New Mutations Found in Anaplastic Thyroid Cancer Lead to Dramatic Response and Acquired Resistance to Everolimus
A study involving a patient with metastatic anaplastic thyroid cancer who achieved a near-complete response to everolimus (Afinitor) that lasted for 18 months, followed by progressive disease, has revealed a previously unknown mutation in the TSC2 gene and in the mTOR protein. The discovery illustrates the benefit of sequencing a patient’s cancer DNA prior to treatment and following disease recurrence and may help guide treatment of patients with similar mutations. The report by Wagle et al is published in The New England Journal of Medicine.
Study Details
The researchers identified a patient with metastatic anaplastic thyroid cancer, an aggressive disease with a median survival of 5 months. Despite surgery, radiation, and chemotherapy, the cancer spread to her lungs. The patient was then enrolled in a phase II study of everolimus for thyroid cancer and had a near-complete response that lasted for 18 months. She then became resistant to the drug and experienced progressive disease. To identify potential genomic mechanisms of exquisite sensitivity and acquired resistance to everolimus, the researchers performed whole-exome sequencing on the pretreatment and drug-resistant tumors as well as on a blood sample.
Whole-exome sequencing of the tumor tissue before treatment and after the development of everolimus resistance revealed a TSC2 nonsense mutation in both tumors and an F2108L mutation in mTOR in the resistant tumor, which blocked everolimus from binding to it.
However, subsequent laboratory experiments found that even the mutated, resistant cancer cells remained sensitive to a different type of mTOR inhibitor, which is about to enter clinical trials. The patient described in the study is still alive 4 years after her initial diagnosis and is scheduled to receive the new therapy.
Overcoming Drug Resistance
According to Jochen Lorch, MD, MSc, a thyroid cancer specialist at the Head and Neck Treatment Center at Dana-Farber Cancer Institute and a senior author of this report, the study results may have broader implications in other cancer types once they become resistant to everolimus. “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,” said Dr. Lorch in a statement.
“Serial biopsies to profile tumors that develop resistance to targeted therapies have the potential not only to uncover mechanisms of therapeutic resistance, but also to suggest effective follow-up treatment,” wrote the study researchers. “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.”
Dr. Lorch is the corresponding author for The New England Journal of Medicine article.
The study was supported by grants from the Next Generation Fund at the Broad Institute of Massachusetts Institute of Technology, Novartis Pharmaceuticals, the Starr Cancer Consortium, and the National Cancer Institute. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
