GENEVA, SwitzerlandA simple genetic tumor-biopsy test that
takes only 2 to 3 days to perform is predictive of which glioblastoma
multiforme patients will likely realize a survival benefit from treatment with
the alkylating agent temozolomide (Temodar), an international team of
scientists has found.
Methylation status of the DNA repair gene MGMT
(O-6-methylguanine-DNA methyltransferase) is the key to determining which of
these brain cancer patients will experience a significant vs marginal effect
from the drug, Monika Hegi, PhD, reported at the 16th EORTC-NCI-AACR Symposium
on Molecular Targets and Cancer Therapeutics (abstract 31). Methylation of the
MGMT promoter silences the gene, she said; the result is that production
of MGMT repair enzyme is prevented, thereby preventing correction of
mutations in DNA.
"These results are important because temozolomide acts
directly against DNA to slow down the replication of cancer cells," explained
Dr. Hegi, head of the Laboratory of Tumour Biology and Genetics, Department of
Neurosurgery, at the University Hospital of Lausanne, Switzerland. "It is bad
news if the patient has nonmethylated MGMT status because the DNA in
these rogue cancer cells is being repaired as fast as the drug causes damage."
Thus far, the investigators have used methylation-specific
PCR to test biopsies from 206 glioblastoma patients who participated in a
573-patient, seven-country phase III study of temozolomide plus radiation
therapy vs radiation therapy alone. The study was organized by the EORTC
(European Organisation for Research and Treatment of Cancer) and the National
Cancer Institute of Canada Clinical Trials Group.
Results for all 573 patients showed a 26% 2-year survival
rate for those treated with temozolomide/radiation therapy vs 10% for the
radiation-alone group. Roger Stupp, MD, of the University of Lausanne
Hospitals, presented the findings at the plenary session of the 40th Annual
Meeting of the American Society of Clinical Oncology (abstract 2) (see ONI,
September 2004, page 2).
Of the 206 patients tested so far for MGMT methylation,
nearly half (45%) were shown to have a methylated MGMT promoter and thus
a silent MGMT gene and an impaired DNA repair system. Among the 206
tested patients, 106 were treated with radiotherapy and temozolomide; of those
106, the 46 patients with a methylated MGMT promoter had a 46% survival
rate at 2 years, compared with a rate of 13.8% in the 60 patients with a
nonmethylated promoter and therefore an active MGMT gene.
As the first randomized trial to test MGMT
methylation status in a large patient population, the study "is a first step
towards molecular diagnostics," Dr. Hegi said. While the genetic predictive
test used could be carried out with relative ease in any genetic laboratory,
availability and quality of the tissue are important considerations.
Nevertheless, wide implementation of the test, she noted, would enable
temozolomide to become a targeted treatment: Tested patients unlikely to
benefit would be spared the expense of the drug and its side effects (eg,
nausea and vomiting, myelosuppression). Such patients also might then enroll in
clinical trials of alternative therapies.
Dr. Hegi said the investigators are searching for possible
new drug targets in glioblastoma by screening for molecular patterns among the
trial tumor biopsies. A substrate for the MGMT enzyme, a drug known as
06-benzylguanine, is being tested to see whether it can deplete activity of
MGMT, making the tumor more sensitive to alkylating agent chemotherapy, she
said. She cautioned that even if the new drug succeeds in making temozolomide
more effective in combination therapy for patients with active MGMT
genes, it could increase toxicity to other organs, because it would block the
protective effect of MGMT against DNA mutations in nonmalignant cells.
In an earlier Swiss study of the test in 38 patients
undergoing resection for newly diagnosed glioblastoma and enrolled in a phase
II trial of concomitant and adjuvant temozolomide and radiation (Clin Cancer
Res 10:1871-1874, 2004), Dr. Hegi and her colleagues found similar results.
She noted, however, that with that study design "we cannot exclude that
promoter methylation of the MGMT gene by itself is associated with
better prognosis or response to therapy. It is conceivable that a methylated
MGMT promoter is a surrogate marker for the presence of an epigenetic
activity in the tumor, affecting other unknown genes. Nevertheless, the
presence of a methylated MGMT promoter is a marker for response to
therapy with temozolomide."
Dr. Hegi said she hopes the results of the present trial
will "enourage and fuel further multidisciplinary research, bridging the gap
between basic research and clinical practice."