MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas

Abstract

Purpose:

While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggests that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated.

Experimental Design:

We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010–2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, co-morbidity, grade, extent of resection, chemotherapy, and radiotherapy.

Results:

We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared to mMGMT (70% [95%CI 64–77%] vs. 81% [95%CI 78–85%], P<.001, adjusted hazard ratio [aHR] 2.35 [95%CI 1.77–3.14]). uMGMT was associated with worse survival in patients who received chemotherapy (63% [95%CI 55–73%] vs. 80% [95%CI 76–84%], P<.001, aHR 2.61 [95%CI 1.89–3.60]) but not in patients who did not receive chemotherapy (P=.38, HR 1.31 [95%CI 0.71–2.42]). Similar results were observed regardless of WHO grade and after single- or multiagent chemotherapy.

Conclusions:

Our study demonstrates an association between mMGMT and OS in 1p/19q-codeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

Introduction

1p/19q-codeleted oligodendrogliomas are relatively less common primary brain tumors with a favorable prognosis compared to IDH-wildtype and IDH-mutant gliomas with 1p/19q-intact (1,2). Standard treatment generally includes maximal safe resection and radiotherapy (3,4), with adjuvant alkylating chemotherapy as the backbone of systemic treatment (5–10). Given favorable long-term outcomes, there is interest in strategies to de-escalate therapy regimens, either with substitution of procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) or omission of radiotherapy, both of which are currently being evaluated in phase III randomized clinical trials (RCTs) (11,12). Level 1 evidence supports adjuvant radiotherapy and PCV for high-risk or anaplastic 1p/19q-codeleted oligodendrogliomas (5–7,12). However, in practice, selection of therapy is highly variable and may be provider- or institution-dependent (11,13–15). There are currently no validated biomarkers that predict response to alkylating chemotherapy or guide more personalized management for these tumors.

MGMT (O⁶-methylguanine-DNA methyltransferase) is a DNA-repair protein that removes alkyl groups from the O⁶ position of guanine, an important site of DNA alkylation (16). Epigenetic silencing of MGMT through promoter methylation is an important biomarker that predicts response to TMZ in glioblastoma (9). Multiple phase III trials have demonstrated that MGMT methylation can be used to consider de-escalation of therapy for elderly patients with glioblastoma or those with poor performance status (16–18). However, the role of MGMT status remains unresolved in grade 2 and 3 gliomas due to molecular heterogeneity and the lack of sufficiently large datasets for this analysis (19–21). The World Health Organization (WHO) now classifies grade 2 and 3 gliomas based on molecular features, rather than tumor morphology alone (22). 1p/19q chromosomal codeletion in the presence of the isocitrate dehydrogenase (IDH) mutation is the defining characteristic of molecular oligodendrogliomas and is present in approximately 70%, 4%, and 2% of histological oligodendrogliomas, astrocytomas, and glioblastomas, respectively (23). Analyses of historical clinical trials that recruited patients based on histological features represent mixed populations of patients by current standards. Prior studies did not determine the effect of MGMT promoter methylation in the context of molecular classifications and, therefore, reported mixed results (21). The IDH mutation leads to accumulation of 2-hydroxyglutarate, an oncometabolite that results in CpG island hypermethylation, including MGMT promoter region sites (24). The MGMT promoter is more frequently methylated in IDH-mutant (1p/19q-codeleted or -intact) vs. IDH-wildtype tumors (5,7,8,21,25,26). Previous studies generally have not resolved the predictive value of MGMT promoter methylation in IDH-mutant tumors independently of 1p/19q-codeletion status (5,7,8,10,27–29).

We recently found that MGMT status is predictive of response to alkylating chemotherapy in IDH-mutant and 1p/19q-codeleted but not IDH-mutant and 1p/19q-intact gliomas (21). While the effect of MGMT methylation on progression-free survival (PFS) was impressive, we did not find a statistically significant effect on overall survival (OS), likely due to the low number of deaths observed. However, the lack of survival benefit could also be explained by effective salvage therapies or acquired resistance through TMZ-induced hypermutation. TMZ-induced hypermutation occurs more commonly in methylated gliomas and is associated with worse outcomes after progression (30–34). We queried the nation’s largest cancer database to determine the association of MGMT methylation and OS in these tumors.

