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

Background

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).

Methods

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.

Results

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).

Conclusions

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.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Vall d’Hebron Institute of Oncology (VHIO).

Disclosure

O. Mirallas: Financial Interests, Personal, Invited Speaker: ROVI; Financial Interests, Institutional, Invited Speaker: Roche, Merck; Other, Personal, Other, Travel Expenses: Kyowa Kirin, Almirall; Other, Personal, Other, Travel Expenses and Conference Fee: Sanofi. G. Velilla: Financial Interests, Personal, Invited Speaker: Neuraxpharm. A. Hernandez Gonzalez: Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche, Sanofi; Financial Interests, Institutional, Other, Research Funding: Janssen. M.A. Vaz Salgado: Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer. M. Gonzalez Rodriguez: Financial Interests, Personal, Invited Speaker: MSD, Pfizer, Roche, AstraZeneca; Financial Interests, Personal, Other, Review clinical cases: Bayer. M. Castro-Henriques Pinto-Machado: Financial Interests, Personal, Advisory Board, Advisory Board on Oncotype Use: Genomic Health; Financial Interests, Personal, Expert Testimony, Personal experience with Palbociclib: Pfizer; Financial Interests, Institutional, Other, advisory tasks for platform design: Roche; Financial Interests, Personal, Invited Speaker, Speaker in local meeting for breast cancer survivorship: Daiichi Sankyo; Other, Personal, Other, travel expenses: Daiichi Sankyo, Pfizer; Other, Personal, Other, financial support for young oncologists regional group: Novartis. M. Martinez Garcia: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Takeda, Seagen, Pierre Fabre, Novocure; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; Non-Financial Interests, Personal, Leadership Role, Member of the board: GEINO, Spanish group of Neuro Oncology; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: BMS Celgene, Roche; Non-Financial Interests, Personal, Principal Investigator, Clinical trial: Cantargia; Non-Financial Interests, Personal, Principal Investigator, Clinical Trial: Laminar Pharma; Non-Financial Interests, Personal, Principal Investigator, clinical trial: Incyte. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, GSK, Takeda, Janssen, Foundation Medicine; Financial Interests, Personal, Advisory Board: Bayer, Roche; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinico-genomics cohorts: Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck. E. Pineda: Financial Interests, Personal, Advisory Board: Novocure. J. Carles Galceran: Financial Interests, Personal, Advisory Board: Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, MSD Oncology, Novartis (AAA), Roche, Sanofi; Financial Interests, Institutional, Invited Speaker: Janssen-Cilag International NV, Lilly, S.A, MedImmune, Novartis Farmacéutica, S.A, Sanofi-Aventis, S.A; Other, Personal, Other, Member of the Commission: Catalan Program of Ambulatory Medication Comission (CAHMDA). C. Balana: Financial Interests, Personal, Advisory Board, Member of the DSMB of two trials: Laminar Pharma. J.M. Sepulveda Sanchez: Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Advisory Board: MSD, Novocure, CeCaVa, Cantex; Financial Interests, Personal and Institutional, Research Grant: Pfizer, Cantex. M. Vieito Villar: Non-Financial Interests, Personal, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. All other authors have declared no conflicts of interest.