Prognostic and Predictive Impact of MGMT Promoter Methylation Status in High Risk Grade 2 Glioma

BackgroundMGMT promoter methylation has been associated with favorable prognosis and survival outcomes in patients with glioblastoma and grade 3 glioma. However, the effects of promoter methylation of MGMT in patients with grade 2 gliomas have not been established. The purpose of the current study is to evaluate the prognostic impact and predictive values of MGMT methylation in patients with grade 2 glioma.MethodsThe National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade 2 glioma. Demographics and clinical characteristics of these patients were examined. Statistics included Kaplan-Meier overall survival (OS) analysis alongside Cox proportional hazards modeling.ResultsA total of 11,223 patients met the selection criteria; 1,252 patients (11%) had MGMT testing. Of the patients who had MGMT testing, 58.5% were MGMT methylated (mMGMT), and 43.5% were MGMT unmethylated (uMGMT). mMGMT patients had greater median overall survival (77.3 months) than both uMGMT patients (42.6 months) and patients with no MGMT status reported (61.9 months (p<0.001 for both). mMGMT was also associated with improved OS, when compared to patients with uMGMT, for patients receiving adjuvant chemoradiation or adjuvant radiation therapy.ConclusionsThis is the largest study to date demonstrating both the prognostic and predictive impact of MGMT methylation on patients with grade II glioma. The current results show that mMGMT is a prognostic factor and possibly a predictive biomarker for grade II glioma patients. MGMT methylation status can be used to determine and stratify patients by risk levels, and thus select patients for treatment intensification.

BIOM-21. THE SIGNIFICANCE OF TERT PROMOTER MUTATIONS, TELOMERE LENGTH AND MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA (GBM): A LARGE MONO-INSTITUTIONAL STUDY

BACKGROUND the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes. METHODS TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, OS. Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio. RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMTmet tumors showed significant improved PFS and OS with a HR of 0.54(95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT-status, TERT-mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant. CONCLUSIONS we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT

NIMG-73. CAPTURING GLIOBLASTOMA HETEROGENEITY USING IMAGING AND DEEP LEARNING: APPLICATION TO MGMT PROMOTER METHYLATION

PURPOSE Intratumor heterogeneity is frequent in glioblastoma (GB), giving rise to the tumor’s resistance to standard therapies and, ultimately, poorer clinical outcomes. Yet heterogeneity is often not quantified when assessing the genomic or methylomic profile of a tumor, when a single tissue sample is analyzed. This study proposes a novel approach to non-invasively characterize heterogeneity across glioblastoma using deep learning analysis MRI scans, using MGMT promoter methylation (MGMTpm) as a test-case, and validates the imaging-derived heterogeneity maps with MGMTpm heterogeneity measured via multiple tissue samples. METHODS Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR) of 181 patients with newly diagnosed glioblastoma, who underwent surgical tumor resection and had MGMT methylation assessment results, were retrospectively collected. We trained a 5-fold cross-validated deep convolutional neural network with six convolutional layers for a discovery cohort of 137 patients by placing overlapping regional patches over the whole tumor on mpMRI scans to capture spatial heterogeneity of MGMTpm status in different regions within the tumor. Our approach effectively hypothesized that despite heterogeneity in the training examples, dominant imaging patterns would be captured by deep learning. Trained model was independently applied to an unseen replication cohort of 44 patients, with multiple tissue specimens chosen from different spatial regions within the tumor, allowing us to compare imaging- and tissue-based MGMTpm estimates. RESULTS Our model yielded AUC of 0.75 (95% CI: 0.65–0.79) for global MGMT status prediction, which reflected the heterogeneity in MGMTpm, but also that a dominant imaging pattern of MGMT methylation seemed to emerge. In methylated patients with multiple tissue samples, a significant Pearson's correlation coefficient of 0.64 (p&lt; 0.05) was found between imaging-based heterogeneity maps and MGMTpm heterogeneity. CONCLUSION A novel method based on mpMRI and deep neural networks yielded imaging-based heterogeneity maps that strongly associated with intratumor molecular heterogeneity in MGMT promoter methylated tumors.

