Abstract
BACKGROUNDS
Despite recent limelight of precision medicine in oncology, effective targeted drugs and diagnostics for molecular markers have not been developed or approved for glioblastoma (GBM) yet. Notably, there remain multiple issues in MGMT testing, including determination of optimal assays and cutoff for methylation status, and its value as “companion diagnostics.” We compared two of MGMT assays, qualitative standard MSP and pyrosequencing, in light of compatibility, predictability, and cutoff points.
METHODS
Sixty-five newly diagnosed GBMs with two MGMT assays performed since 2006. Survival was analyzed for 48 GBMs with wildtype IDH and initial temozolomide use. Extracted DNA was subjected to bisulfite treatment, thereby MGMT status was determined.
RESULTS
Among 65 GBMs, MGMT was methylated (M) in 34, and unmethylated (U) in 31, by MSP. Median methylation rate at CpG sites by Pyro was 15.9%, with average 23.0% for M and 9.5% for U (Mann-Whitney-U, P< 0.001). MGMT status by MSP significantly correlated with that by Pyro with cutoff between 10 – 16% (Fisher, P< 0.001). Patients with MGMT M by MSP showed significantly longer PFS and OS than with U (PFS 13.5 m vs. 5.6 m, P = 0.005; OS 37.7 m vs. 15.8 m, P = 0.001). In contrast, by Pyro (cutoff 14%), only PFS was significantly better in M (11.7 m vs 5.6 m, P = 0.014), but not OS (27.9 m vs. 15.8 m, P = 0.249). No substantial gain for PFS was noted in MGMT M GBMs beyond cutoff 12% by Pyro. Multivariate analysis revealed MGMT M and KPS 70 or higher as independent factors for better PFS and OS using MSP, but only for PFS with Pyro.
CONCLUSIONS
In this study, qualitative MSP exhibited rather better discrimination of prognosis than quantitative Pyro, although showing a high concordance for MGMT status, necessitating further confirmation among assays.
PATH-08. CHALLENGES IN OPTIMIZATION OF MGMT PROMOTER METHYLATION ASSAYS FOR DEVELOPMENT OF COMPANION DIAGNOSIS IN GLIOBLASTOMA
