Diagnosis and Prediction of Taxanes Induced Cardiac Dysfunction
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Observational

Summary: 
      Breast cancer represents the most frequent form of neoplasia in women worldwide, being
      responsible of 1.6% of annual deaths. Therefore, it is a major public health issue and
      research in this field should be a priority. Taxanes, such as paclitaxel and docetaxel, are
      extremely powerful antineoplastic drugs, which alone or in association to anthracyclines,
      increase survival and lower the recurrence rate of cancer, but their use is limited by
      cardiotoxicity. Cardiotoxicity can appear early or late after therapy, and may vary from
      subclinical myocardial dysfunction to irreversible heart failure. Currently, cardiac
      dysfunction induced by taxanes is diagnosed through classical echocardiographic parameters.
      However, these cannot detect subtle, early changes of cardiac structure and function.
      Consequently, description of new parameters, which could detect cardiac dysfunction in an
      early stage, becomes essential for detecting the group of patients at risk for irreversible
      heart failure. The objectives of the investigators project, in patients with breast cancer
      treated with taxanes, are to investigate their mechanisms which lead to cardiac dysfunction,
      to describe new parameters for the early diagnosis of cardiotoxicity, and to define
      predictive models for cardiotoxicity. Meanwhile, project will publish the results in
      prestigious journals, leading to an increase of the visibility of Romanian research
      internationally.
    

Detailed description: 
      Scientific context and motivation. Breast cancer represents the most frequent form of
      neoplasia in women worldwide, comprising 16% off all neoplasias. A report of the World Health
      Organization showed that 1 from 6 cancers is determined by breast cancer and this form of
      neoplasm causes around 550,000 deaths/year, respective 1.6% of all annual deaths in the
      world. The incidence of breast cancer is increasing, over 1.1 million of women being newly
      diagnosed with cancer every year. Although considered a pathology specific to developed
      countries, recently it was established that developing countries, such as Romania, include
      over 69% of all breast cancers. Therefore, breast cancer is currently a major public health
      and economical issue and research on new therapies, as well as monitoring their safety use,
      should be a priority.

      Many studies showed that, due to new chemotherapy, breast cancer can be considered a curable
      disease. And indeed, use of a multidisciplinary approach - surgery, radiotherapy,
      chemotherapy - has conducted to a significant reduction in the mortality. As a consequence of
      increased life expectancy, it becomes essential that specific oncologic therapies should be
      safe.

      Taxanes, inhibitors of cellular mitosis (paclitaxel and docetaxel), relatively new drugs, are
      extremely potent and widely used in different therapeutic regimes. Their single use or the
      association with classical chemotherapy, have been proved to increase significantly rate of
      cure in breast cancer, as well as to reduce recurrences. However, the applicability of these
      drugs on medium or long term is limited by the risk of cardiotoxicity.

      Cardiotoxicity is one of the most important adverse reactions of taxanes, leading to an
      important increase of morbidity and mortality. Cardiotoxicity can appear early or late in the
      course of the disease, and may vary from subclinical myocardial dysfunction to irreversible
      heart failure or even death. Recent research has showed that cardiac dysfunction induced by
      taxanes may increase exponentially with the cumulative dose used; meanwhile, it may be
      augmented by other associated cytotoxic drugs. Data on the susceptibility of patients to
      develop cardiotoxicity are scarce. Some studies suggest that patients without known
      cardiovascular history may develop symptomatic heart failure in direct connection to the
      cumulative dose received, affirmation which has led to the use of reduced doses of
      chemotherapy and, therefore, to a reduction in their efficiency. But also under these
      circumstances, there is a risk of cardiotoxicity induced by taxanes therapy, risk which
      cannot be foreseen by the cumulative dose. Moreover, the cardiac alteration is very
      frequently subclinical and it can appear early (during therapy), late (during the first year
      after therapy) or very late (more than one year after finishing therapy). Consequently, early
      diagnosis of subclinical cardiac dysfunction in patients with breast cancer treated with
      taxanes, as well as the establishment of prediction models for irreversible heart failure is
      essential in the management of such patients.