Methods

Data Source

The National Cancer Database (NCDB) is a retrospective nationwide dataset sponsored by the American College of Surgeons and the American Cancer Society, constituting 70% of incident invasive cancer cases in the United States. Data were collected at over 1500 Commission on Cancer (CoC)–accredited hospitals between 2004 and 2022 (35).

Data Extraction and Patient Selection

We queried the NCDB (2022 submission) to identify all cases of diffuse/anaplastic gliomas, including oligodendroglioma, (International Classification of Diseases (ICD)-O-3 code 9450), anaplastic oligodendroglioma (9451, 9460), diffuse astrocytoma (9400), anaplastic astrocytoma (9401), mixed oligoastrocytic (9382), or glioma, not otherwise specified (9380) within the brain (ICD-O-3 codes C70.0, C71.0–71.9) newly diagnosed between January 1, 2010 and December 31 2019 (3). Data were submitted from COC-accredited cancer programs with follow-up through December 31, 2022. The following variables were collected and coded: age at diagnosis, sex, race, Charlson–Deyo Comorbidity Index, primary site, ICD-O-3 histology, collaborative staging (CS) site-specific factor 1 (WHO grade), CS site-specific factor 2 (MGMT promoter status), CS site-specific factor 5 (1p chromosomal deletion status), CS site-specific factor 6 (19q chromosomal deletion status), surgery at the primary site, chemotherapy, and radiation therapy. Additional brain-specific variables were collected and coded for patients diagnosed from 2018 to 2019: brain molecular markers (including IDH and 1p/19q-codeletion status), loss of heterozygosity of chromosome 1p and chromosome 19q, and methylation of O6-methylguanine-methyltransferase. Patients were included if they tested positive for both chromosome 1p and 19q loss of heterozygosity and positive or negative for MGMT gene promoter methylation. Patients diagnosed from 2018 to 2019 were additionally required to test positive for both IDH-mutation and 1p and 19q loss of heterozygosity. Patients were excluded if they had incomplete or less than one month of follow-up or unknown grade, extent of resection, receipt of chemotherapy, or receipt of radiotherapy.

Variable Selection and Coding

Age, sex, race, Charlson–Deyo Comorbidity Index, WHO grade, extent of resection, chemotherapy, radiotherapy, and MGMT promoter methylation status were included as covariables. The method of molecular marker testing is not specified in national cancer registries. The Charlson-Deyo Comorbidity Index is mapped from ICD-9-CM or ICD-10 secondary diagnosis codes and was categorized as 0, 1, and 2 or greater (36). WHO grade was coded as 2 or 3, consistent with WHO 2021 guidelines for IDH-mutant, 1p/19q-codeleted oligodendrogliomas (22). Extent of resection was based on definitions in the American College of Surgeons Commission on Cancer’s Facility Oncology Registry Data System (FORDS) manual and coded as previously described (3,4,37–41). All cancer-directed treatments submitted by CoC-accredited cancer registries, including surgical resection, chemotherapy, and radiotherapy are recorded only if they are administered as a first course of treatment to destroy, modify, control, or remove cancer tissue.

Primary Outcomes and Exploratory Analyses

The primary outcome was OS in patients who received chemotherapy. Exploratory analyses included OS in all patients, regardless of treatment, and in patients who did not receive chemotherapy (Figure 1). Subgroup analyses stratified patients by WHO grade and use of single- vs. multiagent chemotherapy. A prior study validated that single- and multiagent regimens in patients with 1p/19q-codeleted tumors submitted to the NCDB from three academic medical centers represented TMZ and PCV, respectively, in 100% of cases (15).

Figure 1-.

