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Medullary Thyroid Carcinoma Beyond Surgery: Advances, Challenges, and Perspectives

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Medullary Thyroid Carcinoma Beyond Surgery: Advances, Challenges, and Perspectives 26 9 Endocrine-Related L Ceolin et al. Medullary thyroid carcinoma 26:9 R499–R518 Cancer beyond surgery REVIEW Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives Lucieli Ceolin, Marta Amaro da Silveira Duval, Antônio Felippe Benini, Carla Vaz Ferreira and Ana Luiza Maia Thyroid Unit, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil Correspondence should be addressed to A L Maia: [email protected] Abstract Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid Key Words C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur f medullary thyroid cancer sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of f tyrosine kinase inhibitor the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, f molecular target therapy whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies. Endocrine-Related Cancer (2019) 26, R499–R518 Introduction Medullary thyroid carcinoma (MTC) is a malignant tumor The overall frequency of MTC is not well established, originating in parafollicular or C cells of the thyroid. The but it has recently shown an increase from 0.14 to 0.21 per main secretory product of MTC is calcitonin, a specific 100,000 population between 1983 and 2012 in the USA and highly sensitive biomarker that is produced by normal (Randle et al. 2017). The prevalence is ~2% of all thyroid and neoplastic C cells. Neoplastic C cells also produce the malignancies, 0.4–1.4% of all thyroid nodules, and it carcinoembryonic antigen (CEA). These molecules are is detected in ~0.14% thyroids of subjects submitted to widely used markers for the diagnosis, prognosis, and autopsy (Valle & Kloos 2011, Tuttle et al. 2014, Lim et al. follow-up of MTC patients. 2017). The clinical presentation is mainly in the fourth https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0574 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/08/2021 02:58:47AM via free access -18-0574 Endocrine-Related L Ceolin et al. Medullary thyroid carcinoma 26:9 R500 Cancer beyond surgery and fifth decades of life with a small, but statistically somatic M918T mutations, calcitonin, and CEA doubling significant, increase in diagnosis at a mean age from 50 to times (Meijer et al. 2010). 54 years (Randle et al. 2017). MTC accounts for 13.4% of MTC presents as sporadic (75–80%) or inherited the total deaths attributable to thyroid cancer (Modigliani tumors (20–25%). Hereditary MTC appears as part of the et al. 1998). MEN 2 syndrome. MTC is extremely rare in children, Approximately 35% of patients with MTC who making the probability of a hereditary form very high. present with a palpable thyroid nodule have cervical Germline mutations of the RET (REarranged during metastases, and ~13% have distant metastases (Kebebew Transfection) proto-oncogene cause hereditary cancer, et al. 2005, Roman et al. 2006). The reported 10-year whereas somatic RET mutations are frequently present disease-specific mortality rate for MTC varies from 13.5 to in sporadic disease (Eng et al. 1995, Mulligan 2018). RET 38% (Girelli et al. 1998, Kuo et al. 2018). The tumor stage encodes a transmembrane receptor, and point-activating at the time of diagnosis and the possibility of a complete RET mutations promote continuous phosphorylation of surgical resection mostly determine the likelihood of a distinct set of tyrosine residues, triggering intracellular attaining a cure for MTC. The classical main prognostic signaling pathways responsible for cell survival, factors are age, tumor size, local and distant metastases, differentiation, and proliferation (Fig. 1). Figure 1 Illustration of the activated pathways and genetic aberrations involved in medullary thyroid cancer, as well as the molecular targeted-related compounds. AKT, v-akt murine thymoma viral oncogene homolog; BRAF, serine/threonine-protein kinase B-Raf; c-Kit, tyrosine-protein kinase Kit; c-MET, hepatocyte growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; P38, mitogen-activated protein kinase; PDK-1, pyruvate dehydrogenase kinase isozyme 1; PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma viral oncogene homolog; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor. https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0574 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/08/2021 02:58:47AM via free access Endocrine-Related L Ceolin et al. Medullary thyroid carcinoma 26:9 R501 Cancer beyond surgery Clinical presentation and (Gagel et al. 1989, Decker et al. 1998). Previously, genotype-related phenotypes considered a freestanding syndrome, FMTC, characterized by the presence of an inheritable MTC with no association Hereditary MTC is usually associated with C-cell with other endocrine neoplasia, is now regarded as a hyperplasia, multicentric, and bilateral (Schmid 2015), variant of the MEN 2A spectrum, in which the clinical while the diagnosis of sporadic forms tends to be late, presentation of MTC occurs later, and the prognosis generally in the fifth or sixth decade of life Heshmati( is more favorable in comparison to the other forms of et al. 1997). Lymph node metastases occur in at least 35% MTC. The reclassification into MEN 2A resulted from the of MTC patients at diagnosis, while distant metastases concern that premature categorization of a family with occur in approximately 20% of cases. A minority of FMTC could lead to a failure to identify a PHEO. patients with MTC present systemic manifestations that The clinical course of MTC in patients with MEN 2A include diarrhea, flushing, or painful bone metastases is variable, and the disease progression is associated with (Kebebew et al. 2000, Elisei et al. 2008, Hannah-Shmouni codon-specific mutations in the RET proto-oncogene (Eng et al. 2016). et al. 1996a, Machens et al. 2003). Approximately 98% of Hereditary MTC is inherited as an autosomal dominant MEN 2A is associated with RET mutations in the cysteine- syndrome that involves other endocrine neoplasias, rich extracellular domain, particularly in exons 10 and 11, with a variable degree of expressivity and an age-related codons 609, 611, 618, 620, and 634, which is responsible penetrance, named multiple endocrine neoplasia type for at least 85% of MEN 2A cases and correlated with the 2 (MEN 2). Interestingly, MEN 2 syndrome is classically presence of PHEO, HPT, and CLA (Eng et al. 1996b, Raue defined by the occurrence of multicentric tumor formation & Frank-Raue 2009, Scapineli et al. 2016, Maciel et al. in organs in which the RET proto-oncogene is expressed. 2019). Amino acid change in the intracellular domain This idea emerged because thyroid C cells have long been of RET in exon 13 (codons 768,790 and 791), exon 14 considered to be derived from neural crest cells. However, (codons 804 and 844) and exon 15 (codon 891) are less recent lineage-tracing experiments in mouse embryos frequent. Mutations in exon 8 (codon 533) is rare, but have demonstrated that thyroid C-cell precursors are they have been described in a large Brazilian family (Da derived from anterior endoderm, specifically from the Silva et al. 2003) and are most prevalent in familial cases pharyngeal pouches from which the ultimobranchial in the Greek population (Sarika et al. 2015, Maciel et al. bodies develop (Johansson et al. 2015). These surprising 2019). In 2–5% of cases of apparently hereditary MTC, results may disprove the current concept of a neural crest no RET mutations are found (Leboulleux et al. 2004). Of origin of thyroid C cells and would have implications note, whole exome sequencing has recently identified a for understanding
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