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MGMT Methylation Study (Hegi et al.)

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

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Year of Publication: 2005

Authors: Monika E. Hegi, Annie-Claire Diserens, Thierry Gorlia, ..., Roger Stupp

Journal: New England Journal of Medicine

Citation: N Engl J Med 2005;352:997-1003

Link: https://doi.org/10.1056/NEJMoa043331

PDF: https://doi.org/10.1056/NEJMoa043331

Clinical Question

Does MGMT promoter methylation status predict which glioblastoma patients benefit from the addition of temozolomide to radiotherapy?

Bottom Line

MGMT promoter methylation was found in 45% of GBM tumors and was a powerful independent prognostic factor (HR 0.45, P<0.001). Patients with methylated MGMT derived the greatest benefit from temozolomide (median OS 21.7 vs 15.3 months, HR 0.51), while those with unmethylated MGMT had only marginal benefit (12.7 vs 11.8 months, HR 0.69), establishing MGMT methylation as the most important predictive biomarker in GBM treatment.

        Major Points
        This was a companion translational study to the Stupp trial (EORTC 26981/NCIC CE.3), analyzing MGMT promoter methylation by methylation-specific PCR in available tumor tissue.
Of 573 patients in the trial, adequate paraffin-embedded tissue was available for 307 (53.6%) and MGMT status was successfully determined in 206 (67.1% of tested, 36.0% of total).
MGMT promoter methylation was detected in 92/206 tumors (44.7%); the proportion was similar between treatment groups.
Regardless of treatment, MGMT promoter methylation was an independent favorable prognostic factor for overall survival: HR 0.45 (95% CI 0.32-0.61), P<0.001.
Among patients with methylated MGMT: RT+TMZ produced median OS of 21.7 months (95% CI 17.4-30.4) vs 15.3 months (95% CI 13.0-20.9) with RT alone. Two-year OS was 46.0% vs 22.7% (P=0.007).
Among patients with unmethylated MGMT: RT+TMZ produced median OS of 12.7 months vs 11.8 months with RT alone (HR 0.69; 95% CI 0.47-1.02; P=0.06) — a statistically nonsignificant difference.
Multivariate analysis confirmed MGMT methylation status (P<0.001) and MMSE score as the strongest independent prognostic factors, along with treatment assignment.
A major confounding factor was that >70% of patients in the RT-alone group received temozolomide as salvage therapy at progression, which may have attenuated the treatment-by-biomarker interaction.

      

Design

Study Type: Prospective translational biomarker study nested within the EORTC 26981/NCIC CE.3 randomized trial

Randomization: 1

Blinding: Investigators performing MGMT PCR were blinded to all clinical information

Enrollment Period: August 2000 - March 2002 (parent trial)

Follow-up Duration: Median 28 months (parent trial)

Centers: 66

Countries: 15 countries

Sample Size: 206

Analysis: Kaplan-Meier estimates; log-rank test; Cox proportional-hazards model stratified by treatment group including MGMT status and clinical prognostic factors

Baseline Characteristics

Characteristic	Control	Active

Arms

Field	Experimental	Control
Intervention	RT (60 Gy) + concurrent TMZ (75 mg/m2/day) followed by adjuvant TMZ (150-200 mg/m2, 6 cycles)	Radiotherapy alone (60 Gy)
Duration

Outcomes

Outcome	Type	HR / OR / RR	P-value
Overall survival by MGMT methylation status and treatment: Methylated + RT+TMZ median OS 21.7 months vs Methylated + RT alone 15.3 months (HR 0.51; 95% CI 0.31-0.84) \| Unmethylated + RT+TMZ median OS 12.7 months vs Unmethylated + RT alone 11.8 months (HR 0.69; 95% CI 0.47-1.02)	Primary	0.51
MGMT methylation as independent prognostic factor: HR 0.45 (95% CI 0.32-0.61), P<0.001	Secondary	0.45	P<0.001
Methylated + RT+TMZ: 2-year OS 46.0%; PFS 10.3 months	Secondary
Methylated + RT alone: 2-year OS 22.7%; PFS 5.9 months (P=0.001)	Secondary		P=0.001
Unmethylated + RT+TMZ: PFS 5.3 months; Unmethylated + RT alone: PFS 4.4 months (P=0.02)	Secondary		P=0.02

Funding

Academic — no commercial sponsor. Initiated and carried out by the investigators without commercial involvement.

Based on: MGMT Methylation Study (Hegi et al.) (New England Journal of Medicine, 2005)

Authors: Monika E. Hegi, Annie-Claire Diserens, Thierry Gorlia, ..., Roger Stupp

Citation: N Engl J Med 2005;352:997-1003

Content summarized and formatted by NeuroTrials.ai.

