.

    Google Scholar 

  54. Joung JY, Kim TH, Jeong DJ, Park SM, Cho YY, Jang HW, et al. Diffuse sclerosing variant of papillary thyroid carcinoma: major genetic alterations and prognostic implications. Histopathology. 2016;69:45-53.

    Article  PubMed  Google Scholar 

  55. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocrine pathology. 2002;13:3-16.

    Article  CAS  PubMed  Google Scholar 

  56. Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M, et al. Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. The American journal of pathology. 2002;160:247-54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Seethala RR, Chiosea SI, Liu CZ, Nikiforova M, Nikiforov YE. Clinical and Morphologic Features of ETV6-NTRK3 Translocated Papillary Thyroid Carcinoma in an Adult Population Without Radiation Exposure. The American journal of surgical pathology. 2017;41:446-57.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mayer C, Ofek E, Fridrich DE, Molchanov Y, Yacobi R, Gazy I, Hayun I, Zalach J, Paz-Yaacov N, Barshack I. Direct identification of ALK and ROS1 fusions in non-small cell lung cancer from hematoxylin and eosin-stained slides using deep learning algorithms. Mod Pathol. 2022 Sep 3. https://doi.org/10.1038/s41379-022-01141-4.

    Article  PubMed  Google Scholar 

  59. Saliba M, Mohanty AS, Ho AL, Drilon A, Dogan S. Secretory Carcinoma of the Thyroid in a 49-Year-Old Man Treated with Larotrectinib: Protracted Clinical Course of Disease Despite the High-Grade Histologic Features. Head and neck pathology. 2022;16:612-20.

    Article  PubMed  Google Scholar 

  60. Desai MA, Mehrad M, Ely KA, Bishop JA, Netterville J, Aulino JM, et al. Secretory Carcinoma of the Thyroid Gland: Report of a Highly Aggressive Case Clinically Mimicking Undifferentiated Carcinoma and Review of the Literature. Head and neck pathology. 2019;13:562-72.

    Article  PubMed  Google Scholar 

  61. Chu YH, Barbee J, Yang SR, Chang JC, Liang P, Mullaney K, et al. Clinical Utility and Performance of an Ultrarapid Multiplex RNA-Based Assay for Detection of ALK, ROS1, RET, and NTRK1/2/3 Rearrangements and MET Exon 14 Skipping Alterations. J Mol Diagn. 2022 Jun;24(6):642-654. https://doi.org/10.1016/j.jmoldx.2022.03.006.

    Article  CAS  PubMed  Google Scholar 

  62. Solomon JP, Hechtman JF. Detection of NTRK Fusions: Merits and Limitations of Current Diagnostic Platforms. Cancer research. 2019;79:3163-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D, et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2020;33:38-46.

  64. Yang SR, Aypar U, Rosen EY, Mata DA, Benayed R, Mullaney K, et al. A Performance Comparison of Commonly Used Assays to Detect RET Fusions. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;27:1316-28.

    Article  CAS  PubMed  Google Scholar 

  65. Lee YC, Chen JY, Huang CJ, Chen HS, Yang AH, Hang JF. Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing. Endocrine pathology. 2020;31:348-58.

    Article  CAS  PubMed  Google Scholar 

  66. Ritterhouse LL, Barletta JA. BRAF V600E mutation-specific antibody: A review. Seminars in diagnostic pathology. 2015;32:400-8.

    Article  PubMed  Google Scholar 

  67. Rosenbaum JN, Bloom R, Forys JT, Hiken J, Armstrong JR, Branson J, et al. Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2018;31:791-808.

  68. Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nature medicine. 2014;20:1479-84.

    Article  CAS  PubMed  Google Scholar 

  69. Heydt C, Wölwer CB, Velazquez Camacho O, Wagener-Ryczek S, Pappesch R, Siemanowski J, et al. Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation. BMC medical genomics. 2021;14:62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. National Comprehensive Cancer Network. Thyroid Cancer (Version 2.2022). [cited October 14, 2022]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf

  71. Román-Gil MS, Pozas J, Rosero-Rodríguez D, Chamorro-Pérez J, Ruiz-Granados Á, Caracuel IR, et al. Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies. Cancer treatment reviews. 2022;105:102372.

