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Evolving molecularly targeted therapies for advanced-stage thyroid cancers

Key Points

  • Advances in understanding the genomic and functional alterations contributing to the pathogenesis of thyroid cancers have opened new therapeutic opportunities and are beginning to improve patient outcomes

  • RET mutations are common in medullary thyroid cancers (MTCs), and the multikinase inhibitors vandetanib and cabozantinib, which inhibit RET as well as other kinases, are now approved treatments for this disease

  • Multiple small-molecule multikinase inhibitors that block VEGFR signalling have shown promise in the treatment of radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC): sorafenib and lenvatinib are approved for use in the metastatic setting

  • Use of multikinase inhibitors can result in substantial toxicity, a 1–3% risk of death, and does not conclusively improve overall survival; these agent should thus be used with considerable restraint

  • MAPK-pathway inhibition might improve RAI uptake and, therefore, patient responses to RAI therapy with iodine-131; this combinatorial therapeutic approach is a promising novel strategy in patients with metastatic DTC

  • Early application of intensive multimodality therapy (combining surgery, intensity-modulated radiotherapy and taxane-based chemotherapy) might prolong overall survival of patients with anaplastic thyroid cancer, especially those with early stage disease

Abstract

Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered — and might further refine — patient care, and identify open questions for future research.

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Figure 1: Histological classifications of thyroid cancers.
Figure 2: Dominant signalling pathways associated with thyroid cancers, and clinically relevant inhibitors.

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K.C.B. and M.R. identified and evaluated literature and meeting presentations for inclusion in the article and wrote the manuscript. Both authors made substantial contributions to discussions of content and reviewed/edited the manuscript before submission.

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Correspondence to Keith C. Bible.

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Bible, K., Ryder, M. Evolving molecularly targeted therapies for advanced-stage thyroid cancers. Nat Rev Clin Oncol 13, 403–416 (2016). https://doi.org/10.1038/nrclinonc.2016.19

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