Prognostic and radiographic correlates of a prospectively collected molecularly profiled cohort of IDH1/2 ‐wildtype astrocytomas

Background: In the molecular era, the relevance of tumor grade for prognostication of IDH1/2 ‐wildtype (WT) gliomas has been debated. It has been suggested that histologic grade II and III astrocytomas with molecular features of glioblastoma, IDH1/2 ‐WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. Methods: We integrated prospective clinical sequencing from 564 patients with IDH1/2 ‐WT gliomas (26 grade II, 71 grade III and 467 grade IV) with clinical and radiographic data to assess associations between molecular features, grade and outcome. Results: Compared to histologic grade IV IDH1/2 ‐WT astrocytomas, histologic grade II astrocytomas harbor fewer chromosome 7/10 alterations ( P  = 0.04), EGFR amplifications ( P  = 0.022) and alterations in cell‐cycle effectors ( P  = 1.9e‐11), but a similar frequency of TERT promoter mutations. In contrast, there is no difference in the frequency of these canonical molecular features in histologic grade III vs. IV IDH1/2 ‐WT disease. Progression‐free (PFS) and overall survival (OS) for histologic grade II tumors were significantly longer than grade III tumors ( P  = 0.02 and P  = 0.008, respectively), whereas there was no difference in PFS and OS for histologic grade III compared to grade IV tumors. Median PFS for histologic grade II, III and IV tumors was 19, 11 and 9 months, respectively. Median OS for the same tumors was 44, 23 and 23 months, respectively. In histologic grade II and III IDH1/2 WT tumors, gliomatosis is associated with the absence of cell‐cycle alterations ( P  = 0.008) and enriched in grade II features ( P  = 0.1) and alterations in the PI3K‐AKT pathway ( P  = 0.09). Conclusions: Grade II histology has genotypic and phenotypic associations with prognostic implications in IDH1/2 ‐WT astrocytomas.