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

Abstract

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.