Beneficial Effects of the mTOR Inhibitor Everolimus in Patients with Advanced Medullary Thyroid Carcinoma: Subgroup Results of a Phase II Trial

Medullary thyroid carcinoma (MTC) is a malignant tumour of the neural crest-derived parafollicular C cells. Due to the recent increase in incidence of papillary thyroid carcinoma, MTC now comprises only 1%-2% of all thyroid cancers, 1 but accounts for a significant proportion of thyroid cancer morbidity and mortality. The rate of regional and distant metastasis at presentation is up to 35% and 13%, respectively, 2 and there has been no trend towards earlier stage at diagnosis or improved overall survival in recent decades. 3 Abstract Background: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.Methods: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results:Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. Conclusions:There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

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“…30 Inhibitors of the mTOR pathway have therefore been investigated in advanced MTC, with a phase II trial of everolimus showing some benefit. 46 …”

Section: Other Genetic Pathwaysmentioning

confidence: 99%

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Fussey

Vaidya

Kim

et al. 2019

Clinical Endocrinology

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“…The commonly used treatments for NET are radical surgery and cytoreductive surgery (Schneider et al, 2015). Although surgery plays an important role in the treatment of NET, metastases were found in most patients with NET, indicating that these patients lost the best timing of surgical treatment (Jiménez-Fonseca et al, 2015;Sugimoto et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Zhang

Cheng

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Tumors, especially neuroendocrine tumors (NETs), can cause adverse effects on human health. The expression and significance of Ki-67 and caspase-3 in NET remain to be further explored. Everolimus is an important drug used for the treatment of NETs. In this study, we aimed to investigate whether everolimus exerts anti-tumor effects by suppressing the expression of Ki-67 and caspase-3 in NET. Tumor (different developmental stages) and adjacent tissues were collected from patients with NET. The expression of Ki-67 and caspase-3 were detected in 244 paraffin sections of NET using immunohistochemistry. RT-PCR and western blot were used to detect the expression of Ki-67 and caspase-3 at mRNA and protein levels, respectively. The patients (N = 244) were randomly divided into everolimus-intervention and control groups. RT-PCR and western blot were used to measure the expression changes of Ki-67 and caspase-3 before and after everolimus treatment. The rates of Ki-67 expression in NET grades 1-6 were 14.2, 22.1, 37.5, 59.9, 69.9, and 77.8%, respectively. The difference between the groups was significant. The rates of caspase-3 expression in NET grades 1-6 were 28.6, 33.3, 31.3, 60.0, 80.0, and 88.9%, respectively, and the difference between groups was significant. Moreover, the expression of Ki-67 and caspase-3 showed a significant negative correlation. The expression of Ki-67 decreased while that of caspase-3 increased after everolimus treatment. In conclusion, the decrease in Ki-67 expression and increase in caspase-3 expression after everolimus treatment indicated that everolimus exerted its anti-cancer effect by regulating the expression of Ki-67 and caspase-3.

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“…The combination of lenvatinib with other targeted agents, such as mTOR inhibitors [43][44][45], is a promising area of investigation, while MEK inhibitors, BRAF inhibitors [37,38] and immune-oncology agents [46] also show promise for treating radioiodine-refractory, differentiated thyroid cancer. Adverse events may arise with these new agents and combination therapy, and they may warrant a comprehensive and multidisciplinary approach as required in the management of adverse events of lenvatinib.…”

Section: Discussionmentioning

confidence: 99%

Optimal use of lenvatinib in the treatment of advanced thyroid cancer

2017

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The development of orally active, multitargeted kinase inhibitors (MKIs) represents a significant advance in the treatment of progressive, metastatic thyroid cancer. Lenvatinib, an MKI targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-Kit, and RET, has shown efficacy in stabilizing previously progressive disease, with emerging evidence of a possible benefit in terms of overall survival. However, lenvatinib is associated with a side-effect profile similar to those of other MKIs that might affect the outcome of therapy. The aim of this review is to summarize the clinical efficacy and safety of MKIs in the treatment of advanced thyroid cancer in pivotal phase III trials. Common adverse events that may occur during lenvatinib therapy and their management are discussed, including conditions in which its administration should be temporarily withdrawn and resumed pending resolution of adverse events. We focus on data from a subanalysis of Japanese patients in the SELECT trial and in a post-marketing study in Japan. We suggest that lenvatinib is a valuable treatment option for advanced differentiated thyroid cancer. Monitoring and careful management of adverse events including supportive care are required to ensure continuation of therapy.

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Beneficial Effects of the mTOR Inhibitor Everolimus in Patients with Advanced Medullary Thyroid Carcinoma: Subgroup Results of a Phase II Trial

Cited by 47 publications

References 26 publications

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Optimal use of lenvatinib in the treatment of advanced thyroid cancer

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