Hostname: page-component-7c8c6479df-r7xzm Total loading time: 0 Render date: 2024-03-29T13:36:12.377Z Has data issue: false hasContentIssue false

Clinical Significance of Molecular Biomarkers in Glioblastoma

Published online by Cambridge University Press:  02 December 2014

C. Ang
Affiliation:
Department of Oncology, McGill University and the Segal Cancer Centre - Sir Mortimer B. Davis Jewish General Hospital
M.-C. Guiot
Affiliation:
Department of Pathology, McGill University Health Centre, Montreal Neurological Hospital
A. V. Ramanakumar
Affiliation:
Division of Cancer Epidemiology, Department of Oncology, McGill University
D. Roberge
Affiliation:
Department of Radiation Oncology, McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada
P. Kavan*
Affiliation:
Department of Oncology, McGill University and the Segal Cancer Centre - Sir Mortimer B. Davis Jewish General Hospital
*
3755 Rue Cote Ste Catherine, Pavillon E, Rm E-715 Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Aim:

To review the impact of molecular biomarkers on response to therapy and survival in patients with primary glioblastoma (GBM).

Materials & Methods:

Tissue specimens were analyzed for p53 mutations, EGFR amplification, loss of PTEN and p16, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Demographic and clinical data were gathered from medical records.

Results:

Clinical and pathological data of 125 patients were collected and analysed. MGMT promoter methylation was associated with improved median overall survival (OS) (61 vs. 42 weeks, p = 0.01) and was an important prognosticator independent of age at diagnosis, extent of resection and post-operative ECOG performance status (HR 2.04, 95% CI 1.11-3.75). Among patients with MGMT promoter methylation, survival was significantly improved with chemoradiotherapy (CRT) over radiotherapy (RT) alone (71 vs. 14 weeks, p < 0.01). Furthermore, amongst those treated with temozolomide (TMZ) based CRT, the presence of EGFR amplification, maintenance of PTEN and wild-type p53 and p16 were each associated with trends towards improved survival.

Conclusion:

MGMT promoter methylation is a strong, independent prognostic factor for OS in GBM. EGFR amplification, maintenance of PTEN, wild-type p53 and p16 all appear to be associated with improved survival in patients treated with CRT. However, the prognostic value of these biomarkers could not be ascertained and larger prospective studies are warranted.

Résumé:

RÉSUMÉ:Objectif:

Le but de l’etude etait de reviser l’impact des biomarqueurs moleculaires sur la reponse au traitement et la survie chez les patients atteints de glioblastome primaire (GBP).

Méthode:

Des echantillons de tissus ont ete analyses pour determiner la presence de mutations du gene p53, d’amplification du gene de EGFR, de perte de PTEN et de p16 et de methylation du promoteur de MGMT. Les donnees demographiques et cliniques ont ete tirees des dossiers cliniques.

Résultats:

Les donnees cliniques et anatomopathologiques de 125 patients ont ete recueillies et analysees. La methylation du promoteur de MGMT etait associee a une survie globale (SG) mediane amelioree, soit de 61 semaines par rapport a 42 semaines, (p = 0,01) et etait un facteur de pronostic important, independant de l’age au moment du diagnostic, de l’etendue de la resection et de l’indice de performance postoperatoire ECOG (RR 2,04 ; IC a 95% 1,11 a 3,75). Parmi les patients qui avaient une methylation du promoteur de MGMT, la survie etait amelioree significativement avec la chimioradiotherapie (CRT) par rapport a la radiotherapie seule, soit 71 semaines par rapport a 14 semaines (p < 0,01). De plus, parmi ceux qui avaient ete traites par la CRT a base de temozolomide, la presence d’amplification de EGFR, la conservation de PTEN et de p53 et p16 de type sauvage etaient chacune associees a une tendance a une survie amelioree.

Conclusion:

La methylation du promoteur de MGMT est un facteur de pronostic independent important pour la SG dans le GBM. L’amplification de EGFR, la conservation de PTEN, la presence de p53 et p16 de type sauvage semblent toutes associees a une meilleure survie chez les patients traites par la CRT. Cependant, la valeur de ces biomarqueurs n’a pu etre determinee et devra faire l’objet d’etudes prospectives plus considerables.

Type
Original Article
Copyright
Copyright © The Canadian Journal of Neurological 2010