      Currently, recommendations of diagnosis of cardiac dysfunction induced by taxanes are to use
      functional and structural parameters of conventional echocardiography, such as left
      ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVSF), as well as
      diameters and volumes of the heart chambers. However, sometime, these conventional
      measurements allow only the late diagnosis of cardiac dysfunction, which might be already
      irreversible. Therefore, description of new and simple parameters, able to diagnose more
      subtle, subclinical changes of cardiac function becomes mandatory.

      Recently, it has been showed that myocardial velocities, cardiac deformation, parameters of
      ventricular torsion, and parameters of intra- and inter- ventricular dyssynchrony are
      affected before reduction of LVEF and LVSF. Therefore, these parameters might be useful in
      the early diagnosis of cardiac dysfunction induced by taxanes, and in establishing prediction
      of cardiotoxicity.

      Meanwhile, recently, early diagnosis of cardiac dysfunction is also based on increase of the
      biomarkers. Some of them, such as such as brain natriuretic peptides, troponins, markers of
      cardiac fibrosis and inflammation, might be more important during the subclinical cardiac
      dysfunction induced by chemotherapy, hypothesis that will be also verified.

      Finally, it was suggested that therapy with taxanes might increase the oxidative stress,
      causing endothelial dysfunction with increased arterial stiffness. This might be a mechanisms
      by which taxanes promotes cardiac dysfunction, through alteration of ventriculo-arterial
      coupling.

      In conclusion, early detection of cardiovascular dysfunction and establish of predictive
      models for cardiotoxicity represent a priority in the management of breast cancer. This can
      be done by using new ultrasound technique, assessing subclinical myocardial disease and
      ventriculo-arterial coupling, and new laboratory methods, assessing different biomarkers and
      the oxidative stress.

      Objectives. The main objective of our project is to describe new parameters for the early
      diagnosis of cardiovascular dysfunction patients with early breast cancer, treated with
      taxanes, and to define predictive models for cardiotoxicity.

      Our hypotheses are based on:

        1. Taxanes (alone or in combination with anthracycline) increase oxidative stress, with
           excessive production of free oxygen radicals, and activation of neurohormonal mediators
           of inflammation and fibrosis. Decrease of antioxidant capacity, genetically determined,
           might be an additional mechanism is some patients. Therefore, we will test the
           hypothesis that imbalance between oxidative stress and antioxidant capacity is one of
           the main mechanism of cardiotoxicity induced by taxanes in patients with breast cancer.

        2. Oxidative stress determines endothelial dysfunction with arterial remodeling and
           increased arterial stiffness. We will test the hypothesis that impaired
           endothelial-arterial-ventricular coupling might play an important role in the
           cardiotoxicity induced by chemotherapy.

        3. Subclinical cardiac dysfunction can be diagnosed by looking to new parameters of
           myocardial deformation and torsion, and their timing into the cardiac cycle. We assume
           that these parameters are first affected, before conventional echo parameters, during
           cardiotoxicity induced by chemotherapy.

      Therefore, objectives of our study, in patients with early breast cancer, without
      cardiovascular symptoms, treated with taxanes (alone or in combination with anthracycline),
      are:

        1. To assess imbalance between oxidative stress and antioxidant capacity in order to
           describe new potential mechanisms of cardiotoxicity;

        2. To test implication of some genetic disorders in predicting cardiotoxicity, mainly
           through decrease of antioxidant capacity;

        3. To assess endothelial-arterial-ventricular coupling as a possible determinant of
           cardiotoxicity;

        4. To determine the diagnostic accuracy of new echo parameters, as well as new biomarkers,
           for the early diagnosis of cardiotoxicity.

        5. To establish a standard evaluation protocol, by using these parameters and their
           predictive value, in order to identify patients at risk.

      By achieving these objectives of our research, derived objectives are:

        1. To promote original research in a new and important interdisciplinary field
           (cardiotoxicity induced by chemotherapy);

        2. To increase international visibility of Romanian research by publishing the results;

        3. To increase the research capacity of our unit, also by attracting new researchers;

        4. To further develop an interdisciplinary research center, attached to our new oncology
           unit; to participate to international muticentric studies/networks in the
           cardio-oncology field.

