43P MDM2 alterations in primary brain tumors: A potential niche for targeted therapy

Primary brain tumors (pBT) are a heterogeneous group of neoplasms. Disruption of TP53 tumor suppressor is a common event and MDM2 amplification is a major cause of functional loss of TP53 in patients (pts) with glioblastoma (GBM). We describe the characteristics of a pBT cohort with next-generation sequencing (NGS) and MDM2 alterations (MDM2alt). Patients with pBT who had NGS [Foundation Medicine®, local NGS, Caris®, Oncomine®, copy number (CN) and fusion panels] from the multicentric retrospective database ESCAT-pBTs were included. MDM2alt and the relation with other molecular and clinical findings was explored. In GBM, overall survival (OS) was estimated using Kaplan-Meier, with a comparative of survival distribution in MDM2alt and non-alt groups using log rank test. A total of 493 pts were included between Feb 2018 and Jan 2023 at 8 hospitals in Spain. Median age was 51.6 years (y) (3.3-83.8), 12.2% had ECOG ≥2, 39% were women, 27% were ≤40y and 69% had a diagnosis of GBM (WHO 2021). TP53 mutated(mt) was found in 32% of pBT (mutually exclusive with MDM2alt) and 22% had IDH1mt. Overall prevalence of MDM2alt was 8.5%, 11.8% in GBM and 1.3% in other pBT (p<0.001). Main coexisting alteration (alt) in MDM2alt pts was CDK4 gain in 71.4% compared to 5,7% in non-alt (p<0.001). A similar frequency of PI3KCA/PTENmt was observed in GBM MDM2alt and non-alt groups (38% vs 50%, p=0.15). No significant difference was found in GBM MDM2alt vs non-alt in EGFR amplifications (43% vs 32%; p=0.10) and EGFRmt (19% vs 19%; p=0.84). Median TMB was 5.2 mut/Mb in GBM pts. Median OS in GBM was 22.8 months (mo) (95%CI, 20.3-25.2). In MDM2alt group, median OS was 26.5 mo (95%CI 19.2-33.6), while median OS in non-alt was 22.6 mo (95%CI 20.2-25). No statistically significant differences were found in OS among MDM2alt and non-alt groups (p=0.07). MDM2alt is a common genomic event in molecularly defined GBM and has low prevalence in other pBT. MDM2alt did not appear to be prognostic. MDM2alt associated with high prevalence of CDK4 gain, suggesting a molecularly defined subgroup with chromosomal instability and the potential for targeted therapy with CDK4/6 plus MDM2 inhibitors in clinical trials. These findings enlighten further development of treatment strategies for MDM2alt GBM pts.