Advanced medullary thyroid cancer: pathophysiology and management

Abstract

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3%–4% of thyroid gland neoplasias. MTC may occur sporadically or be inherited. Hereditary MTC appears as part of the multiple endocrine neoplasia syndrome type 2A or 2B, or familial medullary thyroid cancer. Germ-line mutations of the RET proto-oncogene cause hereditary forms of cancer, whereas somatic mutations can be present in sporadic forms of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration, and survival. Nowadays, early diagnosis of MTC followed by total thyroidectomy offers the only possibility of cure. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in an attempt to control metastatic disease. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising agents for MTC treatment, and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs and about the tyrosine kinase inhibitor-associated side effects will help in choosing the best therapeutic approach to enhance their benefits.

RET mutation and increased angiogenesis in medullary thyroid carcinomas

“…Surgical resection is the only effective treatment for these tumors (de Groot et al 2006, Deshpande et al 2011. Despite their relatively slow growth, MTCs are characterized by early metastatic spread, and the effective treatment of patients with advanced disease is still a major challenge (Ferreira & Maia 2013). Indeed, mean survival for patients with MTC is lower than that associated with more common thyroid cancers, and in the presence of distant metastases, the 10-year rate drops as low as 40% (Chau & Haddad 2013).…”

“…Increasing knowledge of the distinct signaling pathways and genetic abnormalities involved in the pathogenesis of cancer has allowed the development of targeted molecular therapies (Ferreira & Maia 2013). Most MTCs are sporadic cancers, but a hereditary pattern is discernible in 25-30% of cases (Pusztaszeri et al 2014).…”

“…Indeed, encouraging results have emerged from clinical trials in which these drugs were tested in MTC (Ferreira & Maia 2013). The TKIs most widely investigated in MTC patients are drugs that target multiple RTKs, including those involved in angiogenesis like VEGFRs and PDGFRs.…”

“…The TKIs most widely investigated in MTC patients are drugs that target multiple RTKs, including those involved in angiogenesis like VEGFRs and PDGFRs. The efficacy of these agents varies widely, with partial responses reported in 0-40% of MTC patients and disease stabilization in 27-55% (Ferreira & Maia 2013). Unfortunately, TKIs also interact with receptors that mediate physiological functions and are thus associated with a number of highly toxic side effects.…”

“…In-depth analysis of the molecular alterations present in the tumor is fundamental for selecting the most effective drug treatment. For example, MTC response rates to vandetanib, one of the most promising TKIs, are higher in RET M918T mutation-positive patients than in those without this mutation, and patients with RET-activating mutations at codon 804 (V804L, V804M) are resistant to vandetanib and some other TKIs as well (Ferreira & Maia 2013).…”