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. 2023 Jul 1;9(7):919-927.
doi: 10.1001/jamaoncol.2023.0990.

Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy

Connor J Kinslow  1   2 , Ann Mercurio  1 , Prashanth Kumar  1 , Ali I Rae  3 , Markus D Siegelin  2   4   5 , Jack Grinband  6   7 , Kekoa Taparra  8 , Pavan S Upadhyayula  2   9 , Guy M McKhann  2   9 , Michael B Sisti  2   9 , Jeffrey N Bruce  2   9 , Peter D Canoll  2   4   5 , Fabio M Iwamoto  2   9 , Lisa A Kachnic  1   2 , James B Yu  1   2 , Simon K Cheng  1   2 , Tony J C Wang  1   2
Affiliations

Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy

Connor J Kinslow et al. JAMA Oncol. .

Erratum in

  • Errors in Figure 3.
    [No authors listed] [No authors listed] JAMA Oncol. 2023 Jul 1;9(7):1009. doi: 10.1001/jamaoncol.2023.2581. JAMA Oncol. 2023. PMID: 37470838 Free PMC article. No abstract available.

Abstract

Importance: O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.

Objective: To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.

Design, setting, and participants: This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.

Exposure: MGMT promoter methylation status.

Main outcomes and measures: Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.

Results: A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.

Conclusions and relevance: This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McKhann reported receiving personal fees from Koh Young Inc and NeuroOne Medical Technologies; and grants from the National Institutes of Health, outside the submitted work. Dr Iwamoto reported receiving personal fees from Mimivax, Praesidia Biotherapeutics, Roche, Novocure, Guidepoint, Sapience, XCures, Abbvie, Alexion, Gennao Bio, Medtronic, Regeneron, and Tocagen; and grants from Glioblastoma Foundation, Rhodes Brain Tumor Center, and Ivy Foundation, outside the submitted work. Dr Kachnic reported receiving grants from Varian Inc; personal fees from New Beta Innovation Limited; serving as editor of the Bones Metastasis chapter for, holding licenses from, and receiving royalties from UpToDate; and receiving nonfinancial support from Radiation Therapy Oncology Group Foundation outside the submitted work. Dr Yu reported receiving personal fees from Boston Scientific, Myovant, and Reflexion Medical; and grants from Pfizer, outside the submitted work. Dr Wang report receiving personal fees and nonfinancial support from AbbVie, Elekta, Merck, Novocure, and the RTOG Foundation; personal fees from Cancer Panels, Doximity, Rutgers, University of Iowa, Wolters Kluwer, and Iylon Precision Oncology; and grants and nonfinancial support from Genentech and Varian, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Schema for Patient Selection and Analyses
CUIMC indicates Columbia University Irving Medical Center; and EORTC, European Organization of Research and Treatment of Cancer.
Figure 2.
Figure 2.. Kaplan-Meier Curves for Progression-Free Survival Based on MGMT Promoter Methylation Status
A, Patients who received chemotherapy. B, Patients with IDH–wild type tumors. C, Patients with IDH–mutant and non-codeleted tumors. D, Patients with IDH–mutant and codeleted tumors.
Figure 3.
Figure 3.. Kaplan-Meier Curves for Overall Survival Based on MGMT Promoter Methylation Status
A, Patients who received chemotherapy. B, Patients with IDH–wild-type tumors. C, Patients with IDH–mutant and non-codeleted tumors. D, Patients with IDH–mutant and codeleted tumors.
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