Schema for Patient Selection and Analyses

Statistical Analysis

All statistical analyses were conducted using the RStudio software Version 1.4.1106 (RStudio, Inc., Boston, Massachusetts). For our primary analysis, we measured the association between MGMT promoter status and OS in patients who received chemotherapy, adjusted for covariables. Descriptive statistics were generated and stratified by MGMT promoter status. Associations between MGMT promoter status and other clinical variables were determined using the Pearson’s chi-square test and the Wilcoxon rank-sum test. Kaplan-Meier estimates were obtained for OS and compared using the log-rank test. Univariable and multivariable Cox proportional hazards regressions were conducted. Variables that were statistically significant on univariable analysis were included in the multivariable model. Schoenfeld’s test of weighted residuals was utilized to assess proportional hazard assumptions in the primary analysis. If the proportional hazards assumptions for a variable were violated, the variable was removed and used as a stratification factor in the Cox models. Exploratory analyses were not corrected for multiple hypothesis testing. All analyses were performed at the .05 significance level based on two-sided statistical testing. This report follows the STROBE and REMARK reporting guidelines for observational and biomarker studies, respectively.

Data Sharing

Raw data for the National Cancer Database Participant User Data File can be accessed by request to the American College of Surgeons (https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/puf/ ). The code used to generate the datasets that were analyzed are available upon request to the corresponding author. The generated datasets cannot be shared, as stated in the NCDB Participant User File Data Use Agreement.

Results

Demographic and Clinical Characteristics

Of 5,247 patients with 1p/19q-codeleted gliomas, we identified 1,398 (26.6%) cases with known MGMT promoter methylation status (Figure 1). After excluding patients with unknown WHO grade, extent of resection, chemotherapy, and radiotherapy (N=101, 7.2%), there were 1,297 patients included in the analysis. Clinical and demographic characteristics are displayed in Table 1. Nine-hundred and thirty-eight (72.3%) patients received chemotherapy as first-line treatment. Among patients who received chemotherapy, 783 (83.5%) received single-agent regimens and 134 (14.3%) received multiagent regimens. The MGMT promoter was methylated in 1,009 (77.8%) patients. MGMT promoter methylation was associated with older age (median 47 vs. 42, P<.001). Median follow-up time was 38 months (IQR 25–58) with 220 deaths (16.9%).

Table 1-.

Patient Demographic and Clinical Characteristics

Characteristic	Methylated, N = 1,0091	Unmethylated, N = 2881	p-value2
Age	47 (37, 57)	42 (31, 55)	<.001
Sex			.94
Male	551 (55%)	158 (55%)
Female	458 (45%)	130 (45%)
Race			.21
Asian/Pacific Islander	31 (3.1%)	12 (4.2%)
Black	30 (3.0%)	15 (5.2%)
Other/Unknown	41 (4.1%)	13 (4.5%)
White	907 (90%)	248 (86%)
Charlson-Deyo Comorbidity Index			.49
0	829 (82%)	230 (80%)
1	114 (11%)	40 (14%)
2 or more	66 (6.5%)	18 (6.2%)
Grade			.08
2	541 (54%)	171 (59%)
3	468 (46%)	117 (41%)
Extent of Resection			.77
Gross-total resection	444 (44%)	124 (43%)
No surgery/subtotal	565 (56%)	164 (57%)
Chemotherapy			.03
Yes	744 (74%)	194 (67%)
No	265 (26%)	94 (33%)
Radiotherapy			.10
Yes	670 (66%)	176 (61%)
No	339 (34%)	112 (39%)

¹n (%); Median (Interquartile Range)

²Pearson’s Chi-square test; Wilcoxon rank sum test

Survival Analysis

Median survival time for all patients was not reached. Among all patients, the 5-year overall survival rates were 70% (95% confidence interval [95%CI] 64–77%) and 81% (95%CI 78–85%) for unmethylated [uMGMT] and methylated [mMGMT] tumors, respectively (P<.001, Figure 2A). uMGMT remained an independent predictor of survival after adjusting for other covariables (HR 2.35 [95%CI 1.77–3.14], P<.001, Supplemental Table 1).

Figure 2-.

Kaplan-Meier curves for overall survival based on MGMT promoter status, stratified by treatment subgroup.

In patients who received chemotherapy, uMGMT was associated with worse survival (5-year survival 63% [95%CI 55–73%] vs. 80% [95%CI 76–84%], P<.001, adjusted HR 2.61 [95%CI 1.89–3.60], Figure 2B, Table 2). MGMT promoter methylation was not prognostic in patients who did not receive chemotherapy (5-year survival 82% [95%CI 74–92%] vs. 86% [95%CI 81–92%] for uMGMT vs. mMGMT, respectively, P=.38, HR 1.31 [95%CI 0.71–2.42], Figure 2C, Supplemental Table 2).

