Molecular alterations in IDH-mutant astrocytoma: A multi-institutional retrospective study

Background. Several molecular alterations have been identified to provide prognosis for patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma. However, contemporary baseline survival data with respect to their molecular alterations are lacking. The prognostic value of histologic grading remains controversial. Methods. This was a retrospective multi-site study of adult IDH-mutant diffuse astrocytoma patients. Overall sur¬vival (OS) was estimated using the Kaplan-Meier method. Associations between OS and measures of interest were evaluated using Cox proportional hazards regression models. Results. We identified 241 eligible patients. The most frequent mutations were IDH1 (98%), TP53 (91%), ATRX (70%), ARID1A (8%), BRCA2 (6%), TSC2 (6%), CDKN2A (6%), and CREBBP (6%). IDH2 mutations were identified in 2%. By univariate analysis, age > 40 (hazard ratio [HR], 2.03; 95% CI, 1.20-3.45; p = .009) was associated with worse OS. Wildtype BRCA2 compared with mutated BRCA2 (HR, 0.42; 95% CI, 0.20-0.90; p = .024) and Central Nervous System World Health Organization (CNS WHO) grade 2 astrocytoma compared with grade 3 disease (HR, 0.40; 95% CI, 0.21-0.78; p = .007) were associated with better OS. In multivariable analysis, age > 40 (HR, 2.06; 95% CI, 1.18- 3.59; p = .011) was associated with worse OS and CNS WHO grade 2 (HR, 0.42; 95% CI, 0.21-0.83; p = .012) remained associated with improved OS. We identified an association between increased tumor mutation burden (TMB) and worse OS. Conclusions. Age and CNS WHO grade remain essentials for risk stratification among IDH-mutant astrocytoma patients. Further studies are warranted to determine the prognostic implications of BRCA2 mutations and TMB.