Survival outcomes of patients with grade 4 IDH mutant astrocytomas: The UT MD Anderson experience.

Abstract

e14092 Background: The WHO 2021 Classification of CNS Tumors distinguished IDH mutant (IDHmt) Grade 4 astrocytomas from IDH wild type glioblastomas based on presence of microvascular proliferation or necrosis, or CDKN2A/B loss in the setting of IDH mutation. These tumors are reported to have relatively better outcomes compared to their IDH wild-type counterparts; however, the heterogeneity of such outcomes within this subtype highlights the need for a better understanding of the factors that affect overall survival. Previous investigations have suggested that homozygous loss of CDKN2A/B portends a worse prognosis in IDHmt astrocytomas independent of pathologic grade. Other mutations that may worsen prognosis include other alterations in the RB1 pathway and in the RTK-PI3K-mTOR pathway. A small subset of these patients also present with tumors that have a histologically evident primitive neuronal component, which appears to be associated with early recurrence and rapid leptomeningeal spread leading to poor outcomes, but with no known molecular drivers. Methods: In this single institution retrospective cohort analysis, we aimed to identify patient- and tumor-specific factors that influence overall survival in patients with Gr 4 IDHmt astrocytomas using the PROACTIVE bio- and data protocol at MD Anderson. We collected data regarding patient demographics and tumor markers from targeted next-gen sequencing from a patient cohort that presented to MD Anderson between 2021-2025. Results: We identified 44 patients (31 male, 13 female) with Gr 4 IDHmt gliomas with median age at diagnosis of 36.5 (range 24-62), of which 36 were Grade 4 at the time of initial diagnosis (25 male, 11 female) and the remainder were previously treated lower grade tumors that underwent malignant transformation. Of tumors that were Gr 4 at initial diagnosis, 31 had the canonical IDH1 R132H mutation whereas 5 had non-canonical mutations (3 IDH1 R132S, 2 IDH1 R132G); one tumor had homozygous CDKN2A/B loss and 2 demonstrated heterozygous loss. MGMT promoter methylation was seen in 11 tumors (3 transformed), and was not reported in 19 tumors (3 transformed); the other 14 tumors (2 transformed) were considered to be MGMT unmethylated. Median follow-up time for the entire cohort was 20.7 months. There were no deaths in the CDKN2A/B homozygous deletion or hemizygous deletion subgroups. One patient with the presence of MGMT promoter methylation (32 yo female) was deceased at 30.3 months (median follow-up 6.3 months for subgroup). Two patients with MGMT promoter unmethylated status were deceased: one patient (34 yo male) died at 6.2 months, and one patient (33 yo male) died at 25.4 months after diagnosis; median follow-up time was 17.4 months for MGMT unmethylated subgroup. Conclusions: Ongoing studies are assessing the significance of additional mutations within this cohort and their relationship with overall survival and will be presented at the conference.