Table 2-.

Univariable and Multivariable Analysis of Overall Survival in Patients who Received Chemotherapy

	Univariable			Multivariable
Characteristic (Reference)	HR1	95% CI1	p-value	HR1	95% CI1	p-value
Age	1.06	1.04, 1.07	<.001	1.05	1.04, 1.06	<.001
Sex (Male)
Female	1.11	0.82, 1.49	.49	—	—	—
Race (White)
Black	0.98	0.40, 2.40	.97	—	—	—
Other/Unknown	0.99	0.44, 2.23	.97	—	—	—
Asian/Pacific Islander	0.56	0.18, 1.75	.32	—	—	—
Charlson-Deyo Comorbidity Index (0)
1	2.01	1.35, 3.00	<.001	1.83	1.22, 2.74	.004
2 or more	3.11	1.99, 4.86	<.001	2.72	1.71, 4.31	<.001
Grade (2)
3	3.01	2.09, 4.35	<.001	3.28	2.25, 4.79	<.001
Extent of Resection (No surgery/Subtotal)
Gross-total resection	0.66	0.48, 0.91	.01	0.63	0.46, 0.88	.006
Radiation (No)
Yes	1.72	1.08, 2.72	.02	1.31	0.82, 2.08	.26
MGMT (Methylated)
Unmethylated	2.07	1.51, 2.85	<.001	2.61	1.89, 3.60	<.001

¹HR = Hazard Ratio, CI = Confidence Interval

Bold is statistically significant.

Subgroup analyses in patients who received chemotherapy were stratified by chemotherapy regimen and WHO grade (Figure 3, 4). The effect-sizes were similar across subgroups. MGMT promoter methylation was prognostic in patients who received single-agent (log-rank P<.001) and multiagent (P=.006) chemotherapy regimens and with grade 2 (P=.02) and 3 tumors (P<.001). A similar effect was observed for patients with high-risk low-grade gliomas, defined per RTOG 9802 as patients with grade 2 tumors and less than gross-total resection (P=.02, Figure 3D, 4) (6,10). Most patients who received chemotherapy also received radiotherapy as part of their first course of treatment (N=801, 85.4%). In patients who received both chemotherapy and radiotherapy, uMGMT was associated with worse survival (5-year survival 59% [95%CI 49–71%] vs. 79% [95%CI 75–83], adjusted HR 2.72 [95%CI 1.93–3.84], P<.001, Supplemental Figure 1). No effect was observed in patients who received chemotherapy alone (P=.64).

Figure 3-.

Kaplan-Meier curves for overall survival based on MGMT promoter status, stratified by chemotherapy regimen (A-B) and WHO grade (C-D). High-risk is defined per RTOG 9802 as grade 2 with less than gross-total resection.

Figure 4-.

Forest plot for overall survival based on MGMT promoter status, stratified WHO grade and chemotherapy regimen. High-risk is defined per RTOG 9802 as grade 2 with less than gross-total resection. Hazard ratios that were adjusted from multivariable analyses.

Sensitivity Analyses

We tested the proportional hazards assumption with the Schoenfeld method for our primary analysis of OS in patients who received chemotherapy. While the univariable test indicated a violation of the proportional hazards assumption for MGMT status (P=.04, Supplemental Figure 2), the residual plot was inconsistent with a specific time-period interaction. As sensitivity analyses, we analyzed patients diagnosed through 2017 (median follow-up 55 months) and patients with longer than 1 year of follow-up and found similar results with no violations of the proportional hazards assumption (Supplemental Figure 3). The proportional hazards assumption in the multivariable model remained unviolated (Supplemental Table 3). Additionally, the univariable tests indicated a violation for age, grade, and Charlson-Deyo Comorbidity Index (Supplemental Figure 5). Similar results were observed after stratifying our analyses by these factors (Figure 3, Supplemental Figure 4).

