Data from a cohort study suggest MGMT promoter methylation could serve as a stratification factor for patients with low-grade and anaplastic gliomas harboring IDH–wild-type or IDH-mutant and co-deleted tumors.
O6-methylguanine-DNA methyltransferase promoter methylation (mMGMT) correlated with prolonged survival among patients with low-grade and anaplastic gliomas treated with alkylating chemotherapy, according to findings from a cohort study published in JAMA Oncology.
Patients with mMGMT promoter expression experienced a median progression-free survival (PFS) of 68 months (95% CI, 54-132) vs 30 months (95% CI, 15-54) among those with tumors with an unmethylated promoter (P <.001). The median overall survival (OS) was higher among those whose tumors had mMGMT vs unmethylated MGMT promoter (uMGMT) at 137 months (95% CI, 104-not reached) vs 61 months (95% CI, 47-97; P <.001), respectively.
MGMT promoter status remained associated with both PFS (Hazard ratio [HR], 1.95; 95% CI, 1.39-2.75; P <.001) and OS (HR, 1.65; 95% CI, 1.11-2.46; P = .01) after adjustment for age, sex, molecular class, grade, and receipt of radiotherapy.
MGMT status also correlated with chemotherapy response in IDH wild-type gliomas with regard to both PFS (HR, 2.15; 95% CI, 1.26-3.66; P = .005) and OS (HR, 1.69; 95% CI, 0.98-2.91; P = .06) after adjusting for clinical factors. The same was true in IDH-mutant/codeleted gliomas with regards to PFS (HR, 2.99; 95% CI, 1.44-6.21; P = .003) and OS (HR, 4.21; 95% CI, 1.25-14.2; P = .02). These associations were not found in IDH-mutant/non-codeleted gliomas.
“To our knowledge, this is the first study to report an independent association of [mMGMT] with response to treatment for low-grade and anaplastic gliomas after accounting for both IDH and 1p/19q codeletion status, and it is the only study to report the association of [mMGMT] with response to treatment in 1p/19q-codeleted tumors,” the investigators wrote.
Analysis occurred between April 2022 and January 2023 based on data from 3 prospective trials. The study cohort included 411 patients with primary grade 2 or 3 glioma with known MGMT promoter status, IDH and 1p/19q codeletion status, and tumor grade from these trials.
The population had a mean age of 44.1 years and most (58%) were men. Most patients (70%) received chemotherapy as their frontline treatment prior to progression, of whom 79% received temozolomide (Temodar)-based regimens and 21% received procarbazine (Matulane), lomustine (Gleostine), and vincristine.
mMGMT expression occurred in 42% of IDH wild-type gliomas (n = 135), 53% of IDH-mutant/non-codeleted gliomas (n = 149), and 74% of IDH-mutant/codeleted gliomas (n = 127; P <.001). Median follow-up was 40 months (interquartile range, 16-84).
The primary analysis examined the association between MGMT promoter status and survival among patients who received chemotherapy. Exploratory analyses examined survival across all patients regardless of treatment, and among those who did not receive chemotherapy.
Among all 411 patients, the association between methylation and PFS was significant but attenuated regardless of treatment (adjusted HR, 1.36; 95% CI, 1.04-1.79; P = .03). The association between methylation and OS, meanwhile, was not significant (adjusted HR, 1.17; 95% CI, 0.86-1.60; P = .31).
Methylation status and treatment with chemotherapy demonstrated no significant interaction in the overall cohort.
According to the investigators, potential limitations to the study included the non-standardized definitions of progression across the 3 assessed trials, and the heterogeneity of treatment and follow-up allowing for unmeasured cofounding variables to affect the results.
“MGMT status may be considered a stratification factor in future clinical trials evaluating the effectiveness of alkylating chemotherapy,” the investigators concluded. “This may be particularly relevant for IDH wild-type and IDH-mutant and codeleted tumors, in which the role of temozolomide and/or procarbazine, lomustine, and vincristine in standard-of-care treatment remains obscure and an area of active investigation.”
Kinslow CJ, Mercurio A, Kumar P, et al. Association of MGMT promotor methylation with survival in low-grade and anaplastic gliomas after alkylating chemotherapy. JAMA Oncol. Published online May 18, 2023. doi:10.1001/jamaoncol.2023.0990