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In young patients with newly diagnosed glioblastoma (GBM), methylation of the MGMT (O-6-methylguanine-DNA methyltransferase) gene promoter has been associated with improved prognosis.1 It is less clear if MGMT methylation is a prognostic biomarker in the elderly GBM patient population since patients >70 were excluded from the largest study documenting the association between methylation of MGMT and improved survival. Considering that the median age at diagnosis of GBM is 64, it is important to clarify the significance of MGMT methylation in elderly patients and determine whether it should influence treatment decisions in this large subset of patients.
Methylation of MGMT silences transcription of the enzyme MGMT which repairs DNA damage that would otherwise lead to cell death. MGMT is an important mediator of resistance to alkylating agents including temozolomide, a standard agent administered to newly diagnosed patients with GBM.3–5 Consequently, this tissue biomarker is increasingly being incorporated into clinical trials and clinical practice. In order to assess the importance of MGMT methylation in elderly patients, we determined the association of MGMT methylation and survival in patients with GBM ≥70.
After receiving approval from our institutional review board, we reviewed MGMT methylation status and clinical characteristics of 64 patients ≥70 with newly diagnosed GBM who underwent resection at our institution from 1998 to 2009. Patients were included if they had enough tissue for MGMT analysis, so this excluded patients who only had a biopsy (consistent with the prior study in younger patients). MGMT analysis was performed by extracting tumor genomic DNA from fixed, paraffin-embedded sections for bisulfite conversion (EZ DNA Methylation-Gold Kit, Zymo Research, Orange, CA). MGMT methylation-specific PCR was performed using PCR primer sets specific for methylated and unmethylated MGMT promoter sequences.6 Kaplan Meier curves and the log-rank test were used to compare median progression free (mPFS) and median overall survival (mOS) in patients who had methylated (ME) MGMT vs unmethylated (UN) MGMT.
Of the 64 patients identified, 37 (57.8%) had ME MGMT and 27 (42.2%) did not (table). These results were slightly higher than the 44.7% of patients who had ME MGMT and the 55.3% who had UN MGMT in the Hegi et al.1 study but similar to a small study in very elderly patients (≥80) where 13/22 patients (59%) had ME MGMT.2 Potential explanations for this small discrepancy include age-related increase in genomic methylation that includes the MGMT promoter or the reduced ability to retrieve usable DNA from archived paraffin-embedded blocks.
Initial treatments for patients in our cohort included chemoradiation (35), radiation alone (16), or chemotherapy alone (3). In ME patients, 24/37 patients received an alkylating agent (temozolomide in 23, BCNU in 1) either as first-line therapy (21) or at recurrence (3). Sixteen of the 27 UN patients received an alkylating agent (all temozolomide): 15 as first-line therapy and 1 at recurrence. A total of 10 patients had no or unknown therapy (6 ME, 4 UN). In patients who received an alkylating agent, mOS in ME patients was 489 days vs 263 days in UN patients (p = 0.0021) and mPFS was 405 days vs 246 days (p = 0.2742) (figure e-1 on the Neurology® Web site at www.neurology.org). In an analysis including all 64 patients, mPFS in ME patients was 328 days vs 173 days in UN patients (p = 0.0241) and mOS was 345 days in ME patients and 223 days in UN patients (p = 0.0178). A univariate Cox proportional hazards model including all 64 patients showed that MGMT methylation was associated with reduced hazard for progression (hazard ratio [HR] 0.427, 95% confidence interval [CI] 0.199, 0.914, p = 0.0283) and death (HR 0.475, 95% CI 0.254, 0.890, p = 0.0283). In a multivariate Cox model including age, extent of resection, Karnofsky performance score, and alkylator use, MGMT methylation was significantly associated with a reduced hazard for progression (HR 0.374, 95% CI 0.138, 1.0, p = 0.0521) and death (HR 0.243, 95% CI 0.097, 0.608, p = 0.0025). These results suggest that MGMT methylation is a positive prognostic biomarker in the elderly GBM patient population independent of treatment received.
Since MGMT methylation was previously thought to be a predictive marker associated with improved response to temozolomide, further work will need to be done to clarify if MGMT methylation is also a predictive marker in elderly patients. We were unable to address this question specifically in our study because of the small number of patients not treated with an alkylating agent.
Tumor tissue markers such as MGMT that may influence prognosis or clinical trial design are just as valid in the elderly population as in younger patients. Although our study was retrospective, it is the largest study of MGMT methylation status in this population. MGMT appears to be a useful prognostic marker in elderly GBM patients and its role in guiding treatment choices as a potential predictive biomarker should be explored in prospective studies.
Statistical analysis was conducted by Dr. Elizabeth Gerstner.
Supplemental data at www.neurology.org
Disclosure: Dr. Gerstner is funded by a K12 training grant (awarded to Dr. Batchelor). Dr. Yip is funded by a Royal College of Physicians and Surgeons of Canada Clinical Investigator Fellowship. D.L. Wang reports no disclosures. Dr. Louis served on scientific advisory boards for the Brain Tumor Society and the Henry Ford Hermlin Brain Tumor Center; has received honoraria from Alnylam Pharmaceuticals and Biogen Idec; his department performs clinical testing for MGMT status and bills for the testing; receives royalties from publishing Greenfield's Neuropathology (Arnold Publishing, 2008–2009) and UpToDate (UpToDate Publishing, 2006–2009); receives research support from the NIH [RO1CA57683 (PI)] and the Simches Endowed Fund for Brain Tumor Research; and has served as an expert witness in brain tumor–related cases. Dr. Iafrate receives research support from AstraZeneca, Fidelity Foundation, and Aid for Cancer Research Foundation; and serves as a consultant for Pfizer, Inc. Dr. Batchelor is on the speakers' bureaus of Schering-Plough Corp. and Enzon Pharmaceuticals, Inc.; serves as consultant/on scientific advisory boards for Acceleron Pharma, AstraZeneca, EMD-Serono, Exelixis Inc., ImClone Systems, Genentech, Inc., Millennium Pharmaceuticals, Inc., and Vertex Pharmaceuticals; serves on the editorial boards of the Journal of Clinical Oncology and Oncologist; receives royalties from publishing UpToDate in Oncology (Up To Date, Inc. 2007–2009); has received non-industry-sponsored speaker honoraria; and receives research support from Millennium Pharmaceuticals, Inc., Schering-Plough Corp., and the NIH [KCA1254401 (PI), R01CA129371-01 (PI), 5K12CA90354-02 (Co-PI, PI), 1R13CA124293-01 (PI)].
Received April 6, 2009. Accepted in final form July 17, 2009.
Address correspondence and reprint requests to Dr. Elizabeth Gerstner, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, MA 02114; gro.srentrap@rentsrege