    Article  PubMed  Google Scholar 

  72. Subbiah V, Shen T, Terzyan SS, Liu X, Hu X, Patel KP, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Annals of oncology : official journal of the European Society for Medical Oncology. 2021;32:261-8.

    Article  CAS  PubMed  Google Scholar 

  73. Subbiah V, Cote GJ. Advances in Targeting RET-Dependent Cancers. Cancer discovery. 2020;10:498-505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Solomon BJ, Tan L, Lin JJ, Wong SQ, Hollizeck S, Ebata K, et al. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2020;15:541-9.

    Article  CAS  PubMed  Google Scholar 

  75. Repetto M, Crimini E, Ascione L, Boscolo Bielo L, Belli C, Curigliano G. The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046. Investigational new drugs. 2022;40:1133-6.

    Article  CAS  PubMed  Google Scholar 

  76. Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. The Lancet Oncology. 2020;21:531-40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. The New England journal of medicine. 2018;378:731-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Drilon A, Li G, Dogan S, Gounder M, Shen R, Arcila M, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Annals of oncology : official journal of the European Society for Medical Oncology. 2016;27:920-6.

    Article  CAS  PubMed  Google Scholar 

  79. Russo M, Misale S, Wei G, Siravegna G, Crisafulli G, Lazzari L, et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer discovery. 2016;6:36-44.

    Article  CAS  PubMed  Google Scholar 

  80. Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, et al. Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Molecular cancer therapeutics. 2021;20:2446-56.

    Article  CAS  PubMed  Google Scholar 

  81. Leroy L, Bonhomme B, Le Moulec S, Soubeyran I, Italiano A, Godbert Y. Remarkable Response to Ceritinib and Brigatinib in an Anaplastic Lymphoma Kinase-Rearranged Anaplastic Thyroid Carcinoma Previously Treated with Crizotinib. Thyroid : official journal of the American Thyroid Association. 2020;30:343-4.

    Article  PubMed  Google Scholar 

  82. Godbert Y, Henriques de Figueiredo B, Bonichon F, Chibon F, Hostein I, Pérot G, et al. Remarkable Response to Crizotinib in Woman With Anaplastic Lymphoma Kinase-Rearranged Anaplastic Thyroid Carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33:e84-7.

  83. Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, et al. Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25:6662-70.

    Article  CAS  PubMed  Google Scholar 

  84. Toyokawa G, Seto T. Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data. Oncology research and treatment. 2015;38:291-8.

    Article  CAS  PubMed  Google Scholar 

  85. Demeure MJ, Aziz M, Rosenberg R, Gurley SD, Bussey KJ, Carpten JD. Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target. World J Surg. 2014;38(6):1296-1305.

    Article  PubMed  Google Scholar 

  86. de Salins V, Loganadane G, Joly C, et al. Complete response in anaplastic lymphoma kinase-rearranged oncocytic thyroid cancer: A case report and review of literature. World J Clin Oncol. 2020;11(7):495-503.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

Dr. Sadow’s salary is supported, in part, by the National Cancer Institute of the National Institutes of Health, Bethesda, USA (1P01CA240239-04).

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  1. Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Ying-Hsia Chu

  2. Departments of Pathology, Massachusetts General Hospital and Harvard Medical School, Pathology Service, WRN 219, 55 Fruit Street, MA, 02114, Boston, USA

    Peter M. Sadow

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Dr. Chu prepared the primary manuscript, figures, and tables with materials from Massachusetts General Hospital. Dr. Sadow conceptualized the manuscript, reviewed, and revised the manuscript. There was joint agreement and approval of the final manuscript for submission.

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Correspondence to Peter M. Sadow.

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The study was performed with Massachusetts General Hospital and Massachusetts General Brigham Internal Review Board approval to Dr. Sadow as Principal Investigator (2011P000013).

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Chu, YH., Sadow, P.M. Kinase Fusion–Related Thyroid Carcinomas: Towards Predictive Models for Advanced Actionable Diagnostics. Endocr Pathol 33, 421–435 (2022). https://doi.org/10.1007/s12022-022-09739-9

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  • DOI: https://doi.org/10.1007/s12022-022-09739-9

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