Journal of Neuro-Oncology

, Volume 85, Issue 3, pp 281–287 | Cite as

Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma

  • Jean-François MineoEmail author
  • Anne Bordron
  • Marc Baroncini
  • Claude-Alain Maurage
  • Carole Ramirez
  • Rose-Mary Siminski
  • Christian Berthou
  • Phong Dam Hieu
Lab Investigation-Human/Animal Tissue



Anti-Human Epithelial Receptor Type 2 (HER2) antibodies have the ability to induce in vitro apoptosis of glioblastoma (GBM) cells. This study was designed to evaluate the variability of HER2 expression in GBM and its role as a possible prognosis factor.


Data of 57 patients with GBM and 16 patients with grade III gliomas were retrospectively analyzed. The expression of HER2 was determined by immunohistochemistry and intensity was noted from 0+ to 3+. We compared the HER2 expression in de novo GBM and in GBM resulting from anaplastic transformation of low-grade glioma (“secondary GBM”). Statistical analysis was performed using univariate analysis and the Kaplan–Meier method.


All GBM expressing highly HER2 (2+ and 3+) were de novo GBM. All secondary GBM expressed HER2 with low intensity (0+ and 1+). Survival time was significantly longer when HER2 expression was low (Log Rank test P = 0.04). The patterns of HER2 expression were similar between grade III gliomas and secondary GBM.


To our best knowledge, our study showed for the first time a significant association between HER2 expression and the type of GBM, with subsequent influence on survival rate. GBM with low-HER2 expression are more likely to be secondary GBM, carrying a better prognosis than de novo GBM.


Glioblastoma De novo glioblastoma Secondary glioblastoma HER2 Survival 



Blood Brain barrier




Human Epithelial Receptor Type 2




Tissue Micro array


World Health Organization


O6-methyl guanine-DNA methyl transferase



The tissue arrayer is a gift of M. Copin “Ligue contre le Cancer,” Nord-Pas de Calais, France; We are grateful to Mrs Tracey Montagnon for her English editorial assistance


