Central Nervous System

SS 13 - CNS 2 - Gliomas

93 - MGMT Protein Expression Adds Prognostic Value Beyond MGMT Promoter Methylation and Stratifies Survival Prognoses of Un-Methylated Glioblastoma Patients

Monday, October 22
10:55 AM - 11:05 AM
Location: Room 004

MGMT Protein Expression Adds Prognostic Value Beyond MGMT Promoter Methylation and Stratifies Survival Prognoses of Un-Methylated Glioblastoma Patients
A. Becker1, E. H. Bell1, J. McElroy2, T. Cui1, M. Geurts3, Z. Liu1, S. J. Haque1, P. Robe3, and A. Chakravarti1; 1Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, OH, 2The Ohio State University, Center for Biostatistics, Columbus, OH, 3Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands

Purpose/Objective(s): In glioblastomas, one of the main mechanisms of resistance to treatment with radiation + temozolomide (Stupp protocol) is carried by the DNA-repair protein MGMT. Methylation of the MGMT promoter region is a key prognostic factor for glioblastoma, however, the current administered standard of care is the same for methylated and un-methylated tumors. Since MGMT protein expression is regulated by alternative post-transcriptional and post-translational mechanisms beyond promoter methylation, we hypothesized that MGMT protein expression assessed by immunohistochemistry could stratify the prognoses of patients with glioblastoma and add prognostic power to MGMT methylation, improving the decision-making process for glioblastoma treatment.

Materials/Methods: We retrospectively analyzed an institutional cohort of 436 adult patients comparing MGMT immunohistochemistry, using a monoclonal antibody and ≥15% of positive nuclei as cut point for high MGMT expression, and MGMT promoter methylation, assessed by the platform EPIC, from FFPE glioblastomas. Log-rank test for the univariate analysis (UVA) and multivariable (MVA) Cox-regression models accounting for classical clinical factors (age, KPS, IDH1 status etc.), as well as MGMT expression and MGMT promoter methylation were employed to determine association with OS.

Results: Low MGMT expression according to the 15% cutoff was correlated with better OS and was a stronger predictor of survival than MGMT promoter methylation both in UVA [HR: 1.7(1.3-2.3 CI), p=0.00057 vs. HR: 1.6(1.2-2.3 CI), p=0.0028] and MVA [HR: 1.99(1.33-2.98 CI), p=0.001 vs. HR: 1.37(0.96-1.95 CI), p=0.081]. MGMT promoter methylation was strongly associated with low MGMT expression (p=0.005, Fisher’s exact test); nevertheless more than 70% of un-methylated tumors had low MGMT expression levels. In response to Stupp protocol, un-methylated tumors with low MGMT expression had significantly better OS than their counterparts with high MGMT expression (p=0.001), while rare methylated tumors with high MGMT expression had OS similar to the un-methylated tumors (p=0.270). MGMT promoter methylation significantly split OS only in the tumors with inherent low MGMT expression (p=0.02), but not when MGMT expression was ≥15% (p=0.270).

Conclusion: Our data provides evidence that MGMT protein expression is an independent prognostic biomarker for newly diagnosed glioblastomas and the immunohistochemistry test may identify, upfront and at a lower cost, those patients who may not respond to the Stupp protocol. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC).

Author Disclosure: A. Becker: None. J. McElroy: None. T. Cui: None. P. Robe: None. A. Chakravarti: None.

Aline Becker, MD, PhD

Disclosure:
Employment
Arthur G. James Hospital/Ohio State Comprehensive Cancer Center: Employee: Employee

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