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Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. The ability to non-invasively profile tumors can avoid a risky biopsy and opens avenues for testing novel therapies by accurately stratifying patients to receive the right therapy. Here, we provide evidence of EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, an EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM(NCT01112527).    Methods  We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment.    Results  Firstly, longRNASeq allowed the detection of thousands of mRNA, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers.  Secondly, we observed a differential expression profile in serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer.  Thirdly, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification.  Finally, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy.    Conclusion  This study represents the first longitudinal profiling of the EV transcriptome in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring.

OMRT-2. Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma