Current adjuvant therapeutic options for the treatment of Glioblastoma (GBM) are often determined by limited histological information. Additionally, most GBM clinical trials for targeted chemotherapeutic agents do not distinguish the genetic mutational tumor profiles of the patients recruited and have failed to reach successful treatment endpoints. The New York Genome Center (NYGC) has undertaken a glioblastoma clinical sequencing outcome pilot study to better determine personal treatment options for patients with GBM using integrated genomic data. During the initial phase of this study for 2015 NYGC has performed whole genome sequencing (WGS) on 10 primary GBM tumor-normal pairs, analyzed each patient's tumor for single nucleotide variants, structural variants and copy number alterations. In addition RNA sequencing and a DNA methylation assay were also performed on several of the patients. The patient's genomic profile was then compared to a database of known targeted therapeutic approaches. A final tumor board composed of NYGC scientists, GBM consortium scientists and treating oncologists then reviewed all data prior to identifying a final therapeutic strategy. Data from the first 10 patients revealed RB1 variants to be predominant in half of the patients. SNV's in NF1 or PIK3R1 were also discovered in 4 out of 10 samples. Remaining lower frequency variants occurred in TP53, PDGFRA, PTEN, PIK3CA, ERBB3, SMO, STAG2, ACVR1, NFKB1 and JAK3. Analysis of copy number alterations resulted in 8 of 10 patients containing the characteristic chromosome 7 amplification combined with chromosome 10 deletion, affecting EGFR and PTEN, respectively. Extreme amplification with potential double minute structural variation of EGFR containing the A289V mutation was observed in 2 of 10 samples. Two samples contained a potentially targetable over-amplification of the PDGFRA/KIT/KDR chromosome 4 locus. Predominant deletions resided in CDKN2A, ESR2, PTEN and FLT3. Hemizygous deletions of RB1 combined with RB1 nonsense or missense variants were observed in 4 samples. To date, RNA sequencing was performed on 5 patient samples. Most strikingly the combination of DNA and RNA sequencing revealed the presence of a putative activating MET exon skipping event in the extracellular domain. This MET variant was considered as a potential targetable variant. Therapeutic options resulting from WGS genomic profiles were the PI3K inhibitor BKM120 (60%), half of these had an additional aberration in MET and were recommended for the combinatorial trial NCT01870726. Drug recommendations for the treatment of GBM based on specific N = 1 patient genomic profiles were also made for nilotinib, vismodegib and palbociclib. Here, we present the first phase of the NYGC GBM clinical outcome study demonstrating how patient WGS information can provide more precise therapeutic options in the treatment of glioblastoma.
Citation Format: Kazimierz O. Wrzeszczynski, Nicolas Robine, Vladimir Vacic, Anne-Katrin Emde, Bo-Juen Chen, Will Liao, Kanika Arora, Minita Shah, Ewa A. Grabowska, Vanessa Felice, Esra Dikoglu, Catherine Reeves, Mayu Frank, Vaidehi Jobanputra, Michael C. Zody, Toby Bloom, Robert B. Darnell. NYGC glioblastoma clinical outcomes pilot study: Discovering therapeutic potential in glioblastoma through integrative genomics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4497.