Researchers have identified a range of genetic mutations in gliomas that may help them understand how different mutations in the BRAF gene interact with other gene mutations—and which ones are more susceptible to targeted treatments in adults—according to a new study published by Schreck et al in the European Journal of Cancer. The findings were also presented at the 34th European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics (Abstract 3).
Background and Research Methods
In the study, researchers reported that although different mutations in the BRAF gene were well understood in gliomas occurring in children, this was not the case for adults.
First study author Karisa Schreck, MD, PhD, Assistant Professor of Neurology at the Johns Hopkins University School of Medicine, was researching the development of targeted therapy for BRAF-mutant glioma when she began to design her first clinical trial and realized the breadth of BRAF mutations in adults with brain cancer—and that how they responded to traditional chemotherapy was not well understood.
BRAF mutations are important to identify in brain tumors because they can determine the treatment. However, it is unclear what types of BRAF mutations occur in adults with glioma, and whether specific mutations are associated with other gene mutations or with a different clinical course.
Glioblastomas are the most common type of gliomas in adults and children. They occur in 3.23 per 100,000 individuals and have only a 7% 5-year survival rate after diagnosis. New and better treatments are urgently needed, and drugs such as dabrafenib and trametinib—which inhibit the BRAF V600E mutation—have been developed that target specific mutations. Knowing which mutation or combination of genetic mutations are driving a patient’s cancer is crucial to choosing the most likely therapy to prolong survival.
Analyzing the largest group of glioma patients to date, Dr. Schreck and her colleagues collected data on nearly 300 patients with gliomas—206 of whom were adults. They looked at clinical information, including what treatments the patients received, the length of survival, the structure and molecular makeup of tumor tissues, and genetic mutations. The researchers then divided the tumors into three groups based on how the BRAF mutation activated a signaling pathway—extracellular signal-regulated kinase—that contributed to the gliomas: class I (mutations such as BRAF V600E, in which BRAF was able to activate extracellular signal-regulated kinase on its own), class II (mutations in which BRAF needed to pair up with another BRAF molecule to activate extracellular signal-regulated kinase in a process called dimerization), class III (mutations that amplified extracellular signal-regulated kinase signaling through the RAS gene and other signaling molecules), as well as gene rearrangements, amplifications, and other unclassified mutations.
Study Findings
The researchers found that BRAF-mutated gliomas in adults and children had different features. There were more class I BRAF V600E mutations in gliomas in adult , and more BRAF fusions in gliomas in children. BRAF V600E mutations were associated with improved overall survival in adults with gliomas, but for glioblastomas, that improvement disappeared, and increased age was associated with worse survival in these patients.
The researchers also found that BRAF V600E mutations conferred sensitivity to targeted therapy in adult patients. They knew that gliomas with BRAF V600E mutations could be sensitive to treatments with BRAF and MEK inhibitors. Additionally, the study showed that patients who received these treatments tended to live longer than those with the same BRAF mutation and tumor grade who did not receive the treatments. Researchers further demonstrated that there were other BRAF mutations in patients with gliomas that might be targetable using MEK inhibitors or dimerization-disrupting BRAF inhibitors.
Targeted therapies halted the growth or shrank the gliomas in 6 of the 13 adult patients who received this treatment. Six patients had pleomorphic xanthoastrocytoma, 4 had glioblastoma multiforme, 2 had pilocytic astrocytoma, and 1 had another type of astrocytoma. The average time before the cancer progressed was 5 months, and the overall survival time was nearly 14 years. For patients with glioblastomas, the overall survival was 4.5 years.
Conclusion
Dr. Schreck and her colleagues concluded that they found a wide range of genetic mutations in patients with BRAF-driving gliomas. The findings suggest that there may be distinct biological characteristics that influence clinical outcomes, the impact of which needs to be studied further to be fully understand.
“These results show how gliomas can behave differently in adults and children, potentially including how they respond to targeted therapies. The study advances what we know about gliomas in adults and this knowledge will enable us to better match treatments to the cancer, depending on the specific variations in the BRAF gene. It will also enable us to develop new and better therapies to target different genetic variations. Gliomas can be a difficult disease to treat successfully, and we urgently need to find new drugs that help us to improve outcomes for these patients,” said Ruth Plummer, MD, PhD, a Professor of Experimental Cancer Medicine at Newcastle University and the Chair of the 34th EORTC–NCI–AACR Symposium on Molecular Targets and Cancer Therapeutics, who was not involved in the study.
The researchers hope this study will motivate others to include gliomas with these mutations in clinical trials evaluating new BRAF-inhibiting drugs.
Disclosure: For full disclosures of the study authors, visit ejcancer.com.
