MDM2/4 amplification predicts poor response to immune checkpoint inhibitors: a pan-cancer analysis

Abstract

The revolutionary immune checkpoint inhibitors (ICI) treatment has been a landmark of cancer therapy, with long-term survival benefit in advanced cancer patients reported.1 In another aspect, relatively low response rates and hyperprogression remain to be solved in immunotherapy.2 3 There have been some known biomarkers for the prediction of ICI efficacy, such as programmed death-ligand 1 expression, tumour mutational burden (TMB), microsatellite instability (MSI) and mismatch-repair deficiency. The ongoing effort to identify predictive biomarkers is still of great significance. MDM2/4 amplification (AMP) has been reported to be related with hyperprogression during ICI therapy in several cancer types.4–6 But previous studies concerning MDM2/4 AMP were of limited sample size and still require more clinical data support. In this study, we aimed to estimate the prevalence of MDM2 AMP across multiple cancer types and explore its role in the prediction of benefit from ICI treatment. We estimated the prevalence of MDM2/4 AMP in 250 studies involving 30 118 patients from the cBioPortal database (https://www.cbioportal.org). An ICI treatment cohort of 1105 patients obtained from MSK-IMPACT Clinical Sequencing Cohort (MSKCC) was utilised to explore the relationship between MDM2/4 AMP and ICI treatment. The overall survival (OS, calculated from the ICI start date) was calculated using the Kaplan-Meier method and compared between groups (p values by log-rank test). We also performed a multivariable …