Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2, also ErbB2). For the 15-20% of patients with breast cancer overexpressing HER2, trastuzumab therapy is important in the treatment of both early and advanced disease. However, its use results in a risk for cardiotoxicity, especially when it is combined with anthracyclines. In an early clinical study, trastuzumab-induced cardiotoxicity was reported to occur in up to 7% of patients when trastuzumab is used as a single agent. When combined with an anthracycline, cardiotoxicity is notably increased and has been reported to occur in up to 27% of patients. Current clinical management for the trastuzumab-induced cardiotoxicity relies on the use of echocardiography to detect the reduction in left ventricular ejection fraction (LVEF). Based on the extent of LVEF reduction, a decision regarding continuation or discontinuation of trastuzumab therapy is made. However, reduction in LVEF is a part of the late phase of left ventricular dysfunction, which occurs as a part of the heart compensatory mechanism to preserve contractility. Troponin-I is considered as a sensitive and specific biomarker in the diagnosis of myocardial infarction. However, it is not sensitive and specific for the diagnosis of early stage of trastuzumab-induced cardiotoxicity. There are no clinically approved biomarkers that can be used to predict the cardiac dysfunction induced by trastuzumab. Recently, Dr. Wen Jin Wu's group at FDA found that trastuzumab significantly reduced LVEF in mice which was associated with elevated levels of troponin I and cardiac myosin light chain 1 (cMLC-1) in mice sera compared to troponin1 and cMLC-1 levels in control mice. cMLC-1 has been implicated as a marker of heart function and may be a promising laboratory marker with diagnostic potential for the assessment of minimal myocardial damage. These findings provided the rationale for our hypothesis that plasma cMLC-1 level is associated with trastuzumab-induced cardiotoxicity in a cohort of barest cancer patients.
In Aim1, we will determine plasma level of cMLC-1 in breast cancer patients who are treated with or without trastuzumab using sandwich ELISA. Subsequently, in Aim2, we will use archived human plasma collected before and after trastuzumab treatment at multiple time points from a relatively homogenous patient population. The cohort consisted of women with newly diagnosed breast cancer who underwent treatment with anthracyclines followed by taxanes and trastuzumab. At the conclusion of the proposed studies, we will have: i) established for the first time a method to quantitatively measure plasma cMLC-1 in patients treated with or without trastuzumab and ii) determined the correlation between plasma level of cMLC-1 and trastuzumab-induced cardiotoxicity.
Trastuzumab (also known as Herceptin) is a humanized monoclonal antibody directed against the extracellular domain IV of the human epidermal growth factor receptor 2 (HER2) and is an FDA approved targeted therapy for the treatment of HER2-positive breast cancers. Trastuzumab provides significant therapeutic benefits and improves disease free and overall survival after adjuvant chemotherapy. However, trastuzumab treatment is also associated with the cardiac dysfunction. Biomarkers of trastuzumab-induced cardiotoxicity are needed for specific and earlier detection and better clinical management. This grant proposal aims at developing cMLC-1 as a novel predictive biomarker for trastuzumab-induced cardiotoxicity.
