The Actionable Genomic Landscape in Glioblastoma

The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The recent exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumor type. However, lack of precision oncology testing at diagnosis means such therapeutic opportunities are missed. To address this unmet clinical need we established Oncofocus®, a clinically validated precision oncology test for solid tumors, detecting actionable genetic variants in 505 genes linked to 764 anti-cancer targeted agents/combinations and immunotherapies. Analysis of trending data in relation to a cohort of 55 glioblastoma cases has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes. The majority of patients harbored three or more actionable mutations (median 3, range 1-9) affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signaling pathways, DNA-damage repair pathways and cell cycle checkpoints. Oncogenic fusion genes were identified at high frequency (23.6%), including two novel fusions in glioblastoma, namely TBL1XR1-PIK3CA and FIP1L1–PDGFRA. Linkage with anti-PD-L1/PD-1 immunotherapy was also identified in 63.6% of glioblastoma patients as a consequence of either elevated PD-L1 levels or mutations in DNA-damage repair genes. Despite the commonly held perception that treatment options for glioblastoma are limited, we have shown here that glioblastoma harbors a diverse actionable mutational landscape providing a broad therapeutic armamentarium of targeted therapies and immunotherapies. Our data indicates that precision oncology testing should be considered as part of the standard molecular diagnostic work up for glioblastoma.