Survival implications and radiographic predictors of prognosis in patients with IDH-mutant astrocytoma with CDKN2A/b homozygous deletion: An international, multi-centered study.

Abstract

e14035 Background: Isocitrate Dehydrogenase (IDH) 1 or 2 mutations are associated with improved prognosis in glioma patients. Despite their less aggressive clinical course when compared to IDH-wild type gliomas, molecularly-defined IDH-mutant glioma subtypes with poor prognosis have been identified. Among these, CDKN2A/B homozygous deletion represents the strongest negative genetic predictor of prognosis yet identified in IDH-mutant astrocytoma. With the WHO 2021 classification recognizing CDKN2A/B homozygous deletion as sufficient for the designation of astrocytoma, IDH-mutant, WHO Grade 4, the translational implications and potential for therapies targeting CDKN2A/B homozygous deletion are an area of active investigation. We sought to further characterize overall (OS) and progression-free survival (PFS) of CDKN2A/B deleted patients within a large, multi-centered, international cohort and identify clinical characteristics that predict survival for patients with CDKN2A/B deletion. Methods: Patients with IDH-mutant glioma with CDKN2A/B homozygous deletion were retrospectively identified across four institutions (Massachusetts General Hospital, USA; University Hospital Heidelberg, Germany; University Hospital Dresden, Germany, and Foudan-Shanghai, China). IDH-mutation status was determined by immunohistochemistry or next-generation sequencing. CDKN2A/B status was determined by hybridized DNA capture or FISH. Results: We identified 75 patients with IDH-mutant astrocytoma with CDKN2A/B homozygous deletion. The cohort had a median follow-up time of 5.0 years, was 56% male, and had an average age of 38.8 years. Patients were treated with chemotherapy and radiation following initial surgery in 77% of cases. Preoperative contrast enhancement and T2 FLAIR mismatch were identified in 56 and 44% of cases, respectively. Compared to a cohort of 51 patients with CDKN2A/B intact, grade 4, IDH-mutant astrocytoma, those with CDKN2A/B-deleted tumors had significantly shorter median OS and PFS (OS: 4 vs 13.5 years, HR = 6.8, HR 95% CI = 3.1, 14.6, p < 0.0001; PFS: 2.8 vs 5.9 years, HR = 3.0, HR 95% CI = 1.7, 5.2, p = 0.0001). Within the CDKN2A/B deleted cohort, preoperative contrast enhancement predicted worse OS, but not PFS (OS: HR = 2.7, 95% CI = 1.1, 7.4, p = 0.04; PFS: HR = 1.17, 95% CI = 0.7, 3.7, p = 0.24). Conclusions: These data reinforce the strong negative prognostic impact of CDKN2A/B homozygous deletion on OS and PFS and identify a novel association between preoperative contrast enhancement and shorter OS in patients with CDKN2A/Bdeleted, IDH-mutant astrocytoma.