MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma
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.
Background Epigenetic silencing of the MGMT (O6-methylguanine–DNAmethyltransferase) DNA-repair gene by promoter methylation compromisesDNA repair and has been associated with longer survival in patientswith glioblastoma who receive alkylating agents.
Methods We tested the relationship between MGMT silencing inthe tumor and the survival of patients who were enrolled ina randomized trial comparing radiotherapy alone with radiotherapycombined with concomitant and adjuvant treatment with temozolomide.The methylation status of the MGMT promoter was determined bymethylation-specific polymerase-chain-reaction analysis.
Results The MGMT promoter was methylated in 45 percent of 206assessable cases. Irrespective of treatment, MGMT promoter methylationwas an independent favorable prognostic factor (P<0.001 bythe log-rank test; hazard ratio, 0.45; 95 percent confidenceinterval, 0.32 to 0.61). Among patients whose tumor containeda methylated MGMT promoter, a survival benefit was observedin patients treated with temozolomide and radiotherapy; theirmedian survival was 21.7 months (95 percent confidence interval,17.4 to 30.4), as compared with 15.3 months (95 percent confidenceinterval, 13.0 to 20.9) among those who were assigned to onlyradiotherapy (P=0.007 by the log-rank test). In the absenceof methylation of the MGMT promoter, there was a smaller andstatistically insignificant difference in survival between thetreatment groups.
Conclusions Patients with glioblastoma containing a methylatedMGMT promoter benefited from temozolomide, whereas those whodid not have a methylated MGMT promoter did not have such abenefit.
Source Information
From the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery (M.E.H., A.-C.D., M.-F.H., N.T.), the Departments of Radiotherapy (R.O.M.) and Neuropathology (R.C.J.), and the Multidisciplinary Oncology Center (R.S.), University Hospital Lausanne, Lausanne; the Department of Neurosurgery, University Hospital Geneva, Geneva (N.T.); the National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges (M.E.H.); and the Department of Neurosurgery, Inselspital, Bern (L.M.) — all in Switzerland; the Data Center, European Organisation for Research and Treatment of Cancer, Brussels (T.G.); the Department of Neurology, University of Tübingen, Tübingen (M.W.), and the Department of Neurology, University of Regensburg, Regensburg (P.H.) — both in Germany; the Division of Neuropathology, University Hospital Rotterdam, Rotterdam (J.M.K.), and University Medical Center, Utrecht (J.E.C.B.) — both in the Netherlands; the Institute of Neurology, Medical University of Vienna, Vienna, (J.A.H.); and Princess Margaret Hospital, Toronto (W.M.), and the University of Calgary, Calgary, Alta. (J.G.C.) — both in Canada.
Address reprint requests to Dr. Hegi at the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital (CHUV), BH19-110, 1011 Lausanne, Switzerland, or at monika.hegi{at}chuv.hospvd.ch.
Treatment of Brain Tumors
Paulino A. C., Teh B. S., Sadeh M., Seiter K., Ashby L., LaRocca R., Ryken T., Aiken R. D., Rutkowski S., Ottensmeier H., Pietsch T., Stupp R., Hegi M. E., DeAngelis L. M.
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N Engl J Med 2005;
352:2350-2353, Jun 2, 2005.
Correspondence
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Hamstra, D. A., Galban, C. J., Meyer, C. R., Johnson, T. D., Sundgren, P. C., Tsien, C., Lawrence, T. S., Junck, L., Ross, D. J., Rehemtulla, A., Ross, B. D., Chenevert, T. L.
(2008). Functional Diffusion Map As an Early Imaging Biomarker for High-Grade Glioma: Correlation With Conventional Radiologic Response and Overall Survival. JCO
26: 3387-3394
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Colman, H., Aldape, K.
(2008). Molecular Predictors in Glioblastoma: Toward Personalized Therapy. Arch Neurol
65: 877-883
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Liang, X.-J., Choi, Y., Sackett, D. L., Park, J. K.
(2008). Nitrosoureas Inhibit the Stathmin-Mediated Migration and Invasion of Malignant Glioma Cells. Cancer Res.
68: 5267-5272
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Iafrate, A. J., Louis, D. N.
(2008). "MGMT for pt mgmt": Is Methylguanine-DNA Methyltransferase Testing Ready for Patient Management?. J. Mol. Diagn.
10: 308-310
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Vlassenbroeck, I., Califice, S., Diserens, A.-C., Migliavacca, E., Straub, J., Di Stefano, I., Moreau, F., Hamou, M.-F., Renard, I., Delorenzi, M., Flamion, B., DiGuiseppi, J., Bierau, K., Hegi, M. E.
(2008). Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma. J. Mol. Diagn.
10: 332-337
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Murat, A., Migliavacca, E., Gorlia, T., Lambiv, W. L., Shay, T., Hamou, M.-F., de Tribolet, N., Regli, L., Wick, W., Kouwenhoven, M. C.M., Hainfellner, J. A., Heppner, F. L., Dietrich, P.-Y., Zimmer, Y., Cairncross, J. G., Janzer, R.-C., Domany, E., Delorenzi, M., Stupp, R., Hegi, M. E.
(2008). Stem Cell-Related "Self-Renewal" Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma. JCO
26: 3015-3024
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Sarkaria, J. N., Kitange, G. J., James, C. D., Plummer, R., Calvert, H., Weller, M., Wick, W.
