Faculty Bibliography

BACKGROUND:Astrocytoma, isocitrate dehydrogenase-mutant, WHO grade 4 (Astro4), is a new tumor type in the 2021 WHO classification of central nervous system tumors that has been poorly characterized in the literature. This study evaluates predictors of prognosis in a large cohort of newly diagnosed Astro4. METHODS:We retrospectively identified 128 consecutive adult patients who presented with an initial diagnosis of Astro4 at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2010 and 2021. Clinical, molecular, and radiological characteristics were recorded, and their associations with overall survival (OS) and progression-free survival (PFS) were measured by log-rank test and Cox proportional hazards model. RESULTS:The median age at diagnosis was 37.1 years, and 61.7% were men. The median OS was 5.9 years (95% confidence interval, 4.4 - 7.3), while the median PFS was 2.7 years (1.8 - 3.6). Age ≥50 and homozygous CDKN2A/B deletion were independent negative prognosticators of OS on univariate and multivariate analyses [hazard ratio (HR), 2.21 (1.16 - 4.21), p=0.019; HR, 2.61 (1.27 - 5.38), p=0.013]. Maximal resection of enhancing disease was associated with longer PFS on univariate and multivariate analyses [HR, 0.48 (0.26 - 0.87), p=0.019]. There were no significant differences in OS or PFS based on MGMT promoter methylation status, T2/FLAIR extent of resection, T2/FLAIR mismatch, radiological pseudoprogression, or enhancement on the pre-operative scan. CONCLUSIONS:Our study comprehensively characterizes a large cohort of newly diagnosed patients with Astro4, emphasizing the prognostic value of CDKN2A/B deletion, age, and the extent of resection of enhancing disease in these patients.

Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.