PATH-29. CLINICAL SIGNIFICANCE OF TEMOZOLOMIDE-INDUCED SOMATIC HYPERMUTATION IN INITIALLY LOW-GRADE IDH-MUTANT DIFFUSE GLIOMAS

Abstract INTRODUCTION Diffuse low-grade gliomas (DLGG) treated with temozolomide (TMZ) can develop somatic hypermutation. We present data on the incidence and prognostic importance of somatic hypermutation in IDH-mutant DLGGs. METHODS We analyzed 120 patients treated on a phase II clinical trial of TMZ for sub-totally resected DLGGs to estimate the risk of recurrence and transformation after TMZ. To understand the prognostic significance of somatic hypermutation, we determined hypermutation status by exome or targeted sequencing on tumors from 81 patients with recurrent IDH-mutant DLGGs. 63/81 patients received TMZ before recurrence, including 28 patients treated on-trial. RESULTS With median follow-up of 8.7 years, 89 patients from the phase II trial progressed, 60 underwent 1 re-operation, and 36 had histologically confirmed transformation. The 8-year freedom from transformation was 48.2% and 59.9% for IDH-mutant astrocytomas and oligodendrogliomas, respectively; risk of transformation increased with pre-TMZ tumor volume (HR 2.5 per 100cc, p