Expression of EGFRvIII in Glioblastoma: Prognostic Significance Revisited.
Maurizio Martini, Roberto Pallini, Nicola Montano, Tonia Cenci, Benedetto D'Alessandro, Luigi M Larocca. Catholic University, School of Medicine, Rome, Italy
Background: In vitro and in vivo studies have shown that expression of the epidermal growth factor receptor variant III (EGFRvIII) is associated with increased proliferation and aggressiveness of glioma cells. However, the impact of EGFRvIII on survival of patients with glioblastoma (GBM) has not definitively been established.
Design: We prospectively evaluated 73 adult patients with primary GBM who underwent surgical resection followed by standard radiotherapy and temozolomide. Clinical variables included age, sex, Karnofsky Performance Status (KPS), Radiation Therapy Oncology Group RPA score, and extent of tumor resection. Tumor samples were analyzed for expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for expression of PTEN by immunohistochemistry. Overall survival (OS) curves were estimated by the Kaplan-Meier method. Multivariate analysis was performed by Cox regression model. In 10 patients who presented with tumor recurrence, EGFRvIII was determined both before and after radio-chemotherapy by Real Time RT-PCR. Sensitivity to temozolomide was assessed in EGFRvIII-positive and EGFRvIII-negative GBM cell lines established from the same tumor.
Results: Age<60 years, preoperative KPS>70, RPA score III and IV, and Ki67 index<20% significantly associated with longer OS (p=0.0069, p=0.0035, p<0.0001, and p=0.0286, respectively). EGFRvIII expression did identify patients with significantly longer OS (p=0.0047). Patients with EGFRvIII expression and normal PTEN showed better OS relative to those cases with EGFRvIII expression and loss of PTEN (p=0.0054; 0.0028). On multivariate analysis, age>60 years (p=0.0089), KPS≥70 (p=0.0078), Ki67 index≤20% (p=0.0069), and expression of EGFRvIII (p=0.0255) were independent prognosticators for OS. In GBMs recurring after radio-chemotherapy, EGFRvIII was reduced by 4.5 fold in average as compared with the paired tumors at primary surgery. In vitro, the EGFRvIII-negative cells were more resistant to high doses of temozolomide than the EGFRvIII-positive ones.
Conclusions: EGFRvIII expression is associated with prolonged survival of GBM patients treated with surgery and adjuvant radiotherapy and temozolomide. Depletion of EGFRvIII in recurrent GBMs and low sensitivity to temozolomide in vitro indicate that the EGFRvIII-negative cell fraction is involved in resistance to radio-chemotherapy and tumor repopulation.
Tuesday, March 1, 2011 1:15 PM
Platform Session: Section G, Tuesday Afternoon