O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide

Authors

  • Emmanuèle Lechapt-Zalcman MD, PhD,

    Corresponding author
    1. Department of Pathology, Caen University Hospital, Caen, France
    2. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Centre National de la Recherche Scientifique (CNRS), Caen, France
    3. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, University of Caen Basse-Normandie, Caen, France
    4. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Caen, France
    • Laboratoire d'Anatomie Pathologique, CHU de Caen, Avenue de la Cote de Nacre, F-14033, Caen Cedex, France

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    • Fax: (011) 33 2 31 06 50 63

  • Guénaëlle Levallet PhD,

    1. Department of Pathology, Caen University Hospital, Caen, France
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  • Audrey Emmanuelle Dugué MSc,

    1. Department of Biostatistics and Clinical Research, Caen University Hospital, Caen, France
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  • Anne Vital MD, PhD,

    1. Department of Pathology, Victor Segalen Bordeaux 2 University, Bordeaux, France
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  • Marie-Danièle Diebold MD, PhD,

    1. Department of Pathology, Reims University Hospital, Reims, France
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  • Philippe Menei MD, PhD,

    1. Department of Neurosurgery, Angers University Hospital, Angers, France
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  • Philippe Colin MD,

    1. Courlancy Polyclinic, Reims, France
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  • Philippe Peruzzy MD,

    1. Department of Neurosurgery, Reims University Hospital, Reims, France
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  • Evelyne Emery MD, PhD,

    1. Department of Neurosurgery, Caen University Hospital, Caen, France
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  • Myriam Bernaudin PhD,

    1. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Centre National de la Recherche Scientifique (CNRS), Caen, France
    2. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, University of Caen Basse-Normandie, Caen, France
    3. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Caen, France
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  • Françoise Chapon MD, PhD,

    1. Department of Pathology, Caen University Hospital, Caen, France
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  • Jean-Sébastien Guillamo MD, PhD

    1. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Centre National de la Recherche Scientifique (CNRS), Caen, France
    2. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, University of Caen Basse-Normandie, Caen, France
    3. Mixed Research Unit 6232, Hypoxia and Cerebrovascular Pathophysiology “CERVOxy” Group, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Caen, France
    4. Department of Neurology, Caen University Hospital, Caen, France
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  • The industrial sponsor played no role in study design; or data collection, analysis, or interpretation; or writing of the article. The principal investigators (E.L.-Z. and J.-S.G.) had full access to the data and were responsible for submission of the article.

Abstract

BACKGROUND:

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown.

METHODS:

MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study.

RESULTS:

For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression-free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs 15.1 months; P = .025). Similarly, patients who had low MGMT protein expression (≤15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P = .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features.

CONCLUSIONS:

MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol). Cancer 2012. © 2012 American Cancer Society.

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