BIOM-89. PI3K PATHWAY ALTERATIONS ARE DRIVERS OF PROGRESSION AND PREDICT WORSE OVERALL SURVIVAL IN NEWLY DIAGNOSED MOLECULARLY-DEFINED OLIGODENDROGLIOMA

Abstract BACKGROUND Identification of biomarkers for overall survival (OS) in oligodendroglioma has proven challenging due to 1) rarity of the tumors, 2) long follow-up required for survival analysis, and 3) challenge of confirming molecular features in oligodendroglioma diagnosed prior to 2016. We identified a cohort of molecularly-defined oligodendrogliomas going back over 40 years. METHODS We performed whole exome sequencing on 251 samples (195 at diagnosis, 56 at recurrence) from 238 patients, as well as FISH For CDKN2A status on those with suspected homozygous loss. We performed univariate analysis on frequently altered genes/pathways to identify factors associated with poorer overall survival. RESULTS Among patients with a sample at initial diagnosis, the median OS was 19.7 years (95% confidence interval [CI]: 16.2, 24.1). Besides IDH mutations, the most common mutations were TERT promoter (99.5%), CIC (75%), FUBP1 (35%), and NOTCH1 (14%). Pathways with a high frequency of mutations included PIK3CA/PIK3R1 (22.1%), SWSI/SNF (22.1%), and histone methyltransferases (13.9%). Within the newly diagnosed tissue cohort, 22.1% (43/195) had PI3K mutations, which increased to 34% (19/56) in the recurrent tissue cohort. In twelve paired cases of newly diagnosed and recurrent oligodendroglioma, 36% (4/12) had PIK3CA/PIK3R1 mutations at initial diagnosis, which increased to 64% (7/12) at recurrence. In the newly diagnosed tissue cohort, presence of PI3K mutations was associated with a decrease in median overall survival (p <0.01; 16.3 and 21.7 years with and without mutation), although no significant difference was identified within the cohort of recurrent oligodendroglioma. CONCLUSIONS Our studies in a cohort of molecularly-defined oligodendrogliomas demonstrate that PI3K alterations are associated with worse overall survival in newly diagnosed oligodendroglioma, and showed increased frequency upon tumor recurrence. Additional analyses, including multivariate analysis incorporating known clinical variables that impact survival, are currently underway.