IDH mutation status was not available in national cancer registries before 2018. Although virtually all tumors with 1p/19q codeletion are mutated for IDH1 or IDH2, false positives for 1p/19q codeletion may occur (42). Because false-positive 1p/19q-codeletions are rare in properly worked-up samples (ie. patients with oligodendroglial histology or retained ATRX expression) (43), we performed a sensitivity analysis that only included patients with oligodendroglial histology (ICD-O-3 codes 9450, 9451, 9460, and 9382). Among patients with oligodendroglial tumors that received chemotherapy (N=852, 90.8%), uMGMT was associated with worse survival (adjusted HR=2.63 [95%CI 1.78–3.92], P<.001, Supplemental Figure 5A). Both 1p/19q status and IDH status were available for patients diagnosed from 2018–2019. In the 418 patients diagnosed from 2018–2019 with IDH-mutant and 1p/19q-codeleted tumors, uMGMT was associated with worse survival (adjusted HR=3.00 [95%CI 1.43–6.31], P=.004, Supplemental Figure 5B).

Discussion

In the current study, we found that MGMT promoter methylation is predictive of OS in patients with 1p/19q-codeleted tumors who receive chemotherapy. Similar results were observed in subgroups of patients who were treated with single- and multiagent chemotherapy and with WHO grade 2 and 3 tumors. The effect was strongest in patients who received multimodality therapy with chemotherapy and radiotherapy. MGMT status was not associated with outcomes in patients who did not receive chemotherapy. This is the largest study to evaluate the predictive value of MGMT status in 1p/19q-codeleted oligodendrogliomas and the first to identify an overall survival benefit. Based on our findings, we suggest that MGMT status be used as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

There are currently three major RCTs evaluating treatment de-escalation for patients with 1p/19q-codeleted oligodendrogliomas, with alkylating chemotherapy being a component of every arm (Supplemental Figure 6). CODEL (NCT00887146) is an international phase III RCT, jointly sponsored by the European Organization for Research and Treatment of Cancer (EORTC), North Central Cancer Treatment Group (NCCTG)/Alliance for Clinical Trials in Oncology, and Canadian Cancer Trials Group (CCTG). The initial design compared radiotherapy alone, radiotherapy with TMZ, or TMZ alone and was terminated after the RTOG 9402 and EORTC 26951 trials demonstrated improved OS with the addition of PCV to radiotherapy in patients with anaplastic oligodendrogliomas (44). The current iteration is randomizing patients with grade 2 or 3 1p/19q-codeleted gliomas to radiotherapy plus TMZ versus radiotherapy with PCV, with PFS as the primary endpoint and OS as a secondary endpoint.

The French POLCA (NCT02444000) trial seeks to determine if radiotherapy can be deferred until the time of progression and randomizes patients with anaplastic 1p/19q-codeleted gliomas to PCV alone versus radiotherapy followed by PCV. The primary endpoint is survival without neurocognitive deterioration, with PFS and OS being secondary endpoints. Similarly, the German IMPROVE CODEL (NOA-18, NCT05331521) trial seeks to improve “qualified overall survival”, defined as OS without functional, cognitive, or quality of life deterioration (45). This phase III trial will randomize patients with grade 2 or 3 1p/19q-codeleted gliomas to TMZ and lomustine (CETEG) versus radiotherapy and PCV, testing if chemoradiotherapy can be deferred until progression.

MGMT status will be collected and analyzed in the CODEL and IMPROVE CODEL trials but is not included as a stratification factor. Correlation between exploratory biomarkers (ie. MGMT status) and survival is a prespecified secondary goal of the CODEL trial. In the IMPROVE CODEL trial, MGMT status will be included in a multivariable Cox proportional hazards model. The POLCA trial does not prespecify prospective analysis of MGMT methylation as a study goal, however, conclusions from our study suggest that MGMT promoter status may be evaluated in a post-hoc manner when available. Overall, our results suggest that MGMT status may affect patients with 1p/19q-codeleted tumors that receive alkylating chemotherapy (regardless of grade and chemotherapy regimen) and is thus relevant in every arm of these three major ongoing RCTs.

