Skip to main content

Advertisement

SpringerLink
Log in

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

  • Lab Investigation-Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Findings

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

BBB:

Blood Brain barrier

GBM:

Glioblastoma

HER2:

Human Epithelial Receptor Type 2

IHC:

Immunohistochemistry

TMA:

Tissue Micro array

WHO:

World Health Organization

MGMT:

O6-methyl guanine-DNA methyl transferase

References

  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 55–69

    Google Scholar 

  2. Mineo JF, Quintin-Roue I, Lucas B, Buburuzan V, Besson G (2002) Glioblastomas: clinical study and prognosis factors. Neurochirurgie 48:500–509

    PubMed  Google Scholar 

  3. Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta neuropathol 109:93–108

    Article  PubMed  Google Scholar 

  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 35:13–28

    Article  PubMed  CAS  Google Scholar 

  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 95:190–198

    PubMed  CAS  Google Scholar 

  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):245–253

    Article  Google Scholar 

  7. Devaux BC, O’Fallon JR, Kelly PJ (1993) Resection, biopsy and survival in malignant glial neoplasm. J Neurosurg 78:767–775

    PubMed  CAS  Google Scholar 

  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 352:997–1003

    Article  PubMed  CAS  Google Scholar 

  9. Stark A, Nabavi A, Mehdorn HM, Blömer U (2005) Glioblastoma multiforme-report of 267 cases treated at a single institution. Surg Neurol 63:162–169

    Article  PubMed  Google Scholar 

  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 26:332–335

    Article  PubMed  Google Scholar 

  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 22:537–544

    Article  PubMed  CAS  Google Scholar 

  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 85:705–712

    Article  PubMed  CAS  Google Scholar 

  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 40:1485–1495

    Article  PubMed  CAS  Google Scholar 

  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 27:1372–1375

    Google Scholar 

  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 14:737–744

    PubMed  CAS  Google Scholar 

  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 91:1195–1199

    PubMed  CAS  Google Scholar 

  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 76:249–255

    Article  PubMed  CAS  Google Scholar 

  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 11:335–340

    PubMed  CAS  Google Scholar 

  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 22:1599–1602

    PubMed  CAS  Google Scholar 

  20. Kaplan EL, Meier P (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  21. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1:44–51

    Article  PubMed  CAS  Google Scholar 

  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 80:65–71

    Article  PubMed  CAS  Google Scholar 

  23. Press MF, Cordon-Cardo C, Slamon DJ (1990) Expression of the HER2/neu proto-oncogene in normal adult and fetal tissues. Oncogene 5:953–962

    PubMed  CAS  Google Scholar 

  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 78:1272–1283

    Article  PubMed  CAS  Google Scholar 

  25. Bian XW, Shi JQ, Liu FX (2000) Pathologic significance of proliferative activity and oncoprotein expression in astrocytic tumors. Anal Quant Cytol Histol 22:429–437

    PubMed  CAS  Google Scholar 

  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 68:1140–1145

    PubMed  CAS  Google Scholar 

  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 26:60–70

    PubMed  CAS  Google Scholar 

  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 18:510–520

    Article  PubMed  CAS  Google Scholar 

  29. Dietzmann K, Von Bossanyi P (1994) Coexpression of epidermal groth factor receptor protein and c-erbB2 oncoprotein in human astrocytic tumors. Zentralbl pathol 140:335–341

    PubMed  CAS  Google Scholar 

  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 35:335–346

    Article  PubMed  CAS  Google Scholar 

  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 5:139–146

    Article  PubMed  Google Scholar 

  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 81:427–436

    Article  PubMed  CAS  Google Scholar 

  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 1:124–137

    PubMed  CAS  Google Scholar 

  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 104:19–27

    Article  PubMed  CAS  Google Scholar 

  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 73:620–623

    PubMed  CAS  Google Scholar 

  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 52:371–379

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University Medical Center, Hospital Roger Salengro, 59037, Lille, France

    Jean-François Mineo, Marc Baroncini & Carole Ramirez

  2. Laboratory of Cell Therapy and Hematology, University Medical Center, 29609, Brest, France

    Anne Bordron & Christian Berthou

  3. Laboratory of Pathology, Eurasante, University Medical Center, 59037, Lille, France

    Claude-Alain Maurage

  4. Laboratory of Histology, University Medical Center, 59037, Lille, France

    Rose-Mary Siminski

  5. Department of Neurosurgery, University Medical Center, 29609, Brest, France

    Phong Dam Hieu

Authors
  1. Jean-François Mineo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne Bordron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Baroncini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claude-Alain Maurage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carole Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rose-Mary Siminski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Berthou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Phong Dam Hieu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-François Mineo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mineo, JF., Bordron, A., Baroncini, M. et al. Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neurooncol 85, 281–287 (2007). https://doi.org/10.1007/s11060-007-9424-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9424-1

Keywords

Search

Navigation