Correlation of commercially available quantitative (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival.

BACKGROUND

Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase () promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome.

METHODS

We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase () wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS).

RESULTS

We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for methylated patients vs unmethylated patients. Cox regression analysis confirmed that (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 ( = .053) and 2.463 ( = .023), respectively, when compared to the (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of methylation and improved survival.

CONCLUSIONS

The unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival. These findings will require validation in additional independent clinical data sets.