DNA Repair Gene Key to Response to Temozolomide

GENEVA, Switzerland—A 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.

Molecular Diagnostics

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."