Assessing the MGMT status in glioblastoma: one step forward, two steps back?

O 6-methylguanin-DNA-methyltransferase (MGMT) would undoubtedly be the molecule of the decade in the field of glioblastoma. More than 15 years ago, the first reports indicated that high activity of this protein in glioma tissue was associated with limited benefit from alkylating-agent chemotherapy, at that time largely nitrosoureas 1. In 2000, methylation of the promoter region of the MGMT gene was linked to improved outcomes in a small series of patients treated with whole-brain radiotherapy, bis-chloroethylnitrosourea, and platinum 2. A few years later, in the context of the registration trial for temozolomide in newly diagnosed glioblastoma, a similar polymerase chain reaction (PCR)-based test identified a subpopulation of patients who particularly benefited from adding temozolomide to radiotherapy in the newly diagnosed setting 3. In the ensuing years, two major notions became widely accepted in the neuro-oncology community: first, MGMT promoter methylation assessed by PCR is indeed a powerful prognostic marker in all malignant glioma patient series ever tested 4 , and second, no test other than PCR, including immunochemistry, has gained credibility for reliably predicting clinical benefit 5. In the context of the phase III trial for the integrin antagonist cilengitide, CENTRIC, it has been recognized that even a centralized assessment of the MGMT status by methylation-specific PCR (MSP) has its inherent problems, supporting the notion that MGMT testing will be difficult to standardize. Finally, in 2012, the powerful value of MGMT promoter methylation to predict preferential benefit from temozo-lomide alone over radiotherapy alone in the NOA-08 and Nordic trials of elderly glioblastoma patients 6,7 concluded the history of MGMT in a certain way: first, the results of these trials led to widespread acknowledgment that MGMT testing should now become the standard of care at least in the elderly, and second, it provided the neuro-oncology community with the challenge to introduce MGMT testing in a standardized and reliable manner in clinical practice 8. In that regard, the article by Lalezari and colleagues 9 in the present issue of Neuro-Oncology will be feared at first sight by many to be a step back rather than forward: after immunochemistry for MGMT had almost been declared dead 5 , these authors now try to make a case that double MGMT testing using MSP and immuno-chemistry is superior to MSP alone. They performed im-munochemistry and MSP as well as bisulfite sequencing in a large group of non-study patients with newly diagnosed glioblastoma. Somewhat arbitrarily, they defined …