Influence of expression of EGFR and PTEN on outcome in patients with primary glioblastoma treated with standard radiochemotherapy and cetuximab: Interim analysis from the GERT-Protocol

Abstract

2050 Background: The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma (GBM). Anti-EGFR treatments have shown to be associated with EGFR deletion mutant variant III (EGFRvIII) expression in presence of PTEN expression, suggesting a prognostic role of EGFRvIII expression. We determined molecular biomarkers and correlated these with outcome in the GERT trial. Methods: To date, 39 patients were treated within the GERT protocol (Combs SE et al., 2006) evaluating radiochemotherapy (RCHT) with temozolomide (TMZ) and weekly CTX. Pretreatment paraffin-embedded tumor tissue of 32 patients was available for molecular analysis. Twenty-three patients were male, 9 were female. Median age was 49 years. We analyzed amplification of EGFR, expression of EGFR, EGFRvIII, the tumor-suppressor PTEN and O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Results: Median follow-up was 12 months. Overall survival (OS) at 12 and 24 months was 89% and 42%. Progression-free survival (PFS) was 76% and 45% at 6 and 12 months, respectively. MGMT promoter hypermethylation was detected in 16/32 tumours. Methylated MGMT did not impact PFS or OS (p = 0.48 and p = 0.08). Data on EGFR copy number of 31/32 tumors showed EGFR gene amplification in 11 tumors. EGFR protein expression was found in 23/32 patients. EGFR-amplification did not impact PFS or OS (p = 0.56, p = 0.3). Patients with EGFR expression showed longer PFS (p = 0.05), but unaltered OS (p = 0.06). EGFRvIII was seen in 5/32 patients, only in tumors with EGFR amplification. Expression of EGFRvIII did not influence PFS (p = 0.26) or OS (p = 0.09). Reduced PTEN (22/32) did not influence PFS or OS (p = 0.27, p = 0.85). Outcome was not associated with coexpression of EGFRvIII and PTEN (n = 5); coexpression of EGFR and PTEN (n = 13) significantly influenced PFS (p = 0.005), but not OS (p = 0.10). Conclusions: Expression of EGFR, and coexpression of EGFR/PTEN is associated with significant increase in PFS after RCHT with TMZ and CTX. EGFR-amplification, reduction of PTEN expression and expression of EGFRvIII did not impact PFS nor OS. Randomized data in the primary treatment of GBM might help identify patients for anti-EGFR therapies. [Table: see text]