Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. Methods: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome-sequencing and tumor RNA-sequencing was performed to identify molecular targets for potential matched therapy. A multi-disciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome-sequencing was completed for all patients and RNA-sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression-free 21 months after surgery, three-times longer than the patient's previous time to progression. Analysis of matched non-enhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Conclusion: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system (CNS)-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma.
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