Abstract 4863: Discovery of novel metabolomic plasma biomarkers predictive of radiation induced cardiac toxicity
Authors: Unger Keith , Girgis Michael , Rajagopal Meena , Ceh Yeline , Jayatilake Meth , Li Yaoxiang , Cheema Amrita K. 
Published: August 2019

Abstract
Introduction: Although advancements in cancer treatment have led to increased survivorship, radiation induced heart disease (RIHD) remains a major source of acute and long term morbidity and mortality for cancer survivors, for which there are no diagnostic tests in routine clinical use due to lack efficacy or excessive cost. Several studies have documented RIHD; however, none of these investigations have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of cardiotoxicity. The overarching goal of this pilot study is to determine whether biomolecules secreted in the circulation by latent yet developing cardiotoxic processes can be leveraged for predicting risk of cardiac dysfunction in cancer survivors.
Approach: We used metabolomics/lipidomics analysis, an emerging field that provides information on biological perturbations based on relative changes in the plasma levels of endogenous metabolites, for a retrospective outcome analysis study. Patients treated at GUH with radiation therapy (RT) for locally advanced esophageal cancer (n = 11 x 3 time points), who underwent serial cardiac MRI’s were selected. We identified a subset of patients who developed radiation related heart ischemia and fibrosis in the inferior/ basal segment of the heart associated with the high dose region, as well as associated cardiac functional impairments (n = 6 x 3 time points). We also analyzed plasma and cardiac tissue samples from groups male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day x 5 days) of targeted X-ray radiation to the heart. Metabolomic analysis was used as a correlative approach for delineation of novel biomarkers associated with radiation induced cardiac toxicity.
Results: Global metabolomics and lipidomics analyses have yielded important data for developing classification algorithms with high predictive accuracy. We are in the process of performing statistical analyses to determine the sensitivity and specificity of the resultant panel, and any influence provided by age and gender on the predictive performance of the biomarker panel. These data will be presented at the AACR meeting.
Conclusion: Cardiac dysfunction following cancer therapy leads to significant morbidity and mortality. While our cohort includes esophageal cancer patients, we believe the cardiac toxicities detailed previously are applicable to other patient populations receiving high dose thoracic radiation therapy. We believe findings from this study are of significant interest to the scientific community since there are critical gaps in knowledge related to mechanisms of cardiac injury, clinical prediction, screening, prevention, and treatment.
Supported by Cancer Center Support Grant (CCSG/NCI/NIH) and funding Ruesch Foundation
Citation Format: Keith Unger, Michael Girgis, Meena Rajagopal, Yeline Ceh, Meth Jayatilake, Yaoxiang Li, Amrita K. Cheema. Discovery of novel metabolomic plasma biomarkers predictive of radiation induced cardiac toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4863.