The Prognostic Significance of Epidermal Growth Factor Receptor Amplification and Epidermal Growth Factor Receptor Variant III Mutation in Glioblastoma: A Systematic Review and Meta-Analysis with Implications for Targeted Therapy

Abstract

Glioblastoma (GBM) is the most aggressive and heterogeneous neoplasm among central nervous system tumors, with a dismal prognosis and a high recurrence rate. Among the various genetic alterations found in GBM, the amplification of epidermal growth factor receptor (EGFR) and the EGFR variant III (EGFRvIII) mutation are among the most common, though their prognostic value remains controversial. This systematic review and meta-analysis aimed to provide a comprehensive evaluation of the diagnostic and prognostic significance of EGFR amplification and the EGFRvIII mutation in GBM patients, incorporating recent studies published in the past few years to offer a more complete and up-to-date analysis. An extensive search of the PubMed, Web of Science, and Scopus databases was conducted, including studies that reported on EGFR and/or the EGFRvIII mutation status with detailed survival data. A total of 32 studies with 4208 GBM patients were included. The results indicated that EGFR amplification significantly correlated with worse OS (Overall survival) (HR = 1.27, 95% CI: 1.03-1.57), suggesting that EGFR amplification is an independent prognostic marker. The prognostic value of EGFRvIII was inconclusive, with a pooled hazard ratio for overall survival of 1.13 (95% CI: 0.94-1.36), indicating no significant effect on survival in the general population. However, a subgroup analysis suggested that EGFRvIII may be associated with poorer outcomes, particularly in recurrent GBM patients, where its prognostic significance became more evident. Furthermore, subgroup analyses based on geographic region revealed significant heterogeneity in the prognostic impact of EGFR amplification across different populations. In American cohorts, EGFR amplification was strongly associated with an increased risk of mortality (HR = 1.53, 95% CI: 1.28-1.84, p = 0.001), suggesting that it serves as a more reliable prognostic marker in this region. In contrast, no significant prognostic impact of EGFR amplification was observed in Asian (HR = 0.64, 95% CI: 0.35-1.17) or European (HR = 0.98, 95% CI: 0.80-1.19) populations. Overall, this study underscores the potential of EGFR amplification as a prognostic marker in GBM, while further research is needed to fully elucidate the role of the EGFRvIII mutation, particularly in specific patient subgroups. Clarifying these associations could offer important insights for targeted treatment strategies, improving patient outcomes.

Keywords: EGFR amplification; EGFRvIII mutation; glioblastoma (GBM); prognostic biomarker.

Figure 1

A PRISMA flow chart of the study selection process.

Figure 2

Forest plots illustrating the association between the EGFRvIII mutation or EGFR amplification and the overall survival in GBM patients. Random–effects model was used for analysis. (a) Forest plot showing no significant association between EGFRvIII status and OS in GBM patients. (b) Forest plot demonstrating that EGFR amplification is associated with poorer OS in GBM patients. In both panels, the size of the red squares represents the relative weight of each study in the overall comparison. The blue diamond at the bottom summarizes the pooled effect estimate, including the HR and the 95% CI across all the included studies. HR values of >1.0 indicate a higher risk of mortality for patients with the EGFRvIII mutation or EGFR amplification compared to those without, while values of <1.0 indicate the opposite. Abbreviations: SE, standard error; CI, confidence interval [11,15,16,17,18,19,20,21,22,23,24,26,27,28,29,31,32,33,34,35,36,37,38,39,40,41,42,43,44].

Figure 3

Forest plots illustrating the association of the EGFRvIII mutation and EGFR amplification with progression-free survival in GBM patients. Random-effects model was used for analysis. (a) Forest plot showing no significant association between the EGFRvIII mutation and PFS. (b) Forest plot showing no significant association between EGFR amplification and PFS. In both panels, the size of the red squares represents the relative weight of each study in the overall comparison. The blue diamond at the bottom summarizes the pooled effect estimate, including the HR and 95% CI across all the included studies. HR values of >1.0 indicate a higher risk of progression for patients with the EGFRvIII mutation or EGFR amplification compared to those without, while values of <1.0 indicate the opposite. Abbreviations: SE, standard error; CI, confidence interval [11,19,25,26,27,28,30,31,38,43,44].

Figure 4

Forest plots illustrating the association of genetic alterations and tumor characteristics with overall survival in GBM patients. (a) Forest plot showing no significant association between EGFR amplification co-occurring with EGFRvIII mutation and OS. Random-effects model was used for analysis. (b) Forest plot showing no significant association between IDH wild-type and OS in GBM patients. In both panels, the size of the red squares represents the relative weight of each study in the overall comparison. The blue diamond at the bottom summarizes the pooled effect estimate, including the HR and the 95% CI across all the included studies. Fixed-effects model was used for analysis [16,19,20,22,28,29,34,38,39,42].

Figure 5

Subgroup analyses based on geographic populations and tumor characteristics. (a) Forest plot showing that the EGFRvIII mutation is associated with poorer survival in the Americas but not in Asia or Europe. Random-effects model was used for analysis. (b) A forest plot showing that EGFR amplification has a poor prognostic impact in the Americas but not in Asia or Europe. In both panels, the size of the red squares represents the relative weight of each study in the overall comparison. The blue diamond at the bottom summarizes the pooled effect estimate, including the HR and the 95% CI across all the included studies. Fixed-effects model was used for analysis [10,15,16,17,18,19,20,21,22,23,24,26,27,29,31,32,33,34,35,36,37,38,40,41,42,43,44].

Figure 6

Forest plot showing that EGFRvIII mutation is associated with poorer survival in recurrent GBM. In both panels, the size of the red squares represents the relative weight of each study in the overall comparison. The blue diamond at the bottom summarizes the pooled effect estimate, including the HR and the 95% CI across all the included studies. Fixed-effects model was used for analysis [19,22,23,28,29,31,32,34,35,38,42,43,44].