  1. 1.
    Kleihues P, Cavenee WK (eds) (2000) Tumours of the nervous central system. Pathology and genetics. World health organization of tumours. IARC Press, Lyon, pp 55–69Google Scholar
  2. 2.
    Mineo JF, Quintin-Roue I, Lucas B, Buburuzan V, Besson G (2002) Glioblastomas: clinical study and prognosis factors. Neurochirurgie 48:500–509PubMedGoogle Scholar
  3. 3.
    Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta neuropathol 109:93–108PubMedCrossRefGoogle Scholar
  4. 4.
    Rainov N, Dobberstein K, Bahn H, Holzhausen H, Lautenschlager C, Heidecke V, Burkert W (1997) Prognosis factors in malignant glioma: influence of the overexpression of oncogene and tumor suppressor gene products on survival. J Neurooncol 35:13–28PubMedCrossRefGoogle Scholar
  5. 5.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, Demonte F, Lang FF, McCutheon IE, Hassenbuch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extend of resection of resection and survival. J Neurosurg 95:190–198PubMedGoogle Scholar
  6. 6.
    Mineo JF, Bordron A, Ramirez C, Baroncini M, Maurage CA, Blond S, Dam Hieu P (2007) Prognosis factors of Glioblastoma multiforme: a multivariate analysis in 340 patients. Acta Neurochir 149(3):245–253CrossRefGoogle Scholar
  7. 7.
    Devaux BC, O’Fallon JR, Kelly PJ (1993) Resection, biopsy and survival in malignant glial neoplasm. J Neurosurg 78:767–775PubMedGoogle Scholar
  8. 8.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, De Tribolet N, Weller M, Kros JM, Hainfeller JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross G, Janser RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  9. 9.
    Stark A, Nabavi A, Mehdorn HM, Blömer U (2005) Glioblastoma multiforme-report of 267 cases treated at a single institution. Surg Neurol 63:162–169PubMedCrossRefGoogle Scholar
  10. 10.
    Koka V, Potti A, Forseen SE, Pervez H, Fraiman GN, Koch M, Levitt R (2003) Role of HER-2/neu overexpression and clinical determinant of early mortality in glioblastoma multiforme. Am J Clin Oncol 26:332–335PubMedCrossRefGoogle Scholar
  11. 11.
    Potti A, Forseen SE, Koka VK, Pervez H, Koch M, Fraiman GN, Mehdi SA, Levitt R (2004) Determination of HER/neu overexpression and clinical predictors of survival in a cohort of 347 patients with primary malignant brain tumors. Cancer Invest 22:537–544PubMedCrossRefGoogle Scholar
  12. 12.
    Gilbertson RJ, Wickramasinghe C, Herman R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry RH, Lunec J, Pearson AD, Ellison D (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712PubMedCrossRefGoogle Scholar
  13. 13.
    Pellikainen J, Naukkarinen A, Ropponen K, Rummukainen J, Kataja V, Kellokoski J, Eskelinen M, Kosma VM (2004) Expression of HER2 and its association with AP-2 in breast cancer. Eur J Cancer 40:1485–1495PubMedCrossRefGoogle Scholar
  14. 14.
    Tateishi M, Teruyoshi I, Mitsudomi T, Kanedo S, Sugimachi K (2004) Prognostic value of c-erbB2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur J Cancer 27:1372–1375Google Scholar
  15. 15.
    Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Twaddell T, Henderson IC, Norton L (1996) Phase II study of weekly intravenous recombinant humanized anti-p185 HER2 monolclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737–744PubMedGoogle Scholar
  16. 16.
    Mineo JF, Bordron A, Quintin-Roué I, Loisel S, Le Ster K, Buhé V, Lagarde N, Berthou C (2004) Recombinant Humanized Anti-HER2/ neu Antibody (Herceptin®) induces cellular death of glioblastomas. Br J Cancer 91:1195–1199PubMedGoogle Scholar
  17. 17.
    Mineo JF, Bordron A, Isabelle QR, Maurage CA, Buhé V, Loisel S, Dubois F, Blond S, Berthou C (2006) Increasing of HER2 membranar density in human glioblastoma U251MG cell line established in a new nude mice model. J Neurooncol 76:249–255PubMedCrossRefGoogle Scholar
  18. 18.
    Staverosky JA, Muldoon LL, Guo S, Evans AJ, Neuwelt AJ, Clinton GM (2005) Herstatin, an autoinhibitor of the epidermal growth factor receptor family, blocks the intracranial growth of glioblastoma. Clin Cancer Res 11:335–340PubMedGoogle Scholar
  19. 19.