(2008). Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma. Clin. Cancer Res.
14: 2900-2908
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Rietschel, P., Wolchok, J. D., Krown, S., Gerst, S., Jungbluth, A. A., Busam, K., Smith, K., Orlow, I., Panageas, K., Chapman, P. B.
(2008). Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma. JCO
26: 2299-2304
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Geiger, G. A., Fu, W., Kao, G. D.
(2008). Temozolomide-Mediated Radiosensitization of Human Glioma Cells in a Zebrafish Embryonic System. Cancer Res.
68: 3396-3404
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Plummer, E. R., Calvert, H.
(2008). Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy. aacredbook
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Esteller, M.
(2008). Epigenetics in Cancer. NEJM
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Kaloshi, G., Everhard, S., Laigle-Donadey, F., Marie, Y., Navarro, S., Mokhtari, K., Idbaih, A., Ducray, F., Thillet, J., Hoang-Xuan, K., Delattre, J.-Y, Sanson, M.
(2008). Genetic markers predictive of chemosensitivity and outcome in gliomatosis cerebri. Neurology
70: 590-595
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Heimberger, A. B., Sun, W., Hussain, S. F., Dey, M., Crutcher, L., Aldape, K., Gilbert, M., Hassenbusch, S. J., Sawaya, R., Schmittling, B., Archer, G. E., Mitchell, D. A., Bigner, D. D., Sampson, J. H.
(2008). Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study. Neuro Oncol Duke
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Kil, W. J., Cerna, D., Burgan, W. E., Beam, K., Carter, D., Steeg, P. S., Tofilon, P. J., Camphausen, K.
(2008). In vitro and In vivo Radiosensitization Induced by the DNA Methylating Agent Temozolomide. Clin. Cancer Res.
14: 931-938
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Sathornsumetee, S., Cao, Y., Marcello, J. E., Herndon, J. E. II, McLendon, R. E., Desjardins, A., Friedman, H. S., Dewhirst, M. W., Vredenburgh, J. J., Rich, J. N.
(2008). Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan. JCO
26: 271-278
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Reardon, D. A., Desjardins, A., Vredenburgh, J. J., Sathornsumetee, S., Rich, J. N., Quinn, J. A., Lagattuta, T. F., Egorin, M. J., Gururangan, S., McLendon, R., Herndon, J. E. II, Friedman, A. H., Salvado, A. J., Friedman, H. S.
(2008). Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma. Neuro Oncol Duke
10: 330-340
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Kesari, S., Schiff, D., Henson, J. W., Muzikansky, A., Gigas, D. C., Doherty, L., Batchelor, T. T., Longtine, J. A., Ligon, K. L., Weaver, S., Laforme, A., Ramakrishna, N., Black, P. McL., Drappatz, J., Ciampa, A., Folkman, J., Kieran, M., Wen, P. Y.
(2008). Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol Duke
10: 300-308
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Assadian, S., Aliaga, A., Del Maestro, R. F., Evans, A. C., Bedell, B. J.
(2008). FDG-PET imaging for the evaluation of antiglioma agents in a rat model. Neuro Oncol Duke
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Zalutsky, M. R., Reardon, D. A., Akabani, G., Coleman, R. E., Friedman, A. H., Friedman, H. S., McLendon, R. E., Wong, T. Z., Bigner, D. D.
(2008). Clinical Experience with {alpha}-Particle Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6. JNM
49: 30-38
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Wick, W., Stupp, R., Beule, A.-C., Bromberg, J., Wick, A., Ernemann, U., Platten, M., Marosi, C., Mason, W. P., van den Bent, M., Weller, M., Rorden, C., Karnath, H.-O., the European Organisation for Research and Treatme,
(2008). A novel tool to analyze MRI recurrence patterns in glioblastoma. Neuro Oncol Duke
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Nagane, M., Kobayashi, K., Ohnishi, A., Shimizu, S., Shiokawa, Y.
(2007). Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide. Jpn J Clin Oncol
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Alonso, M. M., Gomez-Manzano, C., Bekele, B. N., Yung, W.K. A., Fueyo, J.
(2007). Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter. Cancer Res.
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Batista, L. F.Z., Roos, W. P., Christmann, M., Menck, C. F.M., Kaina, B.
(2007). Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating xpc, ddb2, and DNA Double-Strand Breaks. Cancer Res.
67: 11886-11895
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Shirahata, M., Iwao-Koizumi, K., Saito, S., Ueno, N., Oda, M., Hashimoto, N., Takahashi, J. A., Kato, K.
(2007). Gene Expression-Based Molecular Diagnostic System for Malignant Gliomas Is Superior to Histological Diagnosis. Clin. Cancer Res.
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Lefranc, F., Facchini, V., Kiss, R.
(2007). Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas. The Oncologist
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Broniscer, A., Gururangan, S., MacDonald, T. J., Goldman, S., Packer, R. J., Stewart, C. F., Wallace, D., Danks, M. K., Friedman, H. S., Poussaint, T. Y., Kun, L. E., Boyett, J. M., Gajjar, A., for the Pediatric Brain Tumor Consortium,
(2007). Phase I Trial of Single-Dose Temozolomide and Continuous Administration of O6-Benzylguanine in Children with Brain Tumors: a Pediatric Brain Tumor Consortium Report. Clin. Cancer Res.
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Hoelzinger, D. B., Demuth, T., Berens, M. E.
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