MGMT Methylation Study (Hegi et al.)

(2005)

Objective

To determine whether MGMT promoter methylation status predicts benefit from temozolomide added to radiotherapy in patients with glioblastoma

Study Summary

• MGMT promoter methylated in 45% of 206 assessable tumors
• Methylated MGMT + RT+TMZ: median OS 21.7 months vs 15.3 months with RT alone; HR 0.51 (0.31-0.84), P=0.007
• Unmethylated MGMT + RT+TMZ: median OS 12.7 months vs 11.8 months with RT alone; HR 0.69 (0.47-1.02), P=0.06
• MGMT methylation was an independent favorable prognostic factor regardless of treatment; HR 0.45 (0.32-0.61), P<0.001
• Methylated MGMT + RT+TMZ: 2-year OS 46.0% vs 22.7% with RT alone
• Established MGMT methylation as the strongest predictive biomarker for temozolomide benefit in GBM

Intervention

Translational biomarker study nested within the Stupp trial (EORTC 26981/NCIC CE.3): methylation-specific PCR of the MGMT promoter in tumor tissue from patients randomized to RT+TMZ vs RT alone

Inclusion Criteria

Patients enrolled in EORTC 26981/NCIC CE.3 trial with available paraffin-embedded tumor tissue adequate for MGMT methylation-specific PCR analysis

Study Design

Arms: Array

Patients per Arm: Methylated MGMT: 92 (46 per arm); Unmethylated MGMT: 114 (60 RT+TMZ, 54 RT)

Outcome

• Methylated MGMT + RT+TMZ: median OS 21.7 mo; 2-yr OS 46.0%
• Methylated MGMT + RT alone: median OS 15.3 mo; 2-yr OS 22.7%; P=0.007
• Unmethylated MGMT + RT+TMZ: median OS 12.7 mo; 2-yr OS 13.8%
• Unmethylated MGMT + RT alone: median OS 11.8 mo; 2-yr OS <2%; P=0.06
• MGMT methylation prognostic HR: 0.45 (0.32-0.61), P<0.001
• Methylated PFS: 10.3 (RT+TMZ) vs 5.9 mo (RT); HR 0.48, P=0.001

Bottom Line

Major Points

This was a companion translational study to the Stupp trial (EORTC 26981/NCIC CE.3), analyzing MGMT promoter methylation by methylation-specific PCR in available tumor tissue.
Of 573 patients in the trial, adequate paraffin-embedded tissue was available for 307 (53.6%) and MGMT status was successfully determined in 206 (67.1% of tested, 36.0% of total).
MGMT promoter methylation was detected in 92/206 tumors (44.7%); the proportion was similar between treatment groups.
Regardless of treatment, MGMT promoter methylation was an independent favorable prognostic factor for overall survival: HR 0.45 (95% CI 0.32-0.61), P<0.001.
Among patients with methylated MGMT: RT+TMZ produced median OS of 21.7 months (95% CI 17.4-30.4) vs 15.3 months (95% CI 13.0-20.9) with RT alone. Two-year OS was 46.0% vs 22.7% (P=0.007).
Among patients with unmethylated MGMT: RT+TMZ produced median OS of 12.7 months vs 11.8 months with RT alone (HR 0.69; 95% CI 0.47-1.02; P=0.06) — a statistically nonsignificant difference.
Multivariate analysis confirmed MGMT methylation status (P<0.001) and MMSE score as the strongest independent prognostic factors, along with treatment assignment.
A major confounding factor was that >70% of patients in the RT-alone group received temozolomide as salvage therapy at progression, which may have attenuated the treatment-by-biomarker interaction.

Study Design

Study Type: Prospective translational biomarker study nested within the EORTC 26981/NCIC CE.3 randomized trial
Randomization: Yes
Blinding: Investigators performing MGMT PCR were blinded to all clinical information
Sample Size: 206
Follow-up: Median 28 months (parent trial)
Centers: 66
Countries: 15 countries

Primary Outcome

Definition: Overall survival by MGMT methylation status and treatment: Methylated + RT+TMZ median OS 21.7 months vs Methylated + RT alone 15.3 months (HR 0.51; 95% CI 0.31-0.84) | Unmethylated + RT+TMZ median OS 12.7 months vs Unmethylated + RT alone 11.8 months (HR 0.69; 95% CI 0.47-1.02)

Control	Intervention	HR/OR	P-value
		0.51 (0.31-0.84)

Citation

N Engl J Med 2005;352:997-1003

View Original Publication →

MGMT Methylation Study (Hegi et al.)

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Funding

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