Temodal bardziej efektywny gdy gen MGMT jest wylaczony

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Temodal bardziej efektywny gdy gen MGMT jest wylaczony

Postprzez Crono5 » Cz sie 30, 2007 8:31 am

Silenced Gene May Make Temozolomide More Effective for Some Brain Cancer Patients

Summary

In 2004, a clinical trial confirmed that adding the drug temozolomide to radiation therapy for the treatment of a brain tumor called glioblastoma multiforme helped more patients to live longer. In this related study, researchers report that most of the patients who survived longer on temozolomide had tumors in which a particular gene was turned off. Though this finding is too preliminary to be used as a way to determine which patients should receive temozolomide, the results are a step in that direction.
Source

New England Journal of Medicine, March 10, 2005 (see the journal abstract).
Background

Malignant gliomas are the most common primary brain tumor, accounting for more than half of the more than 18,000 primary malignant brain tumors diagnosed each year in the United States.

The outlook for patients with these tumors is poor. Median survival for patients with moderately severe (grade III) malignant gliomas is three to five years. For patients with the most severe form of malignant glioma (grade IV glioma or glioblastoma multiforme), median survival is less than a year.

In June 2004, researchers announced the results of a large, international, randomized clinical trial in which addition of the drug temozolomide (Temodar®) to radiation therapy increased median survival in patients with glioblastoma multiforme by about two months (see related story). Adding temozolomide to radiation therapy is now considered the standard of care for the initial treatment of these tumors.

Laboratory studies had previously shown that cancer cells that overexpress (make too much of) a protein called MGMT were harder for drugs like temozolomide to kill. Cells that contained no MGMT protein because the gene that produces the protein was switched off succumbed more readily to the drugs. In addition, findings from preliminary clinical trials suggested that patients treated with temozolomide and radiation survived for longer if the MGMT gene was switched off in their tumors. The current study looked at whether this association held true among patients enrolled in the international randomized trial.
The Study

In the original trial, 573 patients were randomly assigned to receive either radiation therapy alone or temozolomide in addition to radiation therapy. Researchers performed genetic tests on tumor tissue from a subset of 307 patients from both groups to find out whether the MGMT gene was turned on or off in the patients’ tumors. Then they compared survival rates in the two groups of patients.

The study’s lead author is Monika E. Hegi, Ph.D., of University Hospital in Lausanne, Switzerland.
Results

For technical reasons, the researchers could determine whether the MGMT gene was switched on or off in only 206 of the 307 patients whose tumors were tested. Within that subgroup of 206 - and regardless of which treatment patients received - median survival was six months’ longer for patients with a switched-off MGMT gene (18.2 months) than for those with a switched-on gene (12.2 months).

The best outcomes of all were seen in patients with a switched-off MGMT gene who received temozolomide in addition to radiation. Their median survival was 21.7 months. By contrast, patients with a switched-off gene who received radiation alone survived for a median of 15.3 months.

Among patients with a switched-on MGMT gene, those treated with temozolomide survived for a median of 12.7 months; those treated with radiation alone survived for a median of 11.8 months - a difference that was barely more than might have occurred by chance.

The researchers saw similar trends when they looked at how long patients survived before their disease progressed. Patients with a switched-off gene who were treated with temozolomide had the longest progression-free survival: 10.3 months compared with 5.9 months for those with a switched-off gene who were treated with radiation alone. Among patients with a switched-on gene, those treated with temozolomide progressed after 5.3 months; those treated with radiation alone progressed after 4.4 months.
Limitations

The researchers could determine whether the MGMT gene was switched on or off in only about a third of the patients enrolled in the trial, says Howard Fine, M.D., Chief of the Neuro-Oncology Branch at the National Cancer Institute's Center for Cancer Research.

Furthermore, the test to determine the status of the MGMT gene has not been standardized, says Fine, which means that different researchers performing the test in another laboratory might get different results.

