MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy. ClinicalTrials.gov: NCT01016886

Cancer is the leading cause of premature death in Canada. In the last decade, important gains in cancer survival have been achieved by advances in adjuvant treatment. However, many oncologic treatments also result in cardiovascular "toxicity". Furthermore, cardiac risk factors such as hypertension, dyslipidemia, and diabetes mellitus are known to contribute to the progression of cardiac damage and clinical cardiotoxicity. As such, for many survivors, the risk of death from cardiac disease exceeds that of recurrent cancer. While provision of care by multidisciplinary teams has been shown to reduce mortality and hospitalizations among heart failure patients, the effect of assessments and interventions by multidisciplinary specialists in cancer patients receiving cardiotoxic chemotherapy regimens is currently unknown. Accordingly, we will examine the effect of a multi-disciplinary team interventions in the early assessment, identification and treatment of cardiovascular risk factors in cancer patients receiving adjuvant systemic therapy. Our main hypothesis is to determine if the incidence of LV dysfunction in cancer patients undergoing adjuvant therapy can be reduced through a multidisciplinary team approach. This is a randomized study comparing intensive multidisciplinary team intervention to usual care in the prevention of LV remodeling in patients receiving anthracycline or trastuzumab-based chemotherapy. Main objectives include early detection strategies for cardiotoxicity using novel biomarkers that reflect myocardial injury, remodeling and/or dysfunction; early identification and intensive treatment of cardiovascular risk factors; and early intervention with supportive care strategies including nutritional and pharmacist counselling, exercise training and cardiology team support. Secondary objectives include correlation of novel biomarkers to clinical outcomes; correlation of multidisciplinary interventions to adverse clinical outcomes; relationship of multidisciplinary interventions and chemotherapy dose density; preservation of lean muscle mass; and patient reported outcomes (symptom intensity and quality of life). Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, TITAN will be the first randomized trial examining the utility of multidisciplinary team care in the prevention of cardiotoxicity. We expect our results to inform comprehensive and holistic care for patients at risk for negative cancer therapy mediated sequelae. ClinicalTrials.gov, NCT01621659 Registration Date 4 June 2012.

Background: The overlap between cancer and cardiovascular care continues to expand, with intersections emerging before, during, and following cancer therapies. To date, emphasis has been placed on how cancer therapeutics influence downstream cardiac health. However, whether active malignancy itself influences chamber volumes, function, or overall myocardial tissue health remains uncertain. We sought to perform a comprehensive cardiovascular magnetic resonance‐based evaluation of cardiac health in patients with chemotherapy‐naïve cancer with comparison with a healthy volunteer population. Methods and Results: Three‐hundred and eighty‐one patients with active breast cancer or lymphoma before cardiotoxic chemotherapy exposure were recruited in addition to 102 healthy volunteers. Both cohorts underwent standardized cardiovascular magnetic resonance imaging with quantification of chamber volumes, ejection fraction, and native myocardial T1. Left ventricular mechanics were incrementally assessed using three‐dimensional myocardial deformation analysis, providing global longitudinal, circumferential, radial, and principal peak‐systolic strain amplitude and systolic strain rate. The mean age of patients with cancer was 53.8±13.4 years; 79% being women. Despite similar left ventricular ejection fraction, patients with cancer showed smaller chambers, increased strain amplitude, and systolic strain rate in both conventional and principal directions, and elevated native T1 versus sex‐matched healthy volunteers. Adjusting for age, sex, hypertension, and diabetes mellitus, the presence of cancer remained associated with these cardiovascular magnetic resonance parameters. Conclusions: The presence of cancer is independently associated with alterations in cardiac chamber size, function, and objective markers of tissue health. Dedicated research is warranted to elucidate pathophysiologic mechanisms underlying these findings and to explore their relevance to the management of patients with cancer referred for cardiotoxic therapies.

Anthracycline chemotherapy agents are commonly used to treat breast cancer, but also result in cardiac injury, and potentially detrimental effects to vascular and skeletal muscle. Preclinical evidence demonstrates that exercise and caloric restriction can independently reduce anthracycline-related injury to the heart as well as cancer progression, and may be promising short-term strategies prior to treatment administration. For women with breast cancer, a short-term strategy may be more feasible and appealing, as maintaining regular exercise training or a diet throughout chemotherapy can be challenging due to treatment symptoms and psychosocial distress. The Caloric Restriction and Exercise protection from Anthracycline Toxic Effects (CREATE) study will determine whether acute application of these interventions shortly prior to receipt of each treatment can reduce anthracycline-related toxicity to the heart, aorta, and skeletal muscle. Fifty-six women with early stage breast cancer scheduled to receive anthracycline treatment will be randomly assigned to one of three groups who will: 1) perform a single, 30-min, vigorous-intensity, aerobic exercise session 24 h prior to each anthracycline treatment; 2) consume a prepared diet reduced to 50% of caloric needs for 48 h prior to each anthracycline treatment; or 3) receive usual cancer care. The primary outcome is magnetic resonance imaging (MRI) derived left ventricular ejection fraction reserve (peak exercise LVEF – resting LVEF) at the end of anthracycline treatment. Secondary outcomes include MRI-derived measures of cardiac, aortic and skeletal muscle structure and function, circulating NT-proBNP, cardiorespiratory fitness and treatment symptoms. Exploratory outcomes include quality of life, fatigue, tumor size (only in neoadjuvant patients), oxidative stress and antioxidants, as well as clinical cardiac or cancer outcomes. MRI, exercise tests, and questionnaires will be administered before, 2–3 weeks after the last anthracycline treatment, and one-year follow-up. The proposed lifestyle interventions are accessible, low cost, drug-free potential methods for mitigating anthracycline-related toxicity. Reduced toxic effects on the heart, aorta and muscle are very likely to translate to short and long-term cardiovascular health benefits, including enhanced resilience to the effects of subsequent cancer treatment (e.g., radiation, trastuzumab) aging, and infection. ClinicalTrials.gov NCT03131024; 4/21/18.