In vivo evaluation of EGFRvIII mutation in primary glioblastoma patients via complex multiparametric MRI signature

Background: Epidermal growth factor receptor variant III (EGFRvIII) is a driver mutation and potential therapeutic target in glioblastoma. Non-invasive in vivo EGFRvIII determination, using clinically acquired multiparametric MRI sequences, could assist in assessing spatial heterogeneity related to EGFRvIII, currently not captured via single-specimen analyses. We hypothesize that integration of subtle, yet distinctive, quantitative imaging/radiomic patterns using machine learning may lead to non-invasively determining molecular characteristics, and particularly the EGFRvIII mutation. Methods: We integrated diverse imaging features, including the tumor's spatial distribution pattern, via support vector machines, to construct an imaging signature of EGFRvIII. This signature was evaluated in independent discovery (n = 75) and replication (n = 54) cohorts of de novo glioblastoma, and compared with the EGFRvIII status obtained through an assay based on next-generation sequencing. Results: The cross-validated accuracy of the EGFRvIII signature in classifying the mutation status in individual patients of the independent discovery and replication cohorts was 85.3% (specificity = 86.3%, sensitivity = 83.3%, area under the curve [AUC] = 0.85) and 87% (specificity = 90%, sensitivity = 78.6%, AUC = 0.86), respectively. The signature was consistent with EGFRvIII+ tumors having increased neovascularization and cell density, as well as a distinctive spatial pattern involving relatively more frontal and parietal regions compared with EGFRvIII- tumors. Conclusions: An imaging signature of EGFRvIII was found, revealing a complex, yet distinct macroscopic glioblastoma phenotype. By non-invasively capturing the tumor in its entirety, the proposed methodology can assist in evaluating the tumor's spatial heterogeneity, hence overcoming common spatial sampling limitations of tissue-based analyses. This signature can preoperatively stratify patients for EGFRvIII-targeted therapies, and potentially monitor dynamic mutational changes during treatment.