Other possible explanations for the survival advantage seen in patients with a switched-off MGMT gene have not been completely ruled out, Fine adds. For example, the switched-off gene might be an incidental marker for a less-aggressive form of the disease and/or one that is more responsive to radiation or chemotherapy, independent of the effects of the MGMT gene itself.
Comments

Although this study’s findings are “intriguing,” further studies need to be done to confirm them, comments Fine.

“If they are ultimately validated, these findings would represent an important step toward the goal of personalizing cancer therapy by identifying whether or not patients are likely to respond to a particular treatment,” he says. “For now, however, it is premature to base recommendations for therapy on the status of the MGMT gene.”

Fine recommends that all patients with glioblastoma multiforme receive chemotherapy with temozolomide in addition to radiation therapy. “Because the drug is well tolerated and because we have no effective alternative therapy to offer, it is reasonable to offer temozolomide to all patients,” he says.

That position is supported by Lisa M. DeAngelis, M.D., of Memorial Sloan-Kettering Cancer Center in New York, in an accompanying editorial. “The minimal toxicity associated with temozolomide and the clear benefit of its use makes it reasonable to give this drug to all patients now,” she writes.


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MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

przedruk z:
http://content.nejm.org/cgi/content/full/352/10/997

Monika E. Hegi, Ph.D., Annie-Claire Diserens, M.Sc., Thierry Gorlia, M.Sc., Marie-France Hamou, Nicolas de Tribolet, M.D., Michael Weller, M.D., Johan M. Kros, M.D., Johannes A. Hainfellner, M.D., Warren Mason, M.D., Luigi Mariani, M.D., Jacoline E.C. Bromberg, M.D., Peter Hau, M.D., René O. Mirimanoff, M.D., J. Gregory Cairncross, M.D., Robert C. Janzer, M.D., and Roger Stupp, M.D.




ABSTRACT

Background Epigenetic silencing of the MGMT (O6-methylguanine–DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.

Methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis.

Results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.

Conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

Obrazek
Figure 2. Kaplan–Meier Estimates of Overall Survival, According to MGMT Promoter Methylation Status.

The difference in survival between patients with a methylated MGMT promoter (92 patients, 65 of whom died) and those with an unmethylated MGMT promoter (114 patients, 105 of whom died) was highly significant (P<0.001 by the log-rank test), indicating that the MGMT methylation status has prognostic value. In the group of patients with a methylated MGMT promoter, there was a risk reduction of 55 percent (hazard ratio for death, 0.45; 95 percent confidence interval, 0.32 to 0.61), as compared with the group with an unmethylated MGMT promoter.


Obrazek
Figure 3. Kaplan–Meier Estimates of Overall and Progression-free Survival, According to MGMT Promoter Methylation Status and Random Assignment to Temozolomide plus Radiotherapy or Radiotherapy Alone.

The Kaplan–Meier estimates for overall survival indicate that the group of patients with a methylated MGMT promoter who were randomly assigned to temozolomide and radiotherapy (46 patients, 40 of whom had progression and 27 of whom died) had a 49 percent risk reduction (hazard ratio for death, 0.51; 95 percent confidence interval, 0.31 to 0.84), as compared with the group with a methylated MGMT promoter who were randomly assigned to radiotherapy only (46 patients, 45 of whom had progression and 38 of whom died) (Panel A). An unmethylated MGMT promoter and random assignment to temozolomide and radiotherapy (60 patients, 53 of whom had progression and 52 of whom died) yielded a risk reduction of 31 percent (hazard ratio for death, 0.69; 95 percent confidence interval, 0.47 to 1.02), as compared with an unmethylated MGMT promoter and random assignment to radiotherapy only (54 patients, all of whom had progression and 53 of whom died). In order to display a possible effect of salvage treatment on overall survival, in particular in the group of patients with a methylated MGMT promoter who were randomly assigned to radiotherapy alone. Kaplan–Meier curves are also shown for progression-free survival (Panel B) in a similar manner.

pelna wersja:
http://tnij.org/temodal_mgmt
Crono5
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