Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, providing lifesaving treatments for an increasing number of malignancies. However, ICIs have also been associated with off-target multi-organ immune-related adverse events, including an increasing incidence of cardiovascular toxicities. After early reports of acute fulminant ICI-myocarditis, active surveillance of ICI cardiotoxicity using cardiac biomarkers such as troponin-I has been recommended. This has resulted in the increased detection of asymptomatic, low- grade cases of unknown natural history and clinical significance. This study will address critical knowledge gaps by investigating risk stratification and outcomes across the entire spectrum of ICI cardiotoxicity subtypes. The applicant’s central hypothesis is that a subset of patients with abnormal troponin-I levels who are asymptomatic have lower risks of adverse cardiac outcomes compared to those with symptomatic disease, and peripheral biomarkers like troponin-I and novel immune markers can help distinguish between “higher” and “lower” risk patients who may tolerate safe continuation of ICIs. To test this hypothesis, the applicant will (1) retrospectively examine cardiac and oncologic outcomes associated with ICI cardiotoxicity stratified by patient symptoms and troponin-I measurements; (2) retrospectively examine the risks of ICI continuation after asymptomatic troponin-I elevation during ICI therapy; and (3) prospectively investigate the role of cardiac, established inflammatory, and novel immune biomarkers in predicting cardiac risks after ICI continuation. These aims will leverage comprehensive data from the Stanford Troponin Monitoring Cohort, consisting of > 1591 consecutive cancer patients with prospectively collected serial troponin-I measurements during each cycle of ICIs, and the International ICI- Myocarditis Registry of > 700 patients with confirmed ICI-myocarditis. The results of this study will lead to critical advances in the field of cardio-oncology by enhancing cardiac risk assessment for ICIs and establishing, for the first time, the role of biomarkers in evaluating the risks of ICI continuation after troponin-I elevation. This will have serious implications for the safe continuation of potentially lifesaving cancer therapies in affected patients. Through this fellowship training, the applicant will also gain important competencies to advance in her long-term goal of becoming a leading physician-scientist in the clinical phenotyping of cardiotoxicity from cancer therapies and forging evidence- based practices in cardio-oncology.
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