Clinical Implications of Aberrant Retinoblastoma Signaling in Patients With Grade 4 IDH-Mutant Astrocytoma: A Retrospective Cohort Study.

Abstract

The data on the prognostic factors of grade 4 isocitrate dehydrogenase (IDH)-mutant astrocytoma remain limited since the 2021 update of the World Health Organization classification of CNS tumors. This study aimed to investigate prognostic factors affecting survival in grade 4 IDH-mutant astrocytoma. In this retrospective cohort study, medical records of patients diagnosed with grade 4 IDH-mutant astrocytoma between 2002 and 2023 across all 3 Mayo Clinic campuses who received standard radiation/temozolomide were reviewed. Clinical, radiographic, and molecular variables collected included age, sex, midline involvement (infiltration of brainstem, basal ganglia, thalamus, hypothalamus, cerebellum, corpus callosum), O(6)-methylguanine-DNA methyltransferase (<i>MGMT</i>) promoter hypermethylation, and cyclin-dependent kinase inhibitor 2A/B (<i>CDKN2A/B</i>) deletion. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier methods and Cox proportional hazards regression. Fifty-eight patients were identified (median age: 36 years, 36% female). The median PFS and OS were 2.4 and 6.9 years, respectively. <i>CDKN2A/B</i> homozygous deletion reduced PFS (1.4 vs 4.5 years, hazard ratio [HR] 4.9, 95% CI 2.1-11, <i>p</i> < 0.001) and OS (2.5 vs not reached [NR], HR 3.9, 95% CI 1.3-12, <i>p</i> = 0.018). Midline involvement also reduced PFS (1.4 vs 4.5 years, HR 4.5, 95% CI 1.8-11, <i>p</i> < 0.001) and OS (2.4 vs 13 years, HR 8.7, 95% CI 2.4-32, <i>p</i> = 0.001). <i>MGMT</i> promoter hypermethylation improved PFS (4.6 vs 1.3 years, HR 0.15, 95% CI 0.037-0.63, <i>p</i> = 0.009). Multivariable analyses revealed that PFS remained significantly reduced by <i>CDKN2A/B</i> homozygous deletion (HR 4.2, 95% CI 1.7-10, <i>p</i> = 0.002) and midline involvement (HR 2.6, 95% CI 1.0-6.4, <i>p</i> = 0.045). A significant association between <i>CDKN2A/B</i> homozygous deletion and midline involvement was observed (χ² = 4.3, <i>p</i> = 0.037). Exploratory analyses revealed that all patients with midline involvement demonstrated aberration in retinoblastoma signaling. <i>CDKN2A/B</i> hemizygous deletion/loss of heterozygosity also reduced OS (2.5 years vs NR, HR 4.9, 95% CI 1.0-23, <i>p</i> = 0.044). <i>CDKN2A/B</i> homozygous deletion and midline involvement independently reduce PFS in patients with grade 4 IDH-mutant astrocytoma treated with standard radiation/temozolomide. Furthermore, midline involvement may be associated with aberrant retinoblastoma signaling. These findings suggest that radiographic and molecular features may have potential utility in informing clinical trial stratification and guiding early clinical decision-making. However, our findings are limited by our small sample size, so further validation in larger, prospective cohorts is needed.