April 29, 2016
Despite decades of intense study, glioma has defied significant strides in the advancement of treatment or prediction of outcomes for patients. Diagnosis and treatment decisions have traditionally been guided by differentiation of tumors into histologic grades.
Researchers at Mayo Clinic in Rochester, Minnesota, in conjunction with colleagues at the University of California, San Francisco (UCSF), have defined a new system for classifying gliomas, based on tumor biomarkers. The study, published in the June 25, 2015, issue of the New England Journal of Medicine, defines five biologically distinct tumor groups, suggesting pathways for developing more-precise treatments.
"The molecular makeup of these tumors serves as a better marker than the grading system for the behavior of these tumors," says Daniel H. Lachance, M.D., a consultant in Neurology at Mayo Clinic's campus in Minnesota. "We believe that the markers we've chosen are likely very close to the fundamental genetic mistakes that initiate these cancers."
Predicting disease course
Mean age at diagnosis for each glioma molecular group
Data from three glioma case series were used: Mayo Clinic; University of California, San Francisco, (UCSF) Adult Glioma Study; and The Cancer Genome Atlas. Vertical lines represent standard deviations. Graph reprinted with permission from the New England Journal of Medicine.
Overall survival in the glioma molecular groups
Adjusted Kaplan-Meier estimates of overall survival in the glioma molecular groups. Overall survival estimates were adjusted for sex and age at diagnosis (on the basis of the 2010 U.S. white population) with the use of the reweighted (direct adjustment) method. Because there was only one triple-positive case among patients with grade IV gliomas, this group wasn't included in Panel B. Graph reprinted with permission from the New England Journal of Medicine.
Although genetic technology has been used in cancer biology to better define tumor types, this work had not yet been done in diffuse gliomas. Researchers at Mayo Clinic have been mining patient data for the past decade to find common genetic markers.
The recent study focused on three molecular alternations that are noteworthy because they occur early during glioma formation, are prevalent in glioma or are strongly associated with overall survival:
- Mutations in the telomerase reverse transcriptase (TERT) promoter
- Mutations in isocitrate dehydrogenase (IDH)
- Codeletion of chromosome arms 1p and 19q
In the study, 1,087 gliomas were scored as negative or positive for each of the three markers. Patient characteristics — age, course of disease, treatment response and outcome — were then compared among the top five molecular groups: triple-positive, TERT- and IDH-mutated, IDH-mutated only, TERT-mutated only and triple-negative.
The data were validated in 351 gliomas from the UCSF Adult Glioma Study and 419 gliomas from The Cancer Genome Atlas study. "The study data were consistent across all three data sets," Dr. Lachance says.
Within each of the five molecular groups, patients had similar age of disease onset and overall survival. The average age at diagnosis was youngest (37 years) among patients who had gliomas with only IDH mutation and oldest (59 years) among patients with only TERT mutations. Among patients with grade II or III gliomas, after adjusting for tumor grade and age at onset, TERT-mutation-only gliomas were most strongly associated with poor overall survival.
Each of the five molecular groups had a particular association with genetic polymorphisms, further indicating a significant underlying biology for each group. Most notably, for any of the three groups with IDH mutation, patients were six times likelier than the general population to have a single-nucleotide polymorphism on chromosome 8q24. "That's an order of magnitude similar to the BRCA mutations found in some families with breast cancer," Dr. Lachance notes.
As a clinician, Dr. Lachance already sees the study's predictive value. He recalls a recent visit with a patient who had a recurrence eight years after treatment for grade III astrocytoma. "It turns out that, according to our study's data, the median survival of patients with her molecular markers is eight to 10 years," Dr. Lachance says. "We must focus on thinking about the fact that there truly are biologically different subtypes of glioma."
Clinical trials and treatments
MRI showing large, deep glioblastoma
MRI scan of the brain of a 62-year-old woman showing a large, deep glioblastoma in the left temporal lobe and thalamus.
Focusing on molecular subgroups of gliomas might well facilitate the development of better-targeted therapies. At Mayo Clinic, the search for improved glioma treatment also encompasses efforts to find individualized treatments, including clinical trials of immunotherapies for glioblastoma.
One of these trials involves a vaccine for patients with newly diagnosed glioblastomas. The immunotherapy uses clinical-grade brain-tumor cell lines developed in the Mayo Clinic Human Cellular Therapy Laboratory as well as dendritic cells cultured from an individual patient's white blood cells. The Food and Drug Administration has approved an expansion of the initial study from eight patients to 20.
"This treatment looks very promising," says Ian F. Parney, M.D., Ph.D., a consultant in Neurosurgery at Mayo Clinic's campus in Minnesota. "The therapy is safe, and we're seeing evidence of some immune responses."
A second trial is studying heat shock protein peptide complex treatment for recurrent glioblastomas. The vaccine in that trial is made from an individual patient's tumor. "We have to get about 7 grams of tumor to make the vaccine. So not every patient is eligible," says Dr. Parney, who co-chairs the large, multicenter study through the Alliance for Clinical Trials in Oncology. "But for patients who are eligible, the initial results have also been very promising."
Therapies based on the measles virus also are in clinical trial, for patients with recurring grade III or grade IV brain tumors. "We're seeing some clear biological effects from the virus, so we're very hopeful going forward," Dr. Parney says.
Plans for additional trials of viral and immune therapies are in development. These trials will involve:
- A dendritic cell vaccine for patients with recurring glioma. The vaccine is similar to the one being tested in newly diagnosed patients but also includes a patient's own lymphocytes. "We're not only giving patients the vaccine to stimulate their immune systems. We're giving them back a little bit of their own immune systems to respond to that vaccine," Dr. Parney says.
- An immune checkpoint inhibitor to modulate the immune systems of patients with newly diagnosed glioblastoma.
- A reovirus treatment for children and young adults with brain tumors. Unlike the measles virus treatment, which is injected directly into the brain tumor, the reovirus treatment is intravenous.
"This is a very exciting time for brain tumor research," Dr. Parney says. "We're really beginning to see new treatments that make a difference in the lives of the people with these tumors."
For more information
Eckel-Passow JE, et al. Glioma groups based on 1p/19q, IDH and TERT promoter mutations in tumors. New England Journal of Medicine. 2015;372:2499.