Stereotactic radiosurgery for glioblastoma considering tumor genetic profiles: an international multicenter study

OBJECTIVE Molecular profiles, such as isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) methylation status, have important prognostic roles for glioblastoma patients. The authors studied the efficacy and safety of stereotactic radiosurgery (SRS) for glioblastoma patients with consideration of molecular tumor profiles. METHODS For this retrospective observational multiinstitutional study, the authors pooled consecutive patients who were treated using SRS for glioblastoma at eight institutions participating in the International Radiosurgery Research Foundation. They evaluated predictors of overall and progression-free survival with consideration of IDH mutation and MGMT methylation status. RESULTS Ninety-six patients (median age 56 years) underwent SRS (median dose 15 Gy and median treatment volume 5.53 cm3) at 147 tumor sites (range 1 to 7). The majority of patients underwent prior fractionated radiation therapy (92%) and temozolomide chemotherapy (98%). Most patients were treated at recurrence (85%), and boost SRS was used for 12% of patients. The majority of patients harbored IDH wild-type (82%) and MGMT-methylated (62%) tumors. Molecular data were unavailable for 33 patients. Median survival durations after SRS were similar between patients harboring IDH wild-type tumors and those with IDH mutant tumors (9.0 months vs 11 months, respectively), as well as between those with MGMT-methylated tumors and those with MGMT-unmethylated tumors (9.8 vs. 9.0 months, respectively). Prescription dose > 15 Gy (OR 0.367, 95% CI 0.190–0.709, p = 0.003) and treatment volume > 5 cm3 (OR 1.036, 95% CI 1.007–1.065, p = 0.014) predicted overall survival after controlling for age and IDH status. Treatment volume > 5 cm3 (OR 2.215, 95% CI 1.159–4.234, p = 0.02) and absence of gross-total resection (OR 0.403, 95% CI 0.208–0.781, p = 0.007) were associated with inferior local control of SRS-treated lesions in multivariate models. Nine patients experienced adverse radiation events after SRS, and 7 patients developed radiation necrosis at 59 to 395 days after SRS. CONCLUSIONS Post-SRS survival was similar as a function of IDH mutation and MGMT promoter methylation status, suggesting that molecular profiles of glioblastoma should be considered when selecting candidates for SRS. SRS prescription dose > 15 Gy and treatment volume ≤ 5 cm3 were associated with longer survival, independent of age and IDH status. Prior gross-total resection and smaller treatment volume were associated with superior local control.

Lack of Benefit of Extending Temozolomide Treatment in Patients with High Vascular Glioblastoma with Methylated MGMT

In this study, we evaluated the benefit on survival of the combination of methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included in the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of extending temozolomide treatment for patients with high vascular glioblastomas, even presenting MGMT methylation. Preliminary results suggest that patients with moderate vascularity and methylated MGMT glioblastomas would benefit more from prolonged adjuvant chemotherapy.

Prognostic Impact of the Combination of MGMT Methylation and TERT Promoter Mutation in Glioblastoma

Background The concept of combinational analysis between the methylation of O6-methylguanine-DNA methyltransferase (MGMT) and telomerase reverse transcriptase promoter (pTERT) mutation in glioblastoma (GBM) has been reported. The main study objective was to determine the prognosis of patients with GBM based on MGMT/pTERT classification, while the secondary objective was to estimate the temozolomide effect on the survival time of GBM with MGMT/pTERT classification. Methods A total of 50 GBM specimens were collected after tumor resection and were selected for investigating MGMT methylation and pTERT mutation. Clinical imaging and pathological characteristics were retrospectively analyzed. Patients with MGMT/pTERT classification were analyzed using survival analysis to develop the nomogram for forecasting and individual prognosis. Results All patients underwent resection (total resection: 28%, partial resection: 64%, biopsy: 8%). Thirty-two percent of all cases received adjuvant temozolomide with radiotherapy. Sixty-four percent of the case was found methylated MGMT, and 56% of the present cohort found pTERT mutation. Following combinational analysis of biomarkers, results showed that the GBMs with methylated MGMT and wild-type pTERT had a superior prognosis compared with other subtypes. Using Cox regression analysis with multivariable analysis, the extent of resection, postoperative chemoradiotherapy, MGMT/pTERT classification were associated with a favorable prognosis. Hence, a web-based nomogram was developed for deploying individual prognostication. Conclusions The interaction of MGMT methylation and pTERT mutation was confirmed for predicting prognosis. The results from the present study could help physicians create treatment strategies for GBM patients in real-world situations.

