The presence of an epidermal growth factor receptor (EGFR) mutation (vIII) in Stage III glioma was associated with poor prognosis and suggests the need for aggressive treatment in patients with such tumors that express the mutation, according to a study presented at the ASCO Annual Meeting by Jan Buckner, MD, Professor of Oncology at the Mayo Clinic College of Medicine.
However, the presence or absence of the vIII mutation made no difference in survival in patients with Stage IV glioma.
“This EGFR mutation in a malignant glioma signals very poor prognosis,” Dr. Buckner said at an ASCO news conference. “Patients without the vIII mutation may even be curable. Stage III tumors with and without this protein look alike under the microscope.”
The finding of an EGFR variant that is a prognostic marker is important, because agents that target the EGFR pathway as well as downstream pathways are now available, he said.
“Malignant gliomas with this mutation represent a more rapidly fatal form of the disease, and drugs available through clinical trials may improve outcomes in these patients.”
EGFR is a transmembrane tyrosine kinase that drives cellular proliferation, angiogenesis, and resistance to chemotherapy, as well as cellular invasion, Dr. Buckner explained. About 40% to 50% of patients have amplification of EGFR, and about 75% of these patients will have gene deletions, the most important of which is the vIII mutant.
How to Identify the Mutation
The mutation can be identified using a simple immunohistochemistry (IHC) test, he continued. Tumor tissue is stained with antibody, and if it turns brown under the microscope, the mutation is present.
The study was based on analysis of tumor tissue specimens from patients enrolled in 10 prospective North Central Cancer Treatment Group clinical trials conducted between 1980 and 1999. The trials included patients with newly diagnosed high-grade gliomas treated with radiation and chemotherapy. No difference in survival was seen between any of the arms in the studies.
Dr. Buckner noted that these studies found that among patients with glioma histology, Grade III anaplastic astrocytoma had the best outcome, with Grade III anaplastic oligoastrocytoma having the next best outcome.
Grade IV glioblastoma multiforme had the worst outcome among glioma patients. Among patients with non-glioma histology, outcome was variable, and at five years some of these patients were still alive.
IHC Tumor Analysis
Tumor specimens were examined for EGFR vIII expression by IHC. Of 168 evaluable specimens, 63 were classified as Grade 3 (56 anaplastic astrocytomas, 7 anaplastic oligoastrocytomas) and 105 as Grade 4 (glioblastoma multiforme).
Expression of EGFR vIII was associated with reduced survival in patients with Stage III tumors, but not Stage IV. Patients with Stage III tumors that expressed vIII had a median survival of 7.2 months versus 33 months for those whose tumors did not express the mutation.
Re-analysis according to tumor histology and age did not change these results, Dr. Buckner said. Among Stage IV patients, neither the patient's age nor the presence or absence of vIII was associated with survival.
“The vIII mutant had no prognostic significance in glioblastoma multiforme patients no matter how we sliced or diced. In the anaplastic glioma patients, vIII mutant is clearly more common in older patients and may explain in part why some older patients [with these tumors] have a worse prognosis,” he stated.
IHC is a useful test for identifying anaplastic gliomas that have a clinical course consistent with the most aggressive brain tumor—i.e., Stage IV glioblastoma multiforme, he said.
“vIII mutant may identify the patients who will benefit from targeted therapies that are downstream from the mutant pathway. Stage III glioma with vIII expression should, therefore, be treated aggressively as if it were Stage IV,” he suggested.
These findings suggest that both tumor grade and the new marker can be used to make treatment decisions. “vIII expression may help select patients for participation in clinical trials and for therapies that target this molecular profile,” Dr. Buckner said.
Study Results Unexpected
Patrick Y. Wen, MD, Clinical Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, noted that 40% to 50% of glioblastoma patients have this amplification, and a significant proportion of this group have the vIII mutation, which sends signals to cause tumor proliferation.
It has been thought that the vIII mutation may be a marker of poor prognosis for glioblastoma, but the trial failed to show this. However, a significant proportion of older patients with Stage III glioma with this marker had a worse prognosis,” Dr. Wen explained.
Going forward, he added, EGFR vIII can be used to identify Grade III patients more likely to do worse and treat them more aggressively or with experimental therapies that inhibit EGFR vIII.