Association of PIK3CA-activating mutations with more disseminated disease at presentation and earlier recurrence in glioblastoma.

Abstract

2029 Background: The PI3K signaling pathway is a potent pro-survival pathway and associated with increased grade of malignancy in glioma. Activating mutations in PIK3CA are observed in 6% to 15% of glioblastomas, although their clinical significance is unknown. Our objective was to examine whether PIK3CA activating mutation is associated with a specific phenotype in newly diagnosed glioblastoma patients. Methods: We molecularly profiled 183 consecutive adult glioblastomas from December 2009 to June 2012. We included in our analysis all newly diagnosed primary glioblastoma patients with a KPS score of 60 or greater who were treated with standard chemoradiation. Molecular profiling consisted of SNaPshot genotyping, FISH for gene amplification (EGFR, MET, PDGFRA), and methylation-specific PCR for MGMT promoter methylation. Results: 158 patients were included in the study (median age: 58 years (range, 23-85), 90 males, median KPS: 90). With a median follow-up of 13.8 months, median progression-free survival (PFS) and overall survival (OS) were 11.6 and 26.2 months, respectively. Established molecular prognostic factors such as IDH1 mutation and MGMT promoter methylation were associated with longer PFS and OS (IDH1: PFS p=0.001, OS p=0.02; MGMT: PFS p=0.0005, OS p=0.0002). 12 patients (7.6%) harbored PIK3CA activating mutation by SNaPshot assay (4 at R88, 4 at hotspots 542-546, 4 at H1047). PIK3CA mutation was associated with younger age (p=0.02) and shorter PFS (6.8 vs. 11.8 months, p=0.0004). Shorter PFS for PIK3CA mutation remained significant after adjusting for age, KPS, gross total resection, IDH1 mutation, and MGMT promoter methylation (p=0.01). There was a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions. Eight of 12 (66.7%) PIK3CA mutant GBMs were disseminated versus 15.1% of PIK3CA wild-type tumors (p=0.0002). Conclusions: PIK3CA activating mutations are associated with younger age and early recurrence in primary glioblastoma. The aggressive behavior of these tumors may be related to their propensity to present with widespread disease.