The present study is the largest to date examining the prognostic and predictive status of MGMT for patients with high risk LGG. These results suggest that MGMT is a prognostic biomarker, as amongst all patients with high risk LGG, there was a statistically significant improved OS amongst all patients with mMGMT when compared to those with uMGMT. These results also demonstrate that MGMT can be a predictive biomarker, as improved OS was limited to patients treated with treated with adjuvant chemoradiation or adjuvant radiation, but not to patients receiving adjuvant chemotherapy or no adjuvant treatment. Additionally, mMGMT was associated with improved OS amongst patients receiving a gross total resection, but not those receiving subtotal resection or only.
The current findings are in concordance with a review of patients enrolled in RTOG 0424 [4]. In this study, which was a single arm Phase II trial evaluated the efficacy of radiation and Temozolomide chemotherapy in patients with high risk LGG, 75 patients had MGMT status available. Patients with mMGMT were found to have improved OS [18], leading the authors to conclude that MGMT was an independent prognostic biomarker for patients with LGG treated with radiation therapy and temozolomide. The present data also suggests that MGMT mehtylation can be a prognostic biomarker, as patients with mMGMT were found to have improved OS compared to patients with uMGMT amongst all patients irrespective of treatment [20]. However, MGMT may also serve as a predictive biomarker, as there was no observed difference between patients with mMGMT and those with uMGMT amongst patients receiving adjuvant chemotherapy only, or amongst patients receiving no adjuvant treatment.
The stratification of patients with LGG into high risk disease status is currently made on the basis clinical factors such as age, extent of resection, and size of tumor [6]. This is different than in patients with higher grade gliomas, in which biomarkers can be used to guide treatment. MGMT has been shown to be a predictive biomarker for patients with Glioblastoma, particularly with response to Temozolomide chemotherapy [21], and consequently Temozolomide alone is an option for elderly patients with mMGMT Glioblastoma. MGMT promoter methylation has also been shown to be predictive for patients with Grade 3 Glioma, as event free survival (EFS) was shown in one trial to be greater with Temozolomide than radiation therapy amongst mMGMT patients, while the opposite was true in patients with uMGMT [22]. The results from this study similar show the predictive significant of MGMT promoter methylation in the high risk LGG population, as patients with mMGMT were found to have greater OS following chemoradiation or radiation but not following chemotherapy alone. This may suggest that patients with uMGMT can be used to select for high risk LGG patients who may have a worse response to the recommended chemoradiation, and may need treatment intensification in order to improve outcomes. Future trials may also be considered comparing the use of Temozomide chemotherapy alone to radiation therapy amongst patients with mMGMT to determine if this treatment can achieve medical equipoise as has been seen in patients with Grade 3 Glioma or elderly patients with Glioblastoma.
The reasons why mMGMT only was predictive for outcome for patients receiving adjuvant radiation or chemoradiation but not patients receiving adjuvant chemotherapy are unclear. This may be caused by the small number of patients in the present analysis receiving chemotherapy alone, that did not allow for enough statistical power to reveal a difference in outcome. Another possible explanation for this observation may be that the mechanism of treatment resistance by MGMT may be different in LGG when compared to HGG or Glioblastoma, just as it has previously been suggested that the mechanism of MGMT related treatment resistance in different in HGG when compared to Glioblastoma [16]. An additional reason may be due to the inability of MGMT methylation status to serve as a predictive biomarker in patients receiving non- Temozolomide chemotherapy.
This study was retrospective and conducted with hospital based data and as such is subject to certain limitations. First, there are variations of the definition of gross total resection or subtotal resection, limited information concerning chemotherapy agents, and a lack of information regarding progression free survival. Additionally, as a retrospective study, there is possible selection bias and imbalance between the cohorts. Third, there is also potential miscoding or under coding of the factor that codes for a record of MGMT, and that the true count of patients tested for MGMT may be higher than the value reported in this study. Fourth, there were a limited number of patients receiving no adjuvant treatment or receiving adjuvant chemotherapy, limiting the ability of this study to make strong conclusions regarding the predictive value of MGMT methylation. Finally, the reasons for a particular treatment, such as adjuvant radiation or adjuvant radiation along with chemotherapy, and are possible to be ascertained.
The results of this study suggest that MGMT promoter methylation in patients with low grade (grade 2) glioma is associated with improved OS compared to non-methylated patients. Furthermore, the improved OS with MGMT promoter methylation may be limited to patients who receive either adjuvant radiation or adjuvant chemoradiation, but not those receiving adjuvant chemotherapy alone. Further studies are recommended to confirm the impact of MGMT methylation amongst patients with LGG, though this study suggests that MGMT promoter methylation does have prognostic value amongst patients with high grade LGG.