ICE/ENDO 2014: 16th International Congress of Endocrinology and The Endocrine Society's 96th Annual Meeting:

RET and RAS Mutations in Medullary Thyroid Cancer

At the joint meetings of the International Congress of Endocrinology and The Endocrine Society held June 21-24, 2014 in Chicago, Gilbert J. Cote, PhD presented, RAS Mutations in Medullary Thyroid Cancer. Dr. Cote is a Professor in the Department of Endocrine Neoplasia and Hormonal Disorders at the University of Texas MD Anderson Cancer Center in Houston.

In Medullary Thyroid Cancer (MTC), the calcitonin-producing cells, or C cells, account for approximately 2% to 4% of the thyroid gland and MTC accounts for about 2% to 4% of all thyroid cancers. According to the American Cancer Society, in 2014, there are 2,500 MTC cases in the United States (US) and 12,500 cases worldwide.

Dr. Cote’s presentation addressed three questions:

1.    What are the molecular drivers of MTC tumor progression?

2.    How are we using this knowledge clinically?

3.    Does RAS play a key role in MTC patient care?

Molecular Drivers
RET is a receptor tyrosine kinase, whose role as a MTC driver was uncovered with the discovery of germline mutations causing MEN2 syndromes. After RET was determined to be a driver in hereditary MTC, it was shown that RET mutations are responsible as a driver in sporatic MTC. In Dr. Cote’s slide presentation, he states, “Preclinical studies demonstrate activation of RET slows MTC tumor cell growth and targeting RET slows MTC progression in patients [specific drug studies].”

RAS is part of HRAS, KRAS, and NRAS—all small GTPases.

Key points are taken from Dr. Cote’s presentation include:

  • Prior to the identification of RET in MTC, RAS was first reported as a potential driver.
  • RAS is suggested to be a primary driver in RET-negative sporatic MTC.
  • Once debated, the frequency of RAS mutations in MTC is accepted as important drivers.
  • These findings raise the question as to the role of RAS in the prognosis and targeted therapy.
  • RAS mutation in all thyroid cancers is 14%
  • RAS mutation in all cancers is 16%

Using the Mutation Data
Potential uses include diagnosis, intervention, prognosis, and treatment.

The distribution of different RAS mutations in thyroid cancer (MTC and non-MTC); HRAS Codon 61 is the most frequent target of medullary thyroid cancer and non-medullary thyroid cancer. Dr. Cote stated, “There is a preference in the current literature, or current data base that each RAS mutation affecting Codon 61 are the most prevalent mutations found in MTC, whereas NRAS mutations in Codon 61 are the most prevalent mutation found in non-MTC.”

Good guidelines are lacking for intervention(s) to address how one would use mutation analysis. Dr. Cote explained, “Any MTC diagnosis should really trigger RET germline testing because at least 25% of MTC is hereditary, and their mutations are truly actionable for us to intervene at an early state of disease.”

For a long time, it was thought that somatic RET mutation meant a worse prognosis. In the studies (Schilling and Eilsei) presented by Dr. Cote, the absence of a somatic RET mutation shows a better outcome, whereas the presence of a somatic RET mutation shows a worse outcome. Based on Eilsei’s studies, the RAS mutation acted similarly to the RET mutation. The survival in these groups has increased.

Treatment
There are two drugs approved by the US Food and Drug Administration for the treatment of medullary thyroid cancer: vandetanib and cabozantinib. These drugs work by targeting RET receptor and angiogenesis, as well as other receptors. They do not affect RAS. Dr. Cote raised the question, “Is the treatment of MTC using either of these drugs effective?” Unfortunately, there is no RAS mutation data for either drug.

Summary
Dr. Cote summarized the key points of his presentation:

  • “There are currently no strong clinical data suggesting that the presence of a somatic mutation in MTC should alter treatment.”
  •  “RAS occurs in approximately 14% of sporatic MTC.”
  •  “Treatment for advanced MTC exists because of mutation analysis-defined targets.”
  • “Targeting angiogenesis is clearly important because mutant RAS tumors respond.”

In his closing comments, Dr. Cote drew attention to the need for additional research.    

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