Multi-Omic Prediction of Overall Survival in Patients With Glioblastoma: Additive and Synergistic Value of Clinical Measures, Radiomics, and Genomics

Background. Multi-omic data, i.e., clinical measures, radiomic, and genetic data, capture multi-faceted tumor characteristics, contributing to a comprehensive patient risk assessment. Here, we investigate the additive value and independent reproducibility of integrated diagnostics in prediction of overall survival (OS) in newly diagnosed, treatment-naïve, IDH-wildtype GBM patients, by combining conventional and deep learning methods.Methods. Conventional radiomics and deep learning features were extracted from pre-operative multi-parametric MRI of 516 GBM patients. SVM classifiers were trained on the discovery cohort (n=404) to categorize patient groups of high-risk (OS<6 months) vs all, and low-risk (OS≥18 months) vs all. The trained patient stratification model was independently tested in the replication cohort (n=112) and a patient-wise survival prediction index (SPIradiomics) was produced. Multivariate Cox-PH models were generated for the replication cohort, first based on clinical measures solely, and then by layering on radiomics and molecular information.Results. Evaluation of the high-risk and low-risk classifiers in the discovery/replication cohorts revealed AUCs of 0.78 (95%CI:0.70–0.85)/0.75 (95%CI:0.64–0.79) and 0.75 (95%CI: 0.65–0.84)/0.63 (95%CI: 0.52–0.71), respectively. Cox-PH modeling showed a concordance index of 0.65 (95%CI:0.6–0.7) for clinical data, 0.70 (95%CI:0.65–0.75) for clinical and radiomics, 0.72 (95%CI:0.68–0.77) for clinical, MGMT methylation, and radiomics, and 0.75 (95%CI:0.72–0.79) for the combination of all omics, i.e., clinical, MGMT methylation, radiomics, and genomics.Conclusions. This study signifies the value of integrated diagnostics for improved prediction of OS in GBM. Our multi-omic survival prediction tool is easily scalable and can be used for more effective clinical trial stratification.

Efficacy of Whole-Ventricular Radiotherapy in Patients Undergoing Maximal Tumor Resection for Glioblastomas Involving the Ventricle

Background and PurposePatients with glioblastoma (GBM) involving the ventricles are at high risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the effectiveness of whole-ventricular radiotherapy (WVRT) in reducing intraventricular seeding in patients with GBM and identified patients who could benefit from this approach.Methods and MaterialsWe retrospectively reviewed the data of 382 patients with GBM who underwent surgical resection and temozolomide-based chemoradiotherapy. Propensity score matching was performed to compensate for imbalances in characteristics between patients who did [WVRT (+); n=59] and did not [WVRT (–); n=323] receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.ResultsAll patients in the WVRT (+) group had tumor ventricular involvement and ventricle opening during surgery. In the matched cohort, the WVRT (+) group exhibited a significantly lower 2-year intraventricular failure rate than the WVRT (–) group (2.1% vs. 11.8%; P=0.045), with no difference in other outcomes. Recursive partitioning analysis stratified the patients in the WVRT (–) group at higher intraventricular failure risk (2-year survival, 14.2%) due to tumor ventricular involvement, MGMT unmethylation, and ventricle opening. WVRT reduced the intraventricular failure rate only in high-risk patients (0% vs. 14.2%; P=0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P=0.036).ConclusionsWVRT reduced the intraventricular failure rate in patients with tumor ventricular involvement and ventricle opening during surgery. The MGMT-methylation status may further stratify patients who could benefit from WVRT. Further prospective evaluation of WVRT in GBM is warranted.