A team of researchers from the Massachusetts General Hospital (MGH) and the London Regional Cancer Centre in London, Ontario, have discovered specific genetic changes that indicate whether chemotherapy would be effective in treating patients with anaplastic oligodendrogliomas, a particular type of brain tumor. The discovery, described in the Oct. 7 Journal of the National Cancer Institute, has the potential for significantly improving treatment of patients with these tumors.
"It now will be possible at diagnosis to examine patients' tumors for these genetic changes and determine right away whether chemotherapy will be helpful," says J. Gregory Cairncross, MD, a neuro-oncologist at the London Regional Cancer Center, the paper's first author. "For those who have this genetic pattern, we know that chemotherapy has an excellent chance of shrinking or even eliminating their tumor. And those patients whose tumors would not respond to chemotherapy can avoid the side effects of those powerful drugs."
David Louis, MD, of the MGH Department of Pathology and Neurosurgery Service, the paper's senior author, adds, "This is the first time that molecular genetic analysis has been applied successfully to the diagnosis of brain tumors and the first time we've been able to define which brain tumors are going to respond to chemotherapy." Molecular genetic analysis -- the use of genetic information to classify tumors, as opposed to traditional methods that rely on a tumor's physical appearance -- has been used for several other sorts of tumors, most recently in identifying types of breast cancer susceptible to treatment with the new drug herceptin.
The collaborative study results from the combined expertise of the two research teams. The MGH team previously had identified a number of genetic variants in the malignant brain tumors called gliomas; the London team had discovered that the subtype of tumor called oligodendrogliomas were particular sensitive to chemotherapy drugs and successfully applied an existing treatment regimen using three common anticancer drugs.
Oligodendrogliomas make up at least 10 percent of malignant gliomas, representing several thousand patients diagnosed in North America each year. About two-thirds of malignant oligodendrogliomas respond dramatically to the treatment regimen, usually resulting in complete disappearance of the tumor, For the one-third that do not respond to chemotherapy, the outlook is poor, with survival rates of one to two years after treatment with radiation therapy, the treatment for most malignant brain tumors. Microscopic examination of oligodendrogliomas shows no difference between the tumors that do and do not respond to chemotherapy.
Louis and his team previously had identified three genetic changes characteristic of oligodendrogliomas: loss of part of one copy of chromosome 1, loss of part of one copy of chromosome 19 and deletion of a portion of chromosome 9. Some tumors show only one change while others show combinations of two or three. To test the hypothesis that genetic patterns might correspond with a tumor's chemosensitivity, the MGH team examined DNA samples from 39 oligodendroglioma patients treated by Cairncross and his colleagues and compared the specific genetic changes with each patient's outcome.
They found that tumors with the chromosome 1 loss all responded to chemotherapy, while those without chromosome 1 loss responded far less frequently. Patients whose tumors had chromosome 1 loss also had markedly better survival. The chromosome 19 loss also was associated with longer survival, and the chromosome 9 deletion was associated with a worse prognosis. But overall, the chromosome 1 abnormality was the most powerful and significant factor associated with response to chemotherapy.
"What this means is that patients whose tumors show the chromosome 1 loss have an excellent chance of surviving at least five years after diagnosis because virtually 100 percent of these tumors respond to chemotherapy," says Louis.
"This observation currently applies to a fairly small percentage of brain tumor patients," says Cairncross. "But we know that a small percentage of the more common astrocytic gliomas are also chemosensitive, and we hope that similar predictive genetic changes can be identified in those tumors as well. That will bring us another step closer to our overall goal of curing patients with all kinds of brain tumors."
This study was supported by grants from the U.S. National Institutes of Health, the National Brain Tumor Foundation, the Brain Tumor Society, the Brain Tumor Foundation of Canada and the Canadian Brain Tumor Tissue Bank. Coauthors of the paper include Keisuke Ueki, MD, David Lisle, Dianne Finkelstein, PhD, Jonathan Silver, Paul Stark, MS, and Yasushi Ino, MD, of the MGH; Magdelena Zlatescu, MD, and David Macdonald, MD, of the London Regional Cancer Centre, and Robert Hammond, MD, David Ramsay, MD, of the London Health Sciences Centre.