      Method and approach. Study population. Study will include 60 patients with early breast
      cancer, scheduled to receive taxanes, in monotherapy (30 patients) or associated to
      anthracyclines (30 patients), with doses according to the stage of the disease. Inclusion
      criteria are: (1) Age over 18 years; (2) Informed consent signed; (3) Patients with early
      breast cancer, scheduled to receive chemotherapy; (4) LVEF > 50% and LVSF > 20%. Exclusion
      criteria are: (1) Any history of cardiovascular disease and/or active cardiovascular
      treatment; (2) Diabetes mellitus; (3) Mediastinal irradiation. The protocol will be sent for
      approval to the Local Ethic Committee. All patients referred to the oncology department with
      the diagnosis of breast cancer, and scheduled to receive chemotherapy, will be screened.
      Patients will be evaluated 24 hours before initiation of treatment, and within 24 hours from
      the end of the cycle of chemotherapy. Long-term follow-up will be performed at 1 and 2 years
      after the end of chemotherapy.

      Methods. All patients will be assessed by:

        1. General characteristics: age, sex, height, weight, blood pressure, heart rate, family
           history, risk factors, clinical stage of breast cancer, date of surgical intervention
           (if applicable), date of initiation of chemotherapy, details of the scheme of
           chemotherapy, etc.

        2. Electrocardiogram (12 leads) and routine blood samples.

        3. Biomarkers: brain natriuretic peptides, troponin T, markers of myocardial fibrosis (β
           cross laps and procollagen type-1 amino terminal), and markers of inflammation (PCR-hs,
           IL1, IL6, IL 10, TNFalpha).

        4. Markers of the oxidative stress: concentration of carbonyl in plasmatic proteins, and
           the antioxidant capacity of plasma.

        5. Genetic tests of susceptibility to cardiotoxicity: genomic DNA extraction kit/DNA
           quantification tests/PCR tests.

        6. Echocardiography: detailed echo examination (VIVID 7 GE echo machine, with dedicated
           software ECHOPAC BT09) will be performed, as follows:

             1. Conventional echocardiography will measure/calculate:

                  -  Structural parameters: thickness of the cardiac walls; diameters and volumes
                     of the cardiac cavities, aorta, and pulmonary artery; left ventricular mass;
                     relative wall thickness; wall stress.

                  -  Functional parameters of systolic and diastolic function: ejection fraction,
                     shortening fraction, stroke volume, cardiac output, cardiac index, tricuspid
                     and mitral annular excursions; and, respectively, parameters derived from the
                     transmitral flow, pulmonary veins flow, velocity of propagation of the mitral
                     flow into the LV.

             2. Q analysis by tissue velocity imaging: measurements of systolic and diastolic
                myocardial velocities, and of the isovolumic accelerations, at the level of
                multiple left and right ventricular myocardial segments.

             3. Speckle tracking imaging, which is a new non-invasive method for the assessment of
                cardiac global and regional function; it uses myocardial speckles that represent
                tissue markers that can be tracked frame by frame throughout the cardiac cycles.
                Motion is analyzed by integrating frame by frame changes. This new method offers an
                alternative to techniques such as color-coded tissue velocity imaging for
                myocardial deformation (measured as strain and strain rate) in radial,
                longitudinal, and circumferential directions, in order to assess left and right
                ventricular, systolic and diastolic function, left ventricular torsion, and left
                and right atrial function.

             4. Advanced Q-Scan imaging, which is a new and innovative dedicated parametric
                imaging, supported by the 4D probe, for quantitative display of regional wall
                deformation. It consists of tissue synchronization, a real time parametric imaging
                technique for displaying mechanical synchronicity, and strain and strain rate
                imaging, showing myocardial deformation and the rate of deformation in real time.

