Targeted Oncology

, Volume 5, Issue 3, pp 201–210

Molecular markers in gliomas: impact for the clinician

Review

Abstract

Over the last decade, understanding of glioma on a molecular level has greatly expanded. However, optimal incorporation of molecular markers into clinical care is controversial. We briefly review the potential utility of molecular stratification in refining histologic diagnosis, prognosis, and treatment decisions, focussing on 1p/19q co-deletion, MGMT promoter methylation, EGFR mutations, and IDH mutation. The most recently discovered IDH mutation is a striking example of a rapid implementation of a molecular marker for prognostication into common clinical use.

Keywords

Glioma MGMT Molecular 1p19q Prognostic Predictive EGFR IDH 

References

  1. 1.
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173CrossRefPubMedGoogle Scholar
  2. 2.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRefGoogle Scholar
  3. 3.
    Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE et al (1993) Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704–710CrossRefPubMedGoogle Scholar
  4. 4.
    Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569CrossRefPubMedGoogle Scholar
  5. 5.
    Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, Fischbach AJ, Curran WJ Jr (1998) Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40:51–55PubMedGoogle Scholar
  6. 6.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024CrossRefPubMedGoogle Scholar
  7. 7.
    Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O’Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, Mellinghoff IK (2006) Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3:e485CrossRefPubMedGoogle Scholar
  8. 8.
    Everhard S, Kaloshi G, Criniere E, Benouaich-Amiel A, Lejeune J, Marie Y, Sanson M, Kujas M, Mokhtari K, Hoang-Xuan K, Delattre JY, Thillet J (2006) MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol 60:740–743CrossRefPubMedGoogle Scholar
  9. 9.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMedGoogle Scholar
  10. 10.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  11. 11.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466CrossRefPubMedGoogle Scholar
  12. 12.
    Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121PubMedGoogle Scholar
  13. 13.
    van den Bent MJ, Dubbink HJ, Sanson M, van der Lee-Haarloo CR, Hegi M, Jeuken JW, Ibdaih A, Brandes AA, Taphoorn MJ, Frenay M, Lacombe D, Gorlia T, Dinjens WN, Kros JM (2009) MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol 27:5881–5886CrossRefPubMedGoogle Scholar
  14. 14.
    Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880CrossRefPubMedGoogle Scholar
  15. 15.
    Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M (2010) Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28(16):2712–2718CrossRefPubMedGoogle Scholar
  16. 16.
    Gerson SL (2004) MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4:296–307CrossRefPubMedGoogle Scholar
  17. 17.
    Preusser M, Charles Janzer R, Felsberg J, Reifenberger G, Hamou MF, Diserens AC, Stupp R, Gorlia T, Marosi C, Heinzl H, Hainfellner JA, Hegi M (2008) Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol 18:520–532PubMedGoogle Scholar
  18. 18.
    Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, Steiger HJ, Friedensdorf B, Reifenberger G, Sabel MC (2009) Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res 15:6683–6693CrossRefPubMedGoogle Scholar
  19. 19.
    Wick W, Platten M, Weller M (2009) New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol 11:69–79CrossRefPubMedGoogle Scholar
  20. 20.
    Clarke JL, Iwamoto FM, Sul J, Panageas K, Lassman AB, DeAngelis LM, Hormigo A, Nolan CP, Gavrilovic I, Karimi S, Abrey LE (2009) Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867CrossRefPubMedGoogle Scholar
  21. 21.
