Mutations Explain ‘Extraordinary’ Thyroid Cancer Everolimus Response, Relapse

Repeated mutation analysis gives insight into a patient’s unusual thyroid cancer disease course

medwireNews: US researchers have identified a mutation in a woman with an aggressive form of thyroid cancer that conferred “exquisite” sensitivity to the mTOR inhibitor everolimus, resulting in an “extraordinary” complete response.

When the patient’s disease progressed after 18 months, a second mutation leading to everolimus resistance was identified in the metastatic anaplastic thyroid tumour, the team says in a case report published in the New England Journal of Medicine.

“This is personalized, precision medicine at its best,” said senior author Jochen Lorch, from the Dana-Farber Cancer Center in Boston, Massachusetts, USA, in a press release.

The 57-year-old woman had previously undergone surgery but had positive resection margins and at least three positive lymph nodes and had disease progression despite chemotherapy. She was included in a phase II trial of everolimus and was the only one of seven patients to respond to treatment, with a significant decrease in tumour size after 6 months.

Analysis of the tumour before everolimus revealed a somatic Nonsense mutation in the TSC2 tumour suppressor Gene that activated the mTOR pathway and sensitivity to everolimus. This is the first time that the Q1178* truncation, which removes a domain essential for inhibition of the mTOR complex 1, has been found in thyroid cancer.

A Germline mutation in folliculin, which is also involved in TSC2 and mTOR signalling, was also identified in the patient’s tumour and this too may have increased everolimus sensitivity, the researchers say.

After 18 months, when the tumour developed resistance to everolimus, further analysis showed that the TSC2 mutation was still present but that a new somatic mutation in MTOR (F2108L) was present in 96% of the tumour.

The team was able to demonstrate in vitro that this MTOR (F2108L) mutation conferred significant tumour resistance by preventing everolimus from binding to mTOR. But the mutated cells remained sensitive to direct mTOR kinase inhibition.

“Because we could show that an mTOR inhibitor that is using a different mechanism could overcome resistance in anaplastic thyroid cancer, these findings could provide a rationale for treatment once resistance to everolimus occurs," Jochen Lorch said.

The researchers conclude that serial biopsies help uncover mechanisms of tumour resistance and suggest further treatment options.

“Ultimately, a comprehensive knowledge of mechanisms of acquired resistance, coupled with the ability to diagnose the relevant mechanisms in situ, may lead to the development of therapeutic strategies, including targeted combinations, that are capable of producing long-term responses in many cancers”, they conclude.

Reference

Wagle N, Grabiner B, Van Allen E, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. New Engl J Med 2014; 371: 1426–1433.

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