Specific changes in the BRAF gene may affect response to treatment and survival in adult brain cancer patients

Researchers have identified a range of genetic alterations in glioma brain cancer that will help them understand how different mutations in one particular gene interact with other genetic alterations, and which genes are more susceptible to targeted therapies in adults
.

Dr.
Karisa Schreck, who presented the findings of the largest group of glioma patients to date at the 34th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, said that while different alterations in the BRAF gene can drive glioma development are well understood in gliomas that occur in children, this is not the case
in adults.

Dr.
Schreck, an assistant professor of neurology at the Johns Hopkins University School of Medicine in Baltimore, said her research is focused on developing targeted therapies
for BRAF-mutant gliomas.
When she began designing her first clinical trial, she realized that the breadth of BRAF mutations in adult brain cancer patients and their response to traditional chemotherapy was unclear
.
To her knowledge, her patient cohort is the largest, which allows her to begin answering these questions and allows her to design better clinical trials for these patients [2].

In brain tumors, BRAF changes are important because they can determine treatment
.
However, it is unclear what types of BRAF changes occur in adult glioma patients and whether specific BRAF changes are associated with
other genetic alterations or different clinical processes.

The term "glioma" covers several types of tumors
that originate in glial cells in the brain.
Glioblastoma is the most common type in adults and children, occurring at 3.
23 per 100,000 people, and only 7% of glioblastoma patients survive 5 years
after diagnosis[3].
There is an urgent need for new and better treatments, and drugs have been developed that target specific BRAF mutations, such as dabrafanib and trametinib
that inhibit BRAFv600E mutations.
Understanding which genetic mutations, or combinations of genetic alterations, cause a patient's cancer is critical
to choosing the best treatment that is most likely to prolong survival.

Dr.
Schreck and his colleagues collected data from Dana-Farber/Harvard Cancer Center, Johns Hopkins Hospital, the Genomics Evidence Tumor Information Exchange Project (GENIE), and the Cancer Genome Atlas (TCGA) from nearly 300 glioma patients, 206 of whom were adults
.
They looked at clinical information, including what treatments patients received, how long they lived, and the structural and molecular composition of tumor tissue, including genetic alterations
。 Based on how BRAF changes activate a signaling pathway called ERK (extracellular signaling kinase), they divided tumors into three groups: class I (mutations such as BRAFv600E, in which BRAF is able to activate ERK on its own), class II (in which BRAF needs to be paired with another BRAF molecule to activate ERK during dimerization), class III (mutations amplify ERK signals through RAS genes and other signaling molecules), and gene rearrangement, Amplification and other unclassified changes
.

Dr.
Schreck said she found that braf-altered gliomas in adults and children had different characteristics
.
There are more changes in class BRAFv600E in adults and more BRAF fusion in childhood gliomas (fusion occurs when parts of the BRAF gene are misconnected or "fused" to another gene, leading to cancer).

Changes in BRAFv600E were associated with improved overall survival in adult glioma patients, but for glioblastoma, the most aggressive type of glioma, this improvement disappeared, and increased age was associated with
reduced survival in these patients.

The researchers also found that BRAFv600E is sensitive
to targeted therapy in adult patients.
They knew that gliomas altered by BRAFv600E might be sensitive
to treatment with BRAF and MEK inhibitors.
This study showed that patients who received these treatments lived longer
than those who had the same BRAF changes and no treatment of tumor grade.
They also demonstrated that other BRAF alterations in glioma patients may be targeted with MEK inhibitors or dimerically interfering with BRAF inhibitors
.
They hope the study will inspire researchers to include these mutated gliomas
in clinical trials evaluating new BRAF-inhibiting drugs.

Of the 13 adult patients who received targeted therapy, 6 stopped glioma growth or shrinkage; Six cases were pleomorphic yellow astrocytoma, four were glioblastoma pleomorphe, two were hairy cell astrocytomas, and one was another type of astrocytoma
.
The mean (median) time before cancer progression is 5 months, and overall survival is nearly 14 years
.
In patients with glioblastoma it is 4 and a half
years.

Dr.
Schreck concluded that she and her colleagues found extensive genetic alterations
in this large group of glioma patients driven by BRAF.
She said the findings suggest that there are some distinct biological features that may influence clinical outcomes and that these features need further research to understand their impact
.

Professor Ruth Plummer from Newcastle University in the UK chaired the 34th EORTC-NCI-AACR symposium and was not involved in the study
.
"These results suggest that gliomas manifest differently in adults and children, and may include their response to
targeted therapies," she said.
This research advances our understanding of adult gliomas, which will allow us to better match treatments for cancer based on specific variants in the BRAF gene
.
It will also allow us to develop new and better therapies
that target different genetic variants.
Glioma is a difficult disease to treat successfully, and there is an urgent need to find new drugs that can help us improve the outcomes of
these patients.
”