    Perry JR, Belanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28:2051–2057CrossRefPubMedGoogle Scholar
  22. 22.
    Kong DS, Lee JI, Kim JH, Kim ST, Kim WS, Suh YL, Dong SM, Nam DH (2010) Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol 12:289–296PubMedGoogle Scholar
  23. 23.
    Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M (2004) One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113–2115PubMedGoogle Scholar
  24. 24.
    Brada M, for the BR12 collaborators (2008) A randomised trial of Procarbazine, CCNU and Vincristine (PCV) vs. Temozolomide (5-day or 21-day schedule) for recurrent high-grade glioma (MRC BR12) [Abstract O21]. Neuro Oncol 10:1067Google Scholar
  25. 25.
    Riemenschneider MJ, Hegi ME, Reifenberger G (2010) MGMT promoter methylation in malignant gliomas. Targ Oncol, in press. doi:10.1007/s11523-010-0153-6
  26. 26.
    CBTRUS: Central Brain Tumor Registry of the United States 2008 statistical report: primary brain tumors in the Uninted States. www.cbtrus.org/reports/reports.html. Accessed August 12, 2010
  27. 27.
    Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190PubMedGoogle Scholar
  28. 28.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479CrossRefPubMedGoogle Scholar
  29. 29.
    Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG, Buckner JC (2006) A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66:9852–9861CrossRefPubMedGoogle Scholar
  30. 30.
    Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, Kimmel D, Yates A, Burger PC, Scheithauer BW, Jenkins RB (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645PubMedGoogle Scholar
  31. 31.
    Lassman AB, Panageas KS, Iwamoto FM, DeAngelis LM, Rivera AL, Aldape KD, Cloughesy TF, Eichler A, Louis DN, Paleologos N, Fisher B, Ashby L, Roldan GB, Cairncross JG, Wen PY, Schiff D, Rocque BG, Robins HI, Chamberlain MC, Mason W, Weaver S, Green RM, Kamar FG, Jhanwar S, Rosenblum MK, Abrey LE (2009) International retrospective study of 1000+ adults with anaplastic oligodendroglial tumors [Abstract 283]. Neuro Oncol 11:629Google Scholar
  32. 32.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol 114(2):97–109CrossRefPubMedGoogle Scholar
  33. 33.
    Burger PC (2002) What is an oligodendroglioma? Brain Pathol 12:257–259CrossRefPubMedGoogle Scholar
  34. 34.
    Giannini C, Burger PC, Berkey BA, Cairncross JG, Jenkins RB, Mehta M, Curran WJ, Aldape K (2008) Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402. Brain Pathol 18:360–369CrossRefPubMedGoogle Scholar
  35. 35.
    Giannini C, Scheithauer BW, Weaver AL, Burger PC, Kros JM, Mork S, Graeber MB, Bauserman S, Buckner JC, Burton J, Riepe R, Tazelaar HD, Nascimento AG, Crotty T, Keeney GL, Pernicone P, Altermatt H (2001) Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol 60:248–262PubMedGoogle Scholar
  36. 36.
    McDonald JM, See SJ, Tremont IW, Colman H, Gilbert MR, Groves M, Burger PC, Louis DN, Giannini C, Fuller G, Passe S, Blair H, Jenkins RB, Yang H, Ledoux A, Aaron J, Tipnis U, Zhang W, Hess K, Aldape K (2005) The prognostic impact of histology and 1p/19q status in anaplastic oligodendroglial tumors. Cancer 104:1468–1477CrossRefPubMedGoogle Scholar
  37. 37.
    Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK (1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79:1381–1393CrossRefPubMedGoogle Scholar
  38. 38.
    Kros J, Gorlia T, van den Bent M (2007) Panel review of anaplastic oligodendroglioma from EORTC trial 26951: consensus in diagnosis and influence of 1p/19q [abstract PA-16]. Neuro Oncol 9:545Google Scholar
  39. 39.
    Aldape K, Burger PC, Perry A (2007) Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med 131:242–251PubMedGoogle Scholar
  40. 40.
    Kouwenhoven K, Gorlia T, Kros J, Carpentier A, Brandes A, Sanson M, Taphoorn M, Teepen H, Bernsen H, Frenay M, Tijssen C, Grisold W, Sipos L, Stupp R, Vecht C, Allgeier A, Lacombe D, van den Bent M (2007) EORTC 26951: prognosis of oligodendroglial tumors is an interplay of molecular, histological, and clinical characteristics [abstract PA-18]. Neuro Oncol 9:546Google Scholar
