Pretreatment Circulating Vascular Biomarkers Predict Cancer Therapy-Related Cardiac Dysfunction During HER2+ Breast Cancer Treatment
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Published on: January 28, 2020
Dakota Gustafson1, Priya Mistry1, Crizza Ching2
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Background:
Blood biomarkers to predict cancer therapy-related cardiac dysfunction (CTRCD) risk remain limited.
Objectives:
The aim of this study was to identify circulating biomarkers associated with CTRCD risk in HER2+ breast cancer patients.
Methods:
In the discovery cohort, women with early-stage HER2+ breast cancer receiving anthracycline and trastuzumab therapy underwent serial evaluation with cardiac magnetic resonance imaging (CMR), echocardiography, clinical assessments, and blood biobanking every 3 months. Multiomics profiling of 3 circulating cardiac damage biomarkers and 35 markers of inflammation, angiogenesis and endothelial activation and profiling of >2,000 plasma microRNAs were performed before and early during treatment (3 and 6 months). CTRCD was defined by left ventricular ejection fraction measured on CMR, and sensitivity analyses used echocardiography. Pretreatment protein biomarkers were measured in a validation cohort.
Results:
Among 136 women, 37 (27.2%) developed CMR-defined CTRCD within 15 months. The endothelial activation markers angiopoietin-2, endothelin-1, and endoglin were elevated before and during treatment, while sE-selectin was elevated during treatment in patients who developed CTRCD. Inflammatory biomarkers (myeloperoxidase, interferon-gamma-induced protein-10, and interferon-α) were significantly higher before treatment in patients who developed CTRCD. No differences were observed in cardiac injury biomarkers (troponin I, B-type natriuretic peptide, and growth differentiation factor-15). Pretreatment plasma microRNAs revealed distinct CTRCD-associated signatures. Integrating pretreatment clinical variables, CMR parameters, and biomarkers into a single random forest model, angiopoietin-2, myeloperoxidase, and endoglin were identified as the strongest predictors of CTRCD, findings that were subsequently validated in a cohort of 38 HER2+ breast cancer patients.
Conclusions:
Pretreatment endothelial-centric and inflammatory biomarkers outperformed both clinical and CMR measures in predicting CTRCD during chemotherapy.
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