    Forseen SE, Potti A, Koka V, Koch M, Fraiman G, Levitt R (2002) Identification and relationship of HER2/neu overexpression to short-term mortality in primary malignant brain tumors. Anticancer Res 22:1599–1602PubMedGoogle Scholar
  20. 20.
    Kaplan EL, Meier P (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  21. 21.
    Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1:44–51PubMedCrossRefGoogle Scholar
  22. 22.
    Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H (2000) Loss of heterozygosity on chromosome 10 is more extensive in primary (De Novo) than in secondary glioblastomes. Lab Invest 80:65–71PubMedCrossRefGoogle Scholar
  23. 23.
    Press MF, Cordon-Cardo C, Slamon DJ (1990) Expression of the HER2/neu proto-oncogene in normal adult and fetal tissues. Oncogene 5:953–962PubMedGoogle Scholar
  24. 24.
    Kristt DA, Yarden Y (1996) Differences between phosphotyrosine accumulation and neu/erbB-2 receptor expression in astrocytic proliferative processes: implication for glial oncogenesis. Cancer 78:1272–1283PubMedCrossRefGoogle Scholar
  25. 25.
    Bian XW, Shi JQ, Liu FX (2000) Pathologic significance of proliferative activity and oncoprotein expression in astrocytic tumors. Anal Quant Cytol Histol 22:429–437PubMedGoogle Scholar
  26. 26.
    Harwerth IM, Wels W, Schlegel J, Müller M, Hynes NE (1993) Monoclonal antibodies directed to the erbB2 receptor inhibit in vivo tumour cell growth. Br J cancer 68:1140–1145PubMedGoogle Scholar
  27. 27.
    Sliwkowski M, Lofgren J, Lewis G, Hostaling T, Fendly B, Fox J (1999) Nonclinical studies addressing the mechanism of action of trastuzumab. Semin Oncol 26:60–70PubMedGoogle Scholar
  28. 28.
    Vajkoczy P, Schilling L, Ullrich A, Schmiedek P, Menger M (1998) Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse. J Cereb Blood Flow Metab 18:510–520PubMedCrossRefGoogle Scholar
  29. 29.
    Dietzmann K, Von Bossanyi P (1994) Coexpression of epidermal groth factor receptor protein and c-erbB2 oncoprotein in human astrocytic tumors. Zentralbl pathol 140:335–341PubMedGoogle Scholar
  30. 30.
    Westphal M, Meima L, Szonyi E, Lofgren L, Meissner H, Hamel W, Nikolics K, Sliwkowski M (1997) Heregulins and the Erb-2/3/4 receptors in gliomas. J Neurooncol 35:335–346PubMedCrossRefGoogle Scholar
  31. 31.
    Büchler P, Reber H, Büchler M, Roth M, Büchler M, Friess H, Isacoff W, Hines O (2001) Therapy for pancreatic cancer with a recombinant humanized anti-HER2 antibody. J Gastrointest Surg 5:139–146PubMedCrossRefGoogle Scholar
  32. 32.
    Lang FF, Miller DC, Koslow M, Newcomb EW (1994) Pathways leading to glioblastoma multiforme : a molecular analysis of genetic alterations in 65 astrocytic tumors. J Neurosurg 81:427–436PubMedCrossRefGoogle Scholar
  33. 33.
    Nozaki M, Tada M, Kobayashi H, Zhang CL, Sawamura Y, Abe H, Ishii N, Van Meir EG (1999) Roles of the functional loss of P53 and other genes in astrocytoma tumorigenesis and progression. Neuro-oncology 1:124–137PubMedGoogle Scholar
  34. 34.
    Thomas CY, Chouinard M, Cox M, Parson S, Stalling-Mann M, Garcia R, Jove R, Wharen R (2003) Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. Int J Cancer 104:19–27PubMedCrossRefGoogle Scholar
  35. 35.
    Haapasalo H, Hyytinen E, Sallinen P, Helin H, Kallioniemi OP, Isola J (1996) C-erbB2 in astrocytomas: infrequent overexpression by immunohistochemistry and absence of gene amplification by fluorescence in situ hybridization. Br J Cancer 73:620–623PubMedGoogle Scholar
  36. 36.
    Keles GE, Anderson B, Berger MS (1999) The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol 52:371–379PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Jean-François Mineo
    • 1
    Email author
  • Anne Bordron
    • 2
  • Marc Baroncini
    • 1
  • Claude-Alain Maurage
    • 3
  • Carole Ramirez
    • 1
  • Rose-Mary Siminski
    • 4
  • Christian Berthou
    • 2
  • Phong Dam Hieu
    • 5
  1. 1.Department of NeurosurgeryUniversity Medical Center, Hospital Roger SalengroLilleFrance
  2. 2.Laboratory of Cell Therapy and HematologyUniversity Medical CenterBrestFrance
  3. 3.Laboratory of Pathology, EurasanteUniversity Medical CenterLilleFrance
  4. 4.Laboratory of HistologyUniversity Medical CenterLilleFrance
  5. 5.Department of NeurosurgeryUniversity Medical CenterBrestFrance

Personalised recommendations