References

1. Stupp, R, Mason, WP, van den Bent, MJ, Weller, M, Fisher, B, Taphoorn, MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):98796.Google Scholar
2. Wen, PY, Kesari, S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492507.Google Scholar
3. Hegi, ME, Diserens, AC, Gorlia, T, Hamou, MF, de Tribolet, N, Weller, M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):9971003.CrossRefGoogle ScholarPubMed
4. Liberman, TA, Nussbaum, HR, Razon, N, Kris, R, Lax, I, Soreq, H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313(5998):1447.Google Scholar
5. Quaranta, M, Divella, R, Daniele, A, Di Tardo, S, Venneri, MT, Lolli, I, et al. Epidermal growth factor serum levels and prognostic value in malignant gliomas. Tumori. 2007;93(3):27580.Google Scholar
6. Wagner, M, Menei, P, Guilhot, J, Levillain, P, Michalak, S, Bataille, B, et al. Prognostic molecular markers with no impact on decision making: the paradox of gliomas based on a prospective study. Br J Cancer. 2008;98(11):18308.Google Scholar
7. Houillier, C, Lejeune, J, Benouaich-Amiel, A, Laigle-Donadey, F, Criniere, E, Mokhtari, K, et al. Prognostic impact of molecular markers in a series of 220 primary glioblastoma. Cancer. 2006; 106(10):221823.Google Scholar
8. Korshunov, A, Sycheva, R, Golanov, A. The prognostic relevance of molecular alterations in glioblastomas for patients age < 50 years. Cancer. 2005;104(4):82532.Google Scholar
9. Batchelor, TT, Betensky, Ra, Esposito, JM, Pham, LD, Dorfman, MV, Piscatelli, N, et al. Age-dependent prognostic effects of genetic alterations in glioblastoma. Clin Cancer Res. 2004;10(1 Pt 1): 22833.CrossRefGoogle ScholarPubMed
10. Bianco, R, Shin, I, Ritter, CA, Yakes, FM, Basso, A, Rosen, N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22(18):281222.Google Scholar
11. Koul, D. PTEN signalling pathways in glioblastoma. Cancer Biol Ther. 2008;7(9):13215.Google Scholar
12. Mellinghoff, IK, Wang, MY, Vivanco, I, Haas-Kogan, DA, Zhu, S, Dia, EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005; 353(19):201224.Google Scholar
13. Foulkes, WD. Inherited susceptibility to common cancers. N Engl J Med. 2008;359(20):214353.CrossRefGoogle ScholarPubMed
14. Newcomb, EW, Cohen, H, Lee, SR, Bhalla, SK, Bloom, J, Hayes, RL, et al. Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or Bcl-2 genes. Brain Pathol. 1998;8(4):65567.CrossRefGoogle ScholarPubMed
15. Nozaki, M, Tada, M, Kobayashi, H, Zhang, CL, Sawamura, Y, Abe, H, et al. Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression. Neuro Oncol. 1999; 1(2):12437.Google Scholar
16. Yount, GL, Haas-Kogan, DA, Vidair, CA, Haas, M, Dewey, WC, Israel, MA. Cell cycle synchrony unmasks the influence of p53 function on radiosensitivity of human glioblastoma cells. Cancer Res. 1996;56(3):5006.Google Scholar
17. Nakamura, K, Watanabe, T, Klangby, U, Asker, C, Wiman, K, Yonekawa, Y, et al. p14Arf deletion and methylation in genetic pathways to glioblastomas. Brain Pathol. 2001;11(2):15968.Google Scholar
18. Cankovic, M, Mikkelsen, T, Rosenblum, RL, Zarbo, RJ. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue. Lab Invest. 2007;87(4):3927.Google Scholar
19. Esteller, M, Hamilton, SR, Burger, PC, Baylin, SB, Herman, JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999;59(4): 7937.Google ScholarPubMed
20. Curran, WJ Jr, Scott, CB, Horton, J, Nelson, JS, Weinstein, AS, Fischbach, AJ, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85(9):70410.Google Scholar
21. Li, S, Jiang, T, Li, G, Wang, Z. Impact of p53 status to response of temozolomide in low MGMT expression glioblastoma: preliminary results. Neurol Res. 2008;30(6):56770.Google Scholar
22. Prados, MD, Chang, SM, Butowski, N, DeBoer, R, Parvataneni, R, Carliner, H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4):57984.Google Scholar
23. Ohgaki, H, Kleihues, P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):144553.Google Scholar
24. Mischel, PS, Nelson, SF, Cloughesy, TF. Molecular analysis of glioblastoma: pathway profiling and its implications for patient therapy. Cancer Biol Ther. 2003;2(3):2428.CrossRefGoogle ScholarPubMed
25. Kleihues, P, Ohgaki, H. Primary and secondary glioblastoma: from concept to clinical diagnosis. Neuro-Oncol. 1999;1(1):4451.Google Scholar
26. De Groot, JF, Gilbert, MR, Aldape, K, Hess, KR, Hanna, TA, Ictech, S, et al. Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol. 2008;90(1):8997.Google Scholar
27. Rich, JN, Reardon, DA, Peery, T, Dowell, JM, Quinn, JA, Penne, KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004;22(1):13342.CrossRefGoogle ScholarPubMed
28. Haas-Kogan, DA, Prados, MD, Tihan, T, Eberhard, DA, Jelluma, N, Arvold, ND, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97(12):8807.Google Scholar
29. Huang, F, Kavan, P, Guiot M-C, Markovic, Y, Roberge, D. When temozolomide alone fails: adding procarbazine in salvage therapy of glioma. Can J Neurol Sci. 2008;35(2):1927.Google Scholar