             5. 3D echocardiography allows precise evaluation of the cardiac chamber anatomy and
                function. 4D analysis enables post-processing of multi-plane imaging datasets,
                allows multi-dimensional imaging acquired in parasternal bi-plane and apical
                tri-plane views, and supports 2D, color, as well as, tissue Doppler modes
                (including tissue synchronization imaging). All data can be stored in raw data
                DICOM format and can be recalled for post-processing.

        7. Measurement of endothelial function, parameters of arterial remodeling, and arterial
           stiffness at the level of the common carotid artery (vascular remodeling and arterial
           stiffness indices), and at the level of the brachial artery (endothelial function).
           Assessment will be done using an ALOKA α10 ultrasound machine, using a high resolution
           probe of 7,5-10 MHz, equipped with an "echo-tracking" system. Meanwhile, a dedicated new
           software available on the machine (wave intensity analysis) will be used to assess
           ventriculo-arterial coupling. Another system (Complior) will be used in order to measure
           the pulse wave velocity between 2 arterial sites (carotid-femoral and carotido-radial),
           as another measure of arterial stiffness.

      The research team who will participate in the project has an important experience in the
      field of cardiology and use of the new ultrasound techniques, as well as in the field of
      oncology, especially breast cancer, with many publications, national and international
      communications/ lectures on these topics.

      The Working Plan is well adapted for achieving the goals of this project, and human and
      material resources are appropriate to achieve all the objectives of the projects, taking into
      account the existing and newly acquired resources and infrastructure.

      Impact, relevance, applications. The relevance for the field. Because breast cancer is the
      most frequent neoplasia in women worldwide, including Romania, and the most feared adverse
      effect of chemotherapy is cardiac dysfunction, which leads to a significant increase in
      morbidity, mortality, and economical costs, we believe that the identification in early
      stages of cardiac dysfunction is a health problem of major interest and should represent a
      priority of the cardiology and oncology research. Using new imagistic and laboratory
      parameters might allow their integration into predictive scores, essential to identify
      patients at risk and to optimize treatment strategies in these patients.

      The estimated impact and applications of the project. This project could contribute to the
      elucidation of mechanisms of cardiac dysfunction induced by taxanes (alone or in combination
      with anthracyclines). Moreover, it might be able to introduce into clinical practice new
      diagnostic and predictive methods for patients at risk for developing cardiac dysfunction,
      consequently leading to an optimization of chemotherapy. Therefore, the results of the
      project could be applicative also from social and economic purposes, taking into account the
      disabilities and costs of heart failure that could occur after chemotherapy. Our proposal
      fits into the strategic objectives of our National System of Exploratory Research Projects,
      initiated by CNCSIS. It will create knowledge in the medical field and generate important
      scientific results, nationally and internationally competitive.

      The results of the project might be able to generate:

        1. Publication of results in prestigious, ISI indexed journals, contributing to the rise of
           the visibility of Romanian research at international level;

        2. Increase of the research capacity of our unit, also by attracting new researchers, which
           will have the chance to complete their training in an adequate scientific environment;

        3. A national interdisciplinary (cardiology and oncology) network dedicated to the early
           diagnostic and prediction of cardiotoxicity;

        4. The premises of interdisciplinary, national and international collaboration, with other
           centers with common interest, collaboration which could be the background of new
           research projects.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Study will include 60 patients with early breast cancer, scheduled to receive taxanes, in
        monotherapy (30 patients) or associated to anthracyclines (30 patients), with doses
        according to the stage of the disease.
      
Biospecimen description: 
      Biomarkers: brain natriuretic peptides, troponin T, markers of myocardial fibrosis (β cross
      laps and procollagen type-1 amino terminal), and markers of inflammation (PCR-hs, IL1, IL6,
      IL 10, TNFalpha).

      Markers of the oxidative stress: concentration of carbonyl in plasmatic proteins, and the
      antioxidant capacity of plasma.

      Genetic tests of susceptibility to cardiotoxicity: genomic DNA extraction kit/DNA
      quantification tests/PCR tests.
    
Keywords: BREAST CANCER,; TAXANES,; SUBCLINICAL CARDIAC DYSFUNCTION ,; DIAGNOSTIC TOOLS,; PREDICTIVE MODELS