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Aim: Breast cancer treatment with anthracycline and trastuzumab can result in cancer therapy-related cardiac dysfunction (CTRCD). It is not currently possible to accurately identify patients at risk of CTRCD from clinical and demographic information alone. We sought to identify circulating biomarkers that can be used to identify individuals at risk of CTRCD before or early during cancer treatment. Methods: Multi-omic analysis of circulating biomarkers of cardiac damage, inflammation, and endothelial activation, together with profiling of plasma microRNAs was performed before and early during cancer treatment in 136 women ≥ 18 years of age with HER2+ breast cancer (Stages I-III) undergoing treatment with sequential anthracycline and trastuzumab therapy. Results: We identified three endothelial-centric biomarkers (i.e., Angiopoeitin-2, Endothelin-1 and Endoglin) that were elevated prior to and during cancer treatment, and one marker (i.e., E-Selectin) that was elevated during treatment in patients that went on to develop CTRCD. Additionally, there were significant elevations in inflammatory biomarkers (including Myeloperoxidase, Interferon gamma-induced protein-10 and Interferon-α2) before treatment in patients that developed CTRCD. No appreciable differences were observed in cardiac damage biomarkers (Troponin I, BNP, GDF-15) between groups. Assessment of plasma microRNAs prior to treatment revealed distinct microRNA signatures and predicted disease-relevant pathways in patients who went on to develop CTRCD. A Random Forest machine learning approach using all available baseline clinical, cardiac imaging and biomarker data revealed that pre-treatment Angiopoietin-2, Myeloperoxidase and Endoglin levels were the best predictors of CTRCD risk, and the model was further validated in an independent cohort. Conclusion: A combination of endothelial-centric and inflammatory biomarkers measured before treatment can accurately predict CTRCD during breast cancer therapy. Our findings suggest that sub-clinical vascular activation may predispose to cardiac dysfunction during cancer treatment, and that the vasculature may serve as a potential therapeutic target.
Gustafson et al. (Wed,) studied this question.