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    Research Grants Awarded

    Early Detection And Prediction Of Chemotherapy-Induced Cardiotoxicity In Breast Cancer Patients.

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Rationale. Despite advances in diagnosis and therapy, breast cancer remains a common disease and is usually lethal if it recurs systemically. For the subset of breast cancer patients who have overexpression of HER-2 in their cancerous cells, the antibody trastuzumab (Herceptin), which inhibits the HER2 receptor, has recently been shown to significantly decrease the progression of the disease and to improve survival when added to anthracyclines-based chemotherapy. The use of this novel targeted therapeutic association is, however, limited by its cardiotoxicity which is detected in approximately 20% of patients and manifests itself by a decrease in left ventricular ejection fraction (LVEF). The decrease in LVEF, a precursor to symptomatic heart failure, appears only partially reversible after discontinuation of trastuzumab. More sensitive indices of LV function would be crucial in better adjusting the treatment and avoiding heart failure. In studies that serve as a foundation for this proposal, we reported that myocardial velocities and deformation rate (strain rate) obtained by a novel echocardiographic technique, tissue Doppler imaging (TDI), decrease earlier than LVEF and predict both the late decrease in left ventricular (LV) function and the mortality in a model of murine anthracycline-induced cardiotoxicity. Cardiac biomarkers such as NT-proBNP and troponin have also been shown to be sensitive markers of sub-clinical LV dysfunction and powerful predictors of morbidity and mortality in heart failure. Finally, metabolomics, a novel technique involving the rapid high throughput characterization of the small molecule metabolites present in the body, allows the unique possibility of a functional assessment of major pathways, in particular those involved in myocardial injury and failure. Hypothesis. The objectives of this study are to validate a panel of noninvasive markers that will identify patients at greatest risk for chemotherapy-induced cardiotoxicity. This will allow to customize the breast cancer treatment and its monitoring. Research Aims and Expected Results. Specifically, we will test: Aim 1. Whether tissue Doppler imaging, circulating levels of biomarkers and metabolomic profiling can non-invasively detect subtle manifestations of cardiotoxicity prior to the decrease in LV ejection fraction in breast cancer patients treated with chemotherapy and trastuzumab. Aim 2. Whether tissue Doppler imaging, circulating levels of biomarkers, genetic and metabolomic profiling can identify subgroups of patients at high risk for treatment-induced cardiotoxicity. One hundred women with HER2 positive breast cancer, treated with anthracyclines and trastuzumab will be studied. Women may receive trastuzumab in an adjuvant setting or as a neoadjuvant therapy, after previous treatment by anthracyclines. Visits will be planned before anthracyclines (if available), before the initiation of trastuzumab, and 3, 6, 9 and 12 months after the initiation of trastuzumab. At each visit, the patients will undergo an echocardiogram and blood will be drawn to measure biomarkers and metabolites. Blood will also be stored at the initial visit for determination of HER2 haplotypes. Aim 1. We expect that the decrease in LV endocardial velocities and myocardial strain rate, the increase in biomarkers and the changes in metabolites involved in heart failure or injury pathways will occur earlier than the decrease in LVEF. Aim 2. We anticipate that the decrease in LV endocardial velocities and myocardial strain rate, the increase in biomarkers and the changes in metabolites involved in heart failure or injury pathways will predict the later decrease in LVEF. We will also profile the patients before treatment. The profiling will include the baseline values of the echocardiographic parameters of LV function, the biomarkers, the metabolites. Furthermore, the patients will undergo genetic testing of common haplotypes of HER-2. Based on these techniques, we anticipate to define a group of patients at high risk for chemotherapy-induced heart failure. Clinical Implications. Breast cancer is the most common cancer in women and the chance of developing invasive breast cancer during a woman's lifetime is approximately 1 in 8. Improvements in treatment have significantly increased survival. As treatment of breast cancer progresses towards a cure, it is critical that survivors not be plagued by significant side effects of the therapies such as heart failure that will negatively impact their life style and survival. In the present study, we will validate novel markers that will identify patients with early LV dysfunction or at high risk for the occurrence of cardiotoxicity. Women who can be identified as being at high risk of cardiac toxicity with the more standard regimen, or who begin to show early signs of LV dysfunction, could be treated with alternative chemotherapy and preventive cardiac treatments, allowing to adjust treatments before irreversible LV failure occurs. As the therapeutic arsenal targeting breast cancer develops, more potentially cardiotoxic drugs, such as various tyrosine kinases inhibitors and antiangiogenic factors are used. The indices validated in the present proposal as markers and predictors of heart failure in breast cancer patients may be applied to multiple other therapeutic regimens. The present research will increase our understanding of heart failure associated with breast cancer treatment and will potentially help to decrease its morbidity and mortality.

