1173 Proteomic analysis in patients with immune checkpoint inhibitor (ICI) associated cardiotoxicity

<h3>Background</h3> Cardiotoxicities form rare adverse events secondary to ICIs, but have disproportionately high patient impact. Specifically, ICI myocarditis (ICI-M), has a mortality of up to 50%¹ and the need to permanently discontinue therapy when Grade 2 or higher per treatment guidelines and product labels. Currently no validated biomarkers exist to predict the risk of ICI-M. In this study, we explored the proteome in baseline plasma samples of patients who developed ICI associated cardiotoxicity, to further the molecular understanding of this immunotherapy-related complication. <h3>Methods</h3> We performed a retrospective proteomic analysis using data from Roche sponsored studies with atezolizumab across tumor types. Baseline samples from 14 patients were analyzed, including 8 cases with cardiotoxicity following ICI treatment (reported by investigators as myocarditis n=2, heart failure n=5 and AV block complete n=1) and 6 control patients who received ICI therapy without cardiotoxicity. EDTA plasma samples from these 14 patients were analyzed using Somalogic 7k SomaScan assay v4.1. Differential expression analysis was performed using limma and R. version 4.2.2. A false discovery rate of &lt; 0.05 was considered statistically significant. Data from 14 patients in our cohort was compared with SomaSignal secondary cardiovascular (CV) risk prediction score composed of 27 proteins.² <h3>Results</h3> Differential expression analysis did not reveal statistically significant differences among the 7596 aptamers tested (table 1). FcRIIIa showed the highest fold change (log2FC = -3.7) in cases vs controls, but no statistically significant differential expression was observed. Furthermore, on examination against the CV risk prediction score there was a non-significant trend where on average the 8 cases of ICI cardiotoxicity were predicted to be at higher risk of a cardiac event within 4 years (figure 1). <h3>Conclusions</h3> Proteomic analysis of baseline samples from patients who received ICI therapy did not identify a statistically significant profile of patients at risk of developing cardiotoxicity. However, certain proteins of known importance in response to ICIs demonstrated a nominal increase e.g. FcRIIIa is known to bind IgG, regulate complement activation and is implicated in ICI-M.³ The small sample size and large number of aptamers analyzed limited the power to identify a proteomic signature predictive of ICI cardiotoxicity. Findings from comparison with 27 protein based CV risk prediction score were directionally encouraging, however further research is warranted to identify a proteome based biomarker for ICI cardiotoxicity. <h3>References</h3> Brahmer JR, <i>et al</i>. Society for immunotherapy of cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. <i>J Immunother Cancer</i>. 2021 Jun;<b>9</b>(6):e002435. doi: 10.1136/jitc-2021-002435. PMID: 34172516; PMCID: PMC8237720. Williams SA,<i> et al</i>. A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk. <i>Sci Transl Med</i>. 2022 Apr 6;<b>14</b>(639):eabj9625. doi: 10.1126/scitranslmed.abj9625. Epub 2022 Apr 6. PMID: 35385337. Siddiqui BA,<i> et al</i>. Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis. <i>Cancer Immunol Res</i>. 2024 May 20. doi: 10.1158/2326-6066.CIR-24-0011. Epub ahead of print. PMID: 38768394. <h3>Ethics Approval</h3> Ethics statement: Patients included in this analysis were enrolled in Roche sponsored studies with atezolizumab and had provided informed consent for exploratory biomarker analysis.