Abstract 4667: The complex genomic landscape of glial tumors reveals distinct subclasses and potential therapeutic targets associated with clinical responses to targeted inhibitors
Authors: Chmielecki Juliann , Goldberg Michael E. , Fichtenholtz Alex , Elvin Julia , Frampton Garrett M. , Ali Siraj M. , Ross Jeffrey S. , Morosini Deborah , Miller Vincent A. , Piccioni David , Kesari Santosh , Stephens Philip J. 
Published: August 2015

The genomic landscape of glial tumors is complex, and the identification of effective targeted treatments has proven challenging. To find potential therapeutic vulnerabilities, we analyzed the spectrum of genomic alterations in over 700 confirmed glial tumors. Extracted DNA was subjected to hybrid capture for 236 cancer-related genes plus 19 genes frequently rearranged in cancer, and sequenced to a median depth of &gt;500x. Resultant sequences were assessed for base substitutions, insertions and deletions, copy number changes, and select rearrangements. Glioblastomas showed frequent alterations in CDKN2A/B (55%), TP53 (40%), PTEN (40%), and EGFR (40%), including EGFRviii (18.6%). Anaplastic astrocytomas harbored frequent alterations in TP53 (65%), IDH1 (55%), and ATRX (51%). Astrocytomas, including both low grade and mixed grade tumors, had a similar genomic landscape to that of anaplastic astrocytomas with frequent alterations in TP53 (53%), IDH1 (45%), and ATRX (36%). In addition to known fusions involving EGFR, FGFR3, and BRAF, we also identified rare, but therapeutically relevant, fusions involving ROS1 and PDGFRA that have been reported exclusively in lung cancer and hypereosinophilic syndrome, respectively. Unsupervised clustering of all glial tumors based on genomic alterations identified six distinct classes each driven by unique combinations of genomic events. Tumors driven by concurrent alterations in IDH1, ATRX, and TP53 were associated with younger age and anaplastic astrocytoma histology (p = 2.2×10−16). The addition of NF1 alterations to IDH1, ATRX, and TP53 mutations was modestly enriched in glioblastoma samples (p = 0.04). Other classes showed distinct drivers (MAPK or PI3K pathway alterations) coupled with unique mechanisms of cell cycle deregulation (CDKN2A/B loss, CDK4/MDM2 amplification, or RB1 alterations). The potential clinical importance of these genomic findings was demonstrated in three patients with surgically confirmed recurrent glioblastoma who received molecularly-matched targeted inhibitors as part of second-line therapy. Patients with activation of EGFR via amplification or mutation (R108K), activation of the mTOR pathway via inactivation of NF1, and constitutive activity of BRAF (V600E) were treated with erlotinib, everolimus, and vemurafenib, respectively, administered in combination with chemotherapy. In all three cases, imaging responses and overall survival were deemed far greater than expected by the treating physician. In conclusion, complex genomic data from glial tumors can be grouped into distinct sub-classes driven by unique combinations of alterations. Anecdotal clinical data suggest that subsets of patients may benefit from molecularly matched targeted therapies; larger studies investigating the efficacy of these agents in selected patients are warranted.

Citation Format: Juliann Chmielecki, Michael E. Goldberg, Alex Fichtenholtz, Julia Elvin, Garrett M. Frampton, Siraj M. Ali, Jeffrey S. Ross, Deborah Morosini, Vincent A. Miller, David Piccioni, Santosh Kesari, Philip J. Stephens. The complex genomic landscape of glial tumors reveals distinct subclasses and potential therapeutic targets associated with clinical responses to targeted inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4667. doi:10.1158/1538-7445.AM2015-4667