    Lay Abstract:
    One woman in 8 is expected to be afflicted with breast cancer during her life. One type of breast cancer, the HER2 positive cancer, is particularly aggressive and accompanied by a high death rate. Trastuzumab is a molecule that has shown great benefits in the treatment of these cancers. It is usually combined with other treatments used in breast cancer, such as anthracyclines. One of the main side effects of anthracyclines is that they are toxic to the heart and may lead to failure of the heart to function. Unfortunately, trastuzumab appears to increase the rate of heart failure induced by anthracyclines. The function of the heart is usually defined by the left ventricular ejection fraction (LVEF), a measure that can be obtained using ultrasound. A decrease in the LVEF has been described in about 20% of the patients treated by anthracyclines and trastuzumab. Although this decrease appears to be controlled by heart failure treatments, whether the long-term function of the heart will be preserved and whether cardiac treatment can be withdrawn are unanswered questions. There is a great need to be able to predict which women will have failure of their hearts after cancer treatment. These women may benefit from alternative cancer treatments, closer supervision of their heart function, preventive cardiac treatments. Study hypothesis. The objective of the present study is to identify the women who will have a high risk of heart failure after anthracyclines and trastuzumab. Our study has two aims. The first aim is to detect heart failure at very early stages. The second aim is to identify the women at high risk for heart failure before treatment is instigated. We will use a new heart ultrasound technique called tissue Doppler imaging, and measurements of molecules in the blood that are related to the heart damage and function. We have previously tested the new heart ultrasound technique in mice receiving anthracyclines and found that the analysis of ultrasound examinations done early after treatment predicted the subsequent heart failure and death. The molecules that we will test in the blood have shown that they can detect subtle damage done to the heart and that they predict the function of the heart in diseases of the heart. We will also analyze some genetic variations that may be associated with a greater risk of heart failure. Experiments testing the study hypothesis. One hundred women with HER2 positive breast cancer, treated with anthracyclines and trastuzumab will be studied. These women may have new treatment with anthracyclines and trastuzumab or may have been treated previously with anthhracyclines and be scheduled for trastuzumab. The patients will undergo heart ultrasound and blood tests before the anthracycline treatment (if the anthracyclines were not given previously), before the initiation of trastuzumab treatment, and 3, 6, 9 and 12 months after the initiation of trastuzumab. All the ultrasounds and the blood draws are indicated for the follow-up of the patients; the research protocol will add 15 minutes of additional images to the heart ultrasound and one tablespoon of blood to the blood draws (one and a half tablespoon the first time). The additional ultrasound images allow to measure the speed and the deformation of the heart during each contraction. These indices are able to detect very small decreases in the contraction of the heart, that LVEF is not able to detect. The molecules measured in the blood include troponin, a molecule that increases with heart damage and NT-pro BNP, a molecule that increases with the failure of the heart. Furthermore, using the novel technique of metabolomics, we will be able to span a large range of molecules produced by the heart. Finally, we will test some genetic variations that can be identified in blood cells and may be associated with increased heart failure in women treated by anthracyclines and trastuzumab. For aim 1, we will test whether the ultrasound indices and the molecules measured in the blood at early times points after anthracyclines and trastuzumab predict the later occuring heart failure. For aim 2, we will construct a profile of the patients, including the presence of genetic variations, the production of metabolites, blood markers, ultrasound indices of heart function. From this profile, we will identify the patients at high risk of heart failure. How the project uniquely advances our understanding of breast cancer and leads to reductions in mortality. Breast cancer is the most common cancer in women. Improvements in treatments have greatly increased survival: as treatment of breast cancer progresses towards a cure, it is critical that survivors not be plagued by significant side effects of the treatments such as heart failure that will negatively impact their life style and survival. In the present study, we will validate novel markers that will identify patients with early failure of the heart or at high risk for heart failure. It may be that women who can be identified as being at high risk of heart failure with the more standard regimen, or who begin to show early signs of it, can be treated with alternative cancer treatments and cardiac regimens, preventing irreversible failure of the heart. As the treatments breast cancer progresses, more drugs that may damage the heart are being developed. The indices validated in the present proposal as markers and predictors of heart failure may be applied to multiple other treatments. The present research will increase our understanding of heart failure associated with breast cancer treatment and will potentially help to decrease its morbidity and mortality.