  41. 41.
    Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H (2006) Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol 65:846–854CrossRefPubMedGoogle Scholar
  42. 42.
    Pinto LW, Araujo MB, Vettore AL, Wernersbach L, Leite AC, Chimelli LM, Soares FA (2008) Glioblastomas: correlation between oligodendroglial components, genetic abnormalities, and prognosis. Virchows Arch 452:481–490CrossRefPubMedGoogle Scholar
  43. 43.
    Kraus JA, Lamszus K, Glesmann N, Beck M, Wolter M, Sabel M, Krex D, Klockgether T, Reifenberger G, Schlegel U (2001) Molecular genetic alterations in glioblastomas with oligodendroglial component. Acta Neuropathol 101:311–320PubMedGoogle Scholar
  44. 44.
    Bigner SH, Matthews MR, Rasheed BK, Wiltshire RN, Friedman HS, Friedman AH, Stenzel TT, Dawes DM, McLendon RE, Bigner DD (1999) Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 155:375–386PubMedGoogle Scholar
  45. 45.
    He J, Mokhtari K, Sanson M, Marie Y, Kujas M, Huguet S, Leuraud P, Capelle L, Delattre JY, Poirier J, Hoang-Xuan K (2001) Glioblastomas with an oligodendroglial component: a pathological and molecular study. J Neuropathol Exp Neurol 60:863–871PubMedGoogle Scholar
  46. 46.
    Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24:2707–2714CrossRefPubMedGoogle Scholar
  47. 47.
    van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715–2722CrossRefPubMedGoogle Scholar
  48. 48.
    Iwamoto FM, Nicolardi L, Demopoulos A, Barbashina V, Salazar P, Rosenblum M, Hormigo A (2008) Clinical relevance of 1p and 19q deletion for patients with WHO grade 2 and 3 gliomas. J Neurooncol 88:293–298CrossRefPubMedGoogle Scholar
  49. 49.
    Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M, Schackert G (2007) Long-term survival with glioblastoma multiforme. Brain 130:2596–2606CrossRefPubMedGoogle Scholar
  50. 50.
    Weller M, Berger H, Hartmann C, Schramm J, Westphal M, Simon M, Goldbrunner R, Krex D, Steinbach JP, Ostertag CB, Loeffler M, Pietsch T, von Deimling A (2007) Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937CrossRefPubMedGoogle Scholar
  51. 51.
    van den Bent MJ, Looijenga LH, Langenberg K, Dinjens W, Graveland W, Uytdewilligen L, Sillevis Smitt PA, Jenkins RB, Kros JM (2003) Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features. Cancer 97:1276–1284CrossRefPubMedGoogle Scholar
  52. 52.
    Abrey LE, Louis DN, Paleologos N, Lassman AB, Raizer JJ, Mason W, Finlay J, Macdonald DR, Deangelis LM, Cairncross JG (2007) Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro-oncol 9:314–318CrossRefPubMedGoogle Scholar
  53. 53.
    Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA (1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333–343CrossRefPubMedGoogle Scholar
  54. 54.
    Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:1323–1329CrossRefPubMedGoogle Scholar
  55. 55.
    DeAngelis LM, Burger PC, Green SB, Cairncross JG (1998) Malignant glioma: who benefits from adjuvant chemotherapy? Ann Neurol 44:691–695CrossRefPubMedGoogle Scholar
  56. 56.
    Cairncross JG, Macdonald DR (1988) Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23:360–364CrossRefPubMedGoogle Scholar
  57. 57.
    Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr et al (1994) Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12:2013–2021PubMedGoogle Scholar
  58. 58.
    Macdonald DR, Gaspar LE, Cairncross JG (1990) Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 27:573–574CrossRefPubMedGoogle Scholar
  59. 59.
    Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Ramsay DA, Cairncross JG, Louis DN (2001) Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 7:839–845PubMedGoogle Scholar
  60. 60.