Level 1 evidence supports the use of radiotherapy plus PCV in high-risk low grade or anaplastic 1p/19q-codeleted oligodendrogliomas based on the RTOG 9802, RTOG 9402, and EORTC 26951 studies (5–7,12). PCV monotherapy, TMZ monotherapy, and radiotherapy with TMZ have been investigated in the EORTC 22033, NOA-04, RTOG 0424, and CODEL (initial design) trials (7,8,29,44); however, none of these regimens have demonstrated superiority compared with radiotherapy alone. Despite there being less data to support the use of TMZ in 1p/19q-codeleted oligodendrogliomas and some evidence suggesting it may be inferior (8,15,46), this regimen is often favored by neuro-oncologists, given its favorable hematological toxicity profile (11). Providers at academic centers more often treat with TMZ than PCV (13,14). This is reflected in national data as well, which suggest that TMZ is given to approximately 89% of patients with grade 3 1p/19q-codeleted oligodendrogliomas (15). Furthermore, while the National Comprehensive Cancer Network (NCCN) Guidelines recommend radiotherapy unless the patient has a low-risk tumor or poor performance status (47), radiotherapy is reportedly administered in less than half of patients nationally (3,4). The POLCA, CODEL, and IMPROVE CODEL trials are expected to complete in 2024, 2025, and 2029, respectively. Therefore, results will not be reported for many years and OS data will likely take much longer to mature (48). In the meantime, incorporating MGMT status into decision strategies may aid in selecting appropriate therapies for patients.

Advantages of our study include the analysis of a large national cohort that may be generalizable to the US population. The large sample size decreases the likelihood of a type II error when studying this relatively uncommon tumor. Disadvantages include retrospective analysis and lack of central histological and molecular review. There are risks of biases that cannot be accounted for. For oligodendrogliomas, the follow-up time was relatively short, as median survival time was not reached. IDH status was not available in tumor registries before 2018. To address this, we performed sensitivity analyses limited to tumors with oligodendroglial histology, in which false positives are expected to be exceedingly rare (42,43), and in patients diagnosed after 2018 with information on both IDH-mutation and 1p/19q-codeletion status. 1p/19q and MGMT status are not uniformly reported in national cancer registries and nationwide disparities in molecular marker testing have been described (49,50). Given that MGMT testing is not routinely performed for oligodendrogliomas, it is expected that a large percentage of cases had missing values. Patients with missing data may be systematically different than those included in the analysis, which may potentially limit the generalizability of our findings. However, it is reassuring that the frequency of mMGMT (77.8%) in the current study closely matches that of our previously reported prospective cohort (74%) (21). Overall, our study highlights an opportunity to increase MGMT testing nationwide for oligodendroglial tumors. However, widespread adoption will likely not be realized until further guidance is given from authoritative sources, such as the WHO or the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW).

Conclusion

We found that MGMT status is predictive of OS in patients with 1p/19q-codeleted gliomas who receive chemotherapy. Our results appear to be generalizable to patients who receive single- or multiagent chemotherapy and with grade 2 or 3 tumors. We therefore suggest that MGMT status be considered as a stratification factor in future clinical trials that evaluate alkylating chemotherapy in 1p/19q-codeleted gliomas. These findings are particularly salient in the context of the ongoing CODEL, POLCA, and IMPROVE CODEL trials and in a disease where daily practice often diverges from evidence-based standard-of-care.

Translational Relevance.

MGMT promoter methylation (mMGMT) predicts response to alkylating chemotherapy and routinely guides treatment decisions in glioblastoma. However, its role in grade 2 and 3 glioma remains unclear due to molecular heterogeneity among these tumors. Recent data suggest that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated. In this large cohort study of 1,297 patients with 1p/19q-codeleted oligodendrogliomas, we found that mMGMT is associated with OS, only in patients who receive chemotherapy, suggesting that mMGMT is a biomarker for chemotherapy response. These findings affect interpretation of three major ongoing randomized clinical trials, which evaluate de-escalation of therapy for patients with 1p/19q-codeleted oligodendrogliomas using various alkylating regimens. We suggest that MGMT promoter status be considered as a stratification factor in future clinical trials of patients with 1p/19q-codeleted gliomas that use OS as an endpoint.