Trastuzumab-associated cardiotoxicity in Patient Specific iPSC-derived cardiomyocytes from HER2+ breast cancer patients

Trastuzumab is a monoclonal targeted therapy widely used to treat human epidermal growth factor receptor 2 (HER2+) over expressed breast cancer which confers an aggressive cancer type and comprises ~25% of breast cancer. Trastuzumab yields improved breast cancer related outcomes, but survival benefits are in part offset by cardiotoxicity - as evidenced by 10-15% of patients develop cardiomyopathy and 2-4% develop congestive heart failure. Approximately 20-30% of patients have either temporary or permanent discontinuation of trastuzumab therapy due to its cardiotoxicity, raising concern for inadequate cancer treatment and recurrence. Current screening strategies for trastuzumab-induced cardiotoxicity rely on non-invasive imaging such as echocardiography, but conventional imaging techniques provide limited a priori risk stratification for cardiotoxicity. We have utilized patient-specific iPSC-CMs derived from HER2+ breast cancer patients with and without evidence of TIC as a model to better elucidate the mechanisms of Trastuzumab-indued cardiotoxicity. Overall design: We have recruited HER2+ breast cancer patients with evidence of cardiotoxicity from Trastuzumab (TX) and control HER2+ breast cancer patients without cardiotoxicity (NT). Induced pluripotent stem cells were reprogrammed from the patient's peripheral blood mononuclear cells and then differentiated into iPSC-derived cardiomyocytes (iPSCM-CMs) which were treated with Trastuzumab and performed bulk RNA sequencing.