    Cairncross G, Wang M, Chang S, Shaw E, Jenkins R, Scheithauer B, Buckner J, Fink K, Mehta M, Curran W (2008) A randomized trial of chemotherapy plus radiotherapy (RT) versus RT alone for anaplastic oligodendroglioma (RTOG 9402): the perspective of longer follow-up. Int J Rad Oncol Bio Phys 72:S7–S8Google Scholar
  61. 61.
    Douw L, Klein M, Fagel SS, van den Heuvel J, Taphoorn MJ, Aaronson NK, Postma TJ, Vandertop WP, Mooij JJ, Boerman RH, Beute GN, Sluimer JD, Slotman BJ, Reijneveld JC, Heimans JJ (2009) Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 8:810–818CrossRefPubMedGoogle Scholar
  62. 62.
    DeAngelis LM, Delattre JY, Posner JB (1989) Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789–796PubMedGoogle Scholar
  63. 63.
    DeAngelis LM (2009) Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy. [corrected]. J Clin Oncol 27:5861–5862CrossRefPubMedGoogle Scholar
  64. 64.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773CrossRefPubMedGoogle Scholar
  65. 65.
    Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M, Herold-Mende C, Unterberg A, Jeuken JW, Wesseling P, Reifenberger G, von Deimling A (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1, 010 diffuse gliomas. Acta Neuropathol 118:469–474CrossRefPubMedGoogle Scholar
  66. 66.
    Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154CrossRefPubMedGoogle Scholar
  67. 67.
    Labussiere M, Idbaih A, Wang XW, Marie Y, Boisselier B, Falet C, Paris S, Laffaire J, Carpentier C, Criniere E, Ducray F, El Hallani S, Mokhtari K, Hoang-Xuan K, Delattre JY, Sanson M (2010) All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 74:1886–1890CrossRefPubMedGoogle Scholar
  68. 68.
    Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265CrossRefPubMedGoogle Scholar
  69. 69.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744CrossRefPubMedGoogle Scholar
  70. 70.
    Korshunov A, Meyer J, Capper D, Christians A, Remke M, Witt H, Pfister S, von Deimling A, Hartmann C (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118:401–405CrossRefPubMedGoogle Scholar
  71. 71.
    van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, Frenay M, Tijssen CC, Lacombe D, Idbaih A, van Marion R, Kros JM, Dinjens WN, Gorlia T, Sanson M (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16:1597–1604CrossRefPubMedGoogle Scholar
  72. 72.
    Labussiere M, Idbaih A, Wang XW, Marie Y, Boisselier B, Falet C, Paris S, Laffaire J, Carpentier C, Criniere E, Ducray F, El Hallani S, Mokhtari K, Hoang-Xuan K, Delattre JY, Sanson M (2010) All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 74:1886–1890CrossRefPubMedGoogle Scholar
  73. 73.
    Kuan CT, Wikstrand CJ, Bigner DD (2001) EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 8:83–96CrossRefPubMedGoogle Scholar
  74. 74.
    Fallon KB, Palmer CA, Roth KA, Nabors LB, Wang W, Carpenter M, Banerjee R, Forsyth P, Rich K, Perry A (2004) Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas. J Neuropathol Exp Neurol 63:314–322PubMedGoogle Scholar
  75. 75.
    Hoang-Xuan K, He J, Huguet S, Mokhtari K, Marie Y, Kujas M, Leuraud P, Capelle L, Delattre JY, Poirier J, Broet P, Sanson M (2001) Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression. Neurology 57:1278–1281PubMedGoogle Scholar
  76. 76.
    Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG 2nd, Buckner JC, James CD, Aldape K (2007) Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25:2288–2294CrossRefPubMedGoogle Scholar
  77. 77.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899CrossRefPubMedGoogle Scholar
  78. 78.
    Liu L, Bäcklund LM, Nilsson BR, Grandér D, Ichimura K, Goike HM, Collins VP (2005) Clinical significance of EGFR amplification and the aberrant EGFRvIII transcript in conventionally treated astrocytic gliomas. J Mol Med 83(11):917–926CrossRefPubMedGoogle Scholar
  79. 79.
