Glioblastoma

PharmacoMDx - Glioblastoma
The MGMT gene is a crucial DNA repair gene. MDxHealth’s MGMT assay determines the methylation status of the MGMT gene in tumor tissue, and can be used as a predictive assay for the treatment of glioblastoma.

The MDxHealth MGMT gene test used as a Laboratory Developed Test or as Investigational Use Only tool in the assessment of patients participating in clinical trials has been shown on thousands of patients to be able to distinguish which cancer patients are likely to respond to the most commonly used class of brain cancer drugs called alkylating agents. This patented methylated gene test is attractive for new brain cancer drug developers since they can more easily target their new drugs to the patients who usually do not respond to the traditional alkylating agent drug regime.

At the request of numerous pharmaceutical companies (eg Merck Serono, Roche, and Merck/Schering-Plough) MDxHealth performs clinical trials using the MGMT test via its ISO-certified services lab or sub-contracts to LabCorp's Clinical Trials Services Division.

We are currently providing MGMT testing services for numerous Phase II and Phase III clinical trials, and have successfully completed multiple large phase III studies using MGMT as a stratification or selection biomarker including Merck Serono's, and a completed large international RTOG/EORTC study (0525) to help optimize therapy for patients with malignant brain tumors (glioblastoma multiforme, GBM) with either MGMT-methylated or -unmethylated brain tumors. In collaboration with a number of pharmaceutical partners, we are also exploring the test’s utility in other treatment regimens and in other cancer types.

Brain cancer - epidemiology
Glioblastoma is a very aggressive cancer that typically kills most patients within 12-18 months of diagnosis. Thus it is very important for doctors to try to get the right treatment to the right patient as soon as possible.

•    US incidence of Brain Cancer:    21,808/Year
•    EU (27) incidence of Brain Cancer:    39,948/Year
•    Global incidence of Brain Cancer:    238,796/Year
Globocan 2008

An objective basis for therapy consideration

Methylation of the DNA repair gene MGMT has been shown to be both prognostic and predictive in glioblastoma patients undergoing alkylating agent-based therapy1,2. Performed on tumor tissue samples, our MGMT methylation assay evaluates the methylation status of the MGMT gene, providing medical professionals with an objective basis for therapy consideration. This enables them to optimize patient therapy leading to more personalized and effective treatments.

A patent on the use of the MGMT gene to predict patient response to drug treatment has been exclusively licensed to MDxHealth. To order the test from MDxHealth please contact info@MDxHealth.com.

MGMT methylation testing for gliomas
The road to more personalized and effective treatments

Studies have documented that epigenetic silencing of the MGMT gene is an important factor in predicting the outcome in glioblastoma patients treated with alkylating agents such as temozolomide (TMZ)1 and carmustine (BCNU)2.

Kaplan–Meier Estimates of Overall Survival, According to MGMT Promoter Methylation Status

The difference in survival between patients with a methylated MGMT promoter (92 patients, 65 of whom died) and those with an unmethylated MGMT promoter (114 patients, 105 of whom died) was highly significant (P<0.001 by the log-rank test), indicating that the MGMT methylation status has prognostic value. In the group of patients with a methylated MGMT promoter, there was a risk reduction of 55 percent (hazard ratio for death, 0.45; 95 percent confidence interval, 0.32 to 0.61), as compared with the group with an unmethylated MGMT promoter.
Hegi et al, NEJM 2005;352(10):997-1003.

Literature
Monika E. Hegi, Ph.D., Annie-Claire Diserens, M.Sc., Thierry Gorlia, M.Sc., Marie-France Hamou, Nicolas de Tribolet, M.D., Michael Weller, M.D., Johan M. Kros, M.D., Johannes A. Hainfellner, M.D., Warren Mason, M.D., Luigi Mariani, M.D., Jacoline E.C. Bromberg, M.D., Peter Hau, M.D., René O. Mirimanoff, M.D., J. Gregory Cairncross, M.D., Robert C. Janzer, M.D., and Roger Stupp, M.D., MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma., N Engl J Med. 2005; 352:997-1003

Ilse Vlassenbroeck, Stéphane Califice, Annie-Claire Diserens, Eugenia Migliavacca, Josef Straub, Ivano Di Stefano, Fabrice Moreau, Marie-France Hamou, Isabelle Renard, Mauro Delorenzi, Bruno Flamion, James DiGuiseppi, Katja Bierau, and Monika E. Hegi., Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma. J Mol Diagn. 2008; 10(4): 332–337

Peter Hau, Roger Stupp, Monika E. Hegi, MGMT methylation st < script src="/plugins/editors/tinymce/jscripts/tiny_mce/themes/advanced/langs/en.js" type="text/javascript"> atus: The advent of stratified therapy in glioblastoma?, IOS Press. 2007; 97-104

Roger Stupp, Monika E Hegi, Warren P Mason, Martin J van den Bent, Martin J B Taphoorn, Robert C Janzer, Samuel K Ludwin, Anouk Allgeier, Barbara Fisher, Karl Belanger, Peter Hau, Alba A Brandes, Johanna Gijtenbeek, Christine Marosi, Charles J Vecht, Karima Mokhtari, Pieter Wesseling, Salvador Villa, Elizabeth Eisenhauer, Thierry Gorlia, Michael Weller, Denis Lacombe, J Gregory Cairncross, René-Olivier Mirimanoff ; on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada Clinical Trials Group., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial., Lancet Oncol. 2009; 10: 459–66

Matthias Preusser, Robert Charles Janzer, Jörg Felsberg, Guido Reifenberger, Marie-France Hamou, Annie-Claire Diserens, Roger Stupp, Thierry Gorlia, Christine Marosi1, Harald Heinzl, Johannes A Hainfellner, Monika Hegi, Anti-O6-Methylguanine-Methyltransferase (MGMT) Immunohistochemistry in Glioblastoma Multiforme: Observer Variability and Lack of Association with Patient Survival Impede Its Use as Clinical Biomarker, Brain Pathol. 2008; 18(4):520-32

Markus J. Riemenschneider, Monika E. Hegi and Guido Reifenberger, MGMT promoter methylation in malignant gliomas. Target Oncol. 2010; Volume 5, Number 3, 161-165

Michael Weller, Roger Stupp, Guido Reifenberger, Alba A. Brandes, Martin J. van den Bent, Wolfgang Wick & Monika E. Hegi, MGMT promoter methylation in malignant gliomas: ready for personalized medicine?, Nature Reviews Neurology. 2010; 6, 39-51

Monika E. Hegi, Lili Liu, James G. Herman, Roger Stupp, Wolfgang Wick, Michael Weller, Minesh P. Mehta, Mark R. Gilbert, Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity, Journal of Clinical Oncology. 2008; Vol 26, No 25, 4189-4199

Manel Esteller, M.D., Ph.D., Jesus Garcia-Foncillas, M.D., Ph.D., Esther Andion, B.Sc., Steven N. Goodman, M.D., Ph.D., Oscar F. Hidalgo, M.D., Vicente Vanaclocha, M.D., Stephen B. Baylin, M.D., and James G. Herman, M.D., Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents, N Engl J Med. 2000; 343:1350-1354