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.
Pisupati et al. (Thu,) studied this question.