Anticancer Treatment of Breast Cancer Related to Cardiotoxicity and Dysfunctional Endothelium
Condition: Breast Neoplasms; Endothelial Dysfunction; Cardiovascular Disease; Metabolic Syndrome
MeSH terms: Breast Neoplasms; Cardiovascular Diseases; Cardiotoxicity; Metabolic Syndrome
Study type: Interventional

Summary: 
      Several cytotoxic regimens are related to endothelial cell damage and vascular toxicity.
      Endothelial dysfunction is implicated in the pathogenesis of all known cardiovascular
      diseases (CVD) and closely related to the metabolic syndrome. Both CVD and diabetes
      contributes importantly to total mortality and to breast cancer (BC) specific mortality.

      In the epidemiological part of the project, the investigators will determine the prevalence
      and incidence of cardiovascular and metabolic morbidity/mortality in early BC patients
      compared to the Danish background population.

      In the clinical part, the investigators will study the changes of endothelial function and
      metabolic parameters in BC patients receiving chemotherapy.

      With increasing number of BC survivors, long-term consequences of curative cancer treatment
      should be studied. The investigators hypothesize that cytotoxic therapy worsens metabolic
      parameters possibly through endothelial dysfunction. If this is true, the next step will be
      to evaluate how strict metabolic control will affect prognosis.
    

Detailed description: 
      1. Background

           During the past 30 years, survival of breast cancer patients has improved substantially
           due to earlier diagnosis, improved surgical techniques, introduction of new combination
           of chemotherapy, new hormonal treatment, introduction of targeted treatment, and
           refinement of radiation techniques. With increasing number of cancer survivors, which in
           part are reached by more aggressive treatment, more attention is presently being drawn
           to long-term consequences of curative cancer treatment.

           Comorbidity among breast cancer patients has been thoroughly studied over the past
           years. Previous research has however, primarily focused on prevalence of comorbidity at
           the time of the cancer diagnosis (manifest comorbidity) and less attention has been paid
           to studying latent comorbidity developing after the diagnosis, which can be a result of
           the treatment. Furthermore it is not known if the incidence of this later developed
           comorbidity is different in breast cancer patients compared to the general population.
           Additionally, most studies do not address specific diseases but focus on comorbidity as
           such. Emerging evidence, however, indicates that cardiovascular disease (CVD)
           (encompassing cerebrovascular disease manifested by stroke and TCI and coronary heart
           disease manifested by infarction, arrