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We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR^A289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR^A289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFR^A289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR^A289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR^A289V mutation in glioblastoma, postulating EGFR^A289V as a molecular marker for responsiveness …