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Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma

Christopher E. Pelloski, Karla V. Ballman, Alfred F. Furth, Li Zhang, E. Lin, Erik P. Sulman, Krishna Bhat, J. Matthew McDonald, W.K. Alfred Yung, Howard Colman, Shiao Y. Woo, Amy B. Heimberger, Dima Suki, Michael D. Prados, Susan M. Chang, Fred G. Barker, II, Jan C. Buckner, C. David James, Kenneth Aldape

From the Departments of Radiation Oncology, Biostatistics and Applied Mathematics, Pathology, Neuro-Oncology, and Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Divisions of Biostatistics and Experimental Pathology and Department of Medical Oncology, Mayo Clinic, Rochester, MN; Department of Neurosurgery, University of California San Francisco School of Medicine, San Francisco, CA; and Neurosurgical Service, Massachusetts General Hospital, Boston, MA

Address reprint requests to Kenneth Aldape, MD, Department of Pathology, Unit 85, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: kaldape{at}mdanderson.org

Purpose: The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status.

Patients and Methods: The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class.

Results: The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40–negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers.

Conclusion: Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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