https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/cen.12515

Guidelines for the management of thyroid cancer

Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. Evidence Acquisition: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. Evidence Synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confo...

Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update

The rearranged during transfection (RET) proto-oncogene was identified in 1985 and, very soon thereafter, a rearrangement named RET/PTC was discovered in papillary thyroid carcinoma (PTC). After this discovery, other RET rearrangements were found in PTCs, particularly in those induced by radiation. For many years, it was thought that these genetic alterations only occurred in PTC, but, in the past couple of years, some RET/PTC rearrangements have been found in other human tumours. 5 years after the discovery of RET/PTC rearrangements in PTC, activating point mutations in the RET proto-oncogene were discovered in both hereditary and sporadic forms of medullary thyroid carcinoma (MTC). In contrast to the alterations found in PTC, the activation of RET in MTC is mainly due to activating point mutations. Interestingly, in the past year, RET rearrangements that were different to those described in PTC were observed in sporadic MTC. The identification of RET mutations is relevant to the early diagnosis of hereditary MTC and the prognosis of sporadic MTC. The diagnostic and prognostic role of the RET/PTC rearrangements in PTC is less relevant but still important in patient management, particularly for deciding if a targeted therapy should be initiated. In this Review, we discuss the pathogenic, diagnostic and prognostic roles of the RET proto-oncogene in both PTC and MTC.

A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%–49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%–89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9–3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0–not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications. Clin Cancer Res; 22(1); 44–53. ©2015 AACR.

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A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non-small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.

State-of-the-Art Strategies for Targeting RET-Dependent Cancers

Objective: Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. Methods: We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. Results and conclusions: The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P!0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P!0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings. European Journal of Endocrinology 163 301‐308

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Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

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Multiple endocrine neoplasia type 2 syndromes (MEN 2): Results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes (European Journal of Endocrinology 163 (301-308))

Verga Uberta

Papers

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

Multiple endocrine neoplasia type 2 syndromes (MEN 2): Results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes (European Journal of Endocrinology 163 (301-308))