Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

Abstract

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAF^V600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

Keywords: cabozantinib; differentiated thyroid cancer; lenvatinib; medullary thyroid cancer; pralsetinib; selpercatinib; sorafenib; targeted therapy; tyrosine kinase inhibitors; vandetanib.

Figure 1

Graphic representation of intracellular pathways (i.e., mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K)), activated by tyrosine kinase receptors (i.e., RET, MET, FGFR, PDGFR) in thyroid cancer. Activation of BRAF and MEK also play an important role in the loss of sodium iodide symporter (NIS) activity, leading to RAI refractoriness. The vascular endothelial growth factor receptor is present on the cellular membrane of both tumor and endothelial cells and it is the major player of the new tumor angiogenesis.

Figure 2

Molecular alterations that lead to mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), and receptor kinase pathways activation and promote the progression of follicular thyroid cells to papillary (PTC) and to follicular thyroid cancer (FTC). Additional mutations and rearrangements and an increase of MAPK and PI3K pathways signaling promote further progression to poorly differentiated thyroid cancer (PDTC). Further genetic events, especially involving p53, epigenetic alteration, and infiltration of immune cells, promote the onset of anaplastic thyroid cancer (ATC).