The Feasibility of a Biomarker Guided Strategy in Anthracycline Cardiotoxicity

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Project Summary Anthracyclines are used widely in the treatment of multiple cancers and have led to important oncologic survival gains in breast cancer and lymphoma. However, these agents carry a significant risk of cardiovascular (CV) morbidity and mortality in both malignancies. Doxorubicin-induced CV dysfunction, defined by declines in left ventricular ejection fraction (LVEF), occurs in 10-15% of patients at dosages of 240mg/m2. Cardiotoxic effects worsen with higher doses, and when anthracyclines are used in combination with trastuzumab and/or chest radiation therapy. The development of LVEF declines and heart failure (HF) results in treatment interruptions and worse oncologic outcomes. The NIH and professional societies have recognized the need to understand which cancer patients are at increased risk for cardiotoxicity (CTX) and to develop strategies to mitigate this risk. Trials of prophylactic cardioprotection have suggested modest positive effects, likely secondary to a “one size fits all” approach that includes those at low CTX risk. We hypothesize that widely available CV biomarkers can guide cardioprotection, advancing a personalized approach focused on the identification and treatment of those at increased CTX risk. This proposal leverages the insights gained in R01 HL118018 (Ky, PI) focused on understanding individual patient risk and the perturbations secondary to doxorubicin and/or trastuzumab. In this R21, we propose a randomized, open label pilot study of NT-proBNP monitoring compared to usual care in 100 breast cancer or lymphoma patients receiving doxorubicin. We hypothesize that a biomarker guided treatment strategy that initiates HF therapy in patients who develop increases in NT-proBNP prior to, during or after anthracyclines will be feasible and well-tolerated, and result in attenuation of CTX, compared to usual care. Cancer therapy associated CTX is a significant problem, and decreasing this health burden is a high priority. We will leverage the insights gained through R01 HL118018; obtain the necessary pilot data to support the feasibility, tolerability, and potential efficacy of a biomarker-guided approach and inform a subsequent large trial in patients receiving anthracyclines. Our ultimate goal is to advance a new paradigm of cancer care delivery.