EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status

SIMPLE SUMMARY: We compared gene expression in matched primary and recurrent glioblastoma samples, with a focus on those harbouring extra copies of the gene called EGFR (amplified samples). Our results show that in the setting of newly diagnosed glioblastoma, EGFR-amplified compared to EGFR non-amplified tumours display altered gene expression in the EGFR pathway, but this distinction is lost in the setting of recurrent disease. We validated this finding in an independent dataset. EGFR pathway overexpression may be a common mechanism underlying glioblastoma recurrence. ABSTRACT: Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (n = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.