Abstract 3625: Metabolic phenotypes of doxorubicin-induced cardiotoxicity in breast cancer patients
Authors: Jun Se-Ran , Wallis Katherine , Landes Reid D. , Todorova Valentina K. , Su L. Joseph , Makhoul Sam , Hsu Ping-Ching 
Published: March 2024

Abstract
Background. Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with other chemotherapy regimens to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although DOX has greatly increased the number of long-term cancer survivors, some DOX recipients have experienced DOX-induced cardiotoxicity (DIC). Currently, there are no validated markers that can predict the early development of DIC. Cardiac troponin released by cardiomyocytes has been used in non-clinical studies as a marker of myocardial injury; however, the false positive rates are high, and the predictive value on cardiotoxicity is limited. Therefore, novel biomarkers of DIC are urgently needed to identify patients who are at an increased risk, allowing early detection of the cardiotoxicity before it causes permanent cardiac damage.
Methods. Untargeted metabolomics profiling was performed for plasma samples from a cohort of 28 breast cancer patients who developed abnormal cardiac function (ABN) and those who maintained normal cardiac function (NML). Blood samples were collected before, during, and after DOX-containing chemotherapy. Using both baseline observations and pre-post changes, machine-learning techniques were used to identify metabolite markers that can be used as early indicators of DIC in BC patients. Area under the receiver operating characteristic curve was reported to evaluate the performance of significant metabolites, and metabolite set enrichment analysis (MSEA) and network analysis were used to extrapolate known associations between metabolites and diseases.
Results. Significant separation of plasma metabolomics profiles between ABN and NML patients at baseline was observed. From 1,124 metabolites, abundance of 59 metabolites were found to differ between ABN and NML patients at baseline. Across all patients, levels of 78 metabolites changed between baseline and after the 1st chemotherapy cycle. Of the 6 metabolites identified in both baseline and pre-post data, ABN patients had higher levels of dicarboxylic acids suberate and sebacate derived from ω-oxidation of fatty acids at baseline than NML patients. Enrichment analysis on the metabolites from the pre-post analysis suggested myocardio injury and carnitine palmitoyltransferase deficiency. Network analysis of metabolite-disease interactions further suggests potential impact on neurological health after chemotherapy.
Conclusion. The metabolomics phenotype identified is indicative of impaired beta-oxidation at baseline for ABN patients. In addition, our findings suggest neurotoxic effect from DOX, implicating the potential brain-heart axis involved behind the cardiotoxicity phenotype.
Citation Format: Se-Ran Jun, Katherine Wallis, Reid D. Landes, Valentina K. Todorova, L. Joseph Su, Sam Makhoul, Ping-Ching Hsu. Metabolic phenotypes of doxorubicin-induced cardiotoxicity in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3625.