    Lai R, Recht LD, Reardon DA, Paleologos N, Groves MD, Rosenfeld MR, Meech S, Davis TA, Pavlov D, Sampson JH (2010) Interim data for ACT III: Phase II trial of PF-04948568 (CDX-110) in combination with temozolomide (TMZ) in patients (pts) with glioblastoma (GBM) [Abstract]. J Clin Oncol 28: suppl; abstract 2014Google Scholar
  80. 80.
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KA, Wen PY, Fine HA, Mehta M, Deangelis LM, Lieberman F, Cloughesy TF, Robins HI, Dancey J, Prados MD (2010) A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol 12:95–103PubMedGoogle Scholar
  81. 81.
    Lieberman FS, Cloughesy T, Malkin M, Fine H, Fink K, Junck L, Kuhn J, Mehta M, Wen P, Prados M (2003) Phase I–II study of ZD-1839 for recurrent malignant gliomas and meningiomas progressing after radiation therapy [abstract]. J Clin Oncol 22:105 (abstact 421)Google Scholar
  82. 82.
    Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142CrossRefPubMedGoogle Scholar
  83. 83.
    Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GH, Suh JH, Toms SA, Vogelbaum MA, Weil RJ, Elson P, Barnett GH (2010) Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 98:93–99CrossRefPubMedGoogle Scholar
  84. 84.
    Yung WK, Vredenburgh JJ, Cloughesy TF, Nghiemphu P, Klencke B, Gilbert MR, Reardon DA, Prados MD (2010) Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro Oncol doi:10.1093/neuonc/noq072
  85. 85.
    Vogelbaum MA, Peerboom G, Stevens G, Barnett G, Brewer C (2004) Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results [abstract]. J Clin Oncol 22:1558Google Scholar
  86. 86.
    Lassman AB, Rossi MR, Raizer JJ, Abrey LE, Lieberman FS, Grefe CN, Lamborn K, Pao W, Shih AH, Kuhn JG, Wilson R, Nowak NJ, Cowell JK, DeAngelis LM, Wen P, Gilbert MR, Chang S, Yung WA, Prados M, Holland EC (2005) Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res 11:7841–7850 [published correction appears in Clin Cancer Res 2005;7812(7841):7322]Google Scholar
  87. 87.
    Clarke JL, Pao W, Wu N, Miller VA, Lassman AB (2010) High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol doi:10.1007/s11060-010-0128-6
  88. 88.
    Hofer S, Frei K (2007) Gefitinib concentrations in human glioblastoma tissue. J Neurooncol 82:175–176CrossRefPubMedGoogle Scholar
  89. 89.
    Kuhn J, Robins HI, Mehta M, Fine H, Cloughesy T, Wen PY, Chang S, DeAngelis LM, Lieberman F, Reardon D, Abrey LE, Lassman AB, Aldape K, Yung WK, Dancey J, Lamborn K, Prados M (2008) Tumor sequestration of lapatinib (NABTC 04-01) [Abstract ET-05]. Neuro Oncol 10:783Google Scholar
  90. 90.
    Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, Baumber R, Lamborn KR, Kapadia A, Malec M, Berger MS, Stokoe D (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887CrossRefPubMedGoogle Scholar
  91. 91.
    Custodio A, Calles A, Perez-Segura P (2010) Response to erlotinib in recurrent glioblastoma multiforme showing coexpression of EGFRvIII and PTEN. Clin Transl Oncol 12:310–314CrossRefPubMedGoogle Scholar
  92. 92.
    Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R (2008) Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 14:957–960CrossRefPubMedGoogle Scholar
  93. 93.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268–1274CrossRefPubMedGoogle Scholar
  94. 94.
    Wick W, Weller M, van den Bent M, Stupp R (2010) Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol 28:e188–189; author reply e190–182Google Scholar
  95. 95.
    Lai A, Filka E, McGibbon B, Nghiemphu PL, Graham C, Yong WH, Mischel P, Liau LM, Bergsneider M, Pope W, Selch M, Cloughesy T (2008) Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 71:1372–1380PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of OncologyUniversity Hospital ZürichZürichSwitzerland
  2. 2.Department of Neurology and Brain Tumor CenterMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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