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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1459-1460 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.7139
Methylguanine Methyltransferase Testing in Glioblastoma: When and How?1 Multidisciplinary Oncology Center, University of Lausanne Hospitals, Lausanne, Switzerland
2 Laboratory for Tumor Biology and Genetics, Department of Neurosurgery, and the National Center of Competence in Research Molecular Oncology at the Swiss Institute for Experimental Cancer Research, University of Lausanne Hospitals, Lausanne, Switzerland Controversy remains on the optimal treatment schedule of the alkylating agent temozolomide (TMZ) in malignant glioma and the value of methylguanine methyltransferase (MGMT) determination. This repair enzyme is key in reverting lethal DNA damage induced by alkylating agent chemotherapy, and in the absence of this enzyme, cells are more susceptible to TMZ.1 In this issue of the Journal of Clinical Oncology, Chinot et al2 report on a (too) small phase II study investigating a week-on and week-off dose-dense TMZ administration regimen as neoadjuvant chemotherapy before definitive radiation in 29 eligible patients with unresectable glioblastoma. The aim of this alternative dose-dense administration schedule is not only to increase the dose-intensity by more than two-fold, but to overcome drug resistance by depleting the tumor cells of MGMT. In peripheral blood mononuclear cells, it has been shown that repeated and continuous exposure to TMZ will exhaust the cells of MGMT,3 but whether this also applies to tumor cells remains to be demonstrated. The results of this study were disappointing. Median survival was only 6 months (95% CI, 1 to 11), with only 28% of patients alive at 1 year. Even when considering that this is a poor prognosis group of patients, these results appear inferior to standard therapy, including concomitant chemoradiotherapy, where a median survival of 9 months was reported for patients with unresectable tumors.4 Chinot et al attempted to determine MGMT expression in 25 patients by immunohistochemistry, choosing an arbitrary cutoff based on the median percentage of cells staining positively. They found that 6 of 11 patients with low MGMT expression, but only one of the 14 patients with high MGMT expression responded. The study emphasizes again the importance of MGMT to predict a response to the alkylating agent therapy. The predictive value of MGMT for benefit from alkylating agent chemotherapy, whether this be a nitrosourea or temozolomide, has now been repeatedly shown.5-7 Methylation of the MGMT gene promoter has been found to be a predictive marker for benefit from TMZ treatment in patients treated with temozolomide chemotherapy.8 Analysis of a representative subgroup of patients in a randomized trial showed that the addition of TMZ only benefited patients with a methylated (and thus silenced) MGMT gene promoter, while overall survival and progression-free survival was comparable for TMZ-treated patients with a functional MGMT gene to patients having been treated with initial radiotherapy alone. Based on this data, one may want to conclude that patients without MGMT promoter methylation should not be treated with alkylating agent chemotherapy. In these patients, TMZ has marginal activity at best, and alternative strategies may offer better chances. However, outside clinical trials, alternative strategies are currently not available. Nevertheless, the treatment, although generally well tolerated, carries its risks for toxicity. Also, in countries without reimbursement for chemotherapy, some patients may choose to forego the expense for temozolomide in the absence of MGMT promoter methylation. Furthermore, this analysis was performed retrospectively, and although very provocative and suggestive, requires prospective validation. In an ongoing Intergroup trial by the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG 0525/EORTC 26052-22053), patients with newly diagnosed glioblastoma are stratified by MGMT methylation status before random assignment to a TMZ administration schedule (standard daily dose for 5 days or a dose-dense treatment for 3 of 4 weeks).9 To be eligible for this trial, patients must have undergone at least partial tumor resection, and tumor material must be available for centralized MGMT promoter methylation determination. Thus, not only efficient trial management is necessary, but also the goodwill and collaboration of the neurosurgeons and pathologists at many sites. Repeatedly, investigators advocate performing MGMT determination using the simpler immunohistochemistry staining, rather than a methylation-specific polymerase chain reaction assay (MSP) of the function of the MGMT gene. Although some associations may be found by immunohistochemical MGMT expression, this method has many shortcomings. Heterogeneous MGMT expression within tumors, and high levels of MGMT protein present in infiltrating lymphocytes, microglia, and blood vessels limit the reproducibility of the method. More important, MGMT is an inducible enzyme that may be upregulated after chemotherapy or radiotherapy, thus the expression of the protein at diagnosis might not reflect the functional protein during therapy. The MSP assay requires small quantities of DNA that can be extracted from paraffin-embedded tissue samples or, better yet, from cryopreserved tissue samples. In glioma, the presence of a methylated MGMT allele can be attributed solely to the neoplastic cells, irrespective of contamination of nontumor tissue. In our opinion, determination of the MGMT status by MSP should be included in all ongoing and future clinical trials in malignant glioma if treatment includes the use of alkylating agent chemotherapy. Until validation, this test cannot yet be formally considered for day-to-day clinical decision making outside clinical trials. There is an urgent need to design separate trials and treatment strategies for patients with unmethylated MGMT-replacing alkylating agent therapy by other cytotoxic agents acting with a different mechanism of action, or by adding drugs to overcome resistance by other means (than inhibiting/depleting MGMT that repairs O6-methylguanine). Inhibiting repair of other treatment-related DNA adducts such a N7-methylguanine by targeting base excision repair or poly (adenosine diphosphate-ribose) polymerase will provoke stalling of the replication fork and, thereby, inducing cell death. However, even patients with a methylated MGMT gene promoter are rarely cured with current treatments. Understanding of tumor biology and rational combination with other agents will allow the outcome to be further improved. Appropriately processed, even small tissue biopsies such as needle biopsies (1 µL), allow for molecular analyses of the MGMT status. However, in these cases immediate freezing is required. Prognostic and predictive markers like MGMT promoter methylation status, identification of deletions on chromosomes 1p and 19q, epidermal growth factor receptor overexpression, to name a few, can be determined with accuracy and will guide future therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Roger Stupp, Schering-Plough, Merck (EMD), Novartis; Monika E. Hegi, Schering-Plough, Oncomethylome Sciences Stock: N/A Honoraria: Roger Stupp, Schering-Plough, Merck (EMD), Novartis; Monika E. Hegi, Schering-Plough, Oncomethylome Sciences Research Funds: Monika E. Hegi, Oncomethylome Sciences Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Roger Stupp, Monika E. Hegi Data analysis and interpretation: Roger Stupp, Monika E. Hegi Manuscript writing: Roger Stupp, Monika E. Hegi Final approval of manuscript: Roger Stupp, Monika E. Hegi REFERENCES
1. Gerson SL: Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388-2399, 2002 2. Chinot OL, Barrié M, Fuentes S, et al: Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25:1470-1475, 2007 3. Tolcher AW, Gerson SL, Denis L, et al: Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004-1011, 2003[CrossRef][Medline] 4. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 5. Jaeckle KA, Eyre HJ, Townsend JJ, et al: Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: A Southwest Oncology Group study. J Clin Oncol 16:3310-3315, 1998[Abstract] 6. Esteller M, Garcia-Foncillas J, Andion E, et al: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350-1354, 2000 7. Hegi ME, Diserens AC, Godard S, et al: Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871-1874, 2004 8. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 9. Stupp R, Hegi ME, van den Bent MJ, et al: Changing paradigms: An update on the multidisciplinary management of malignant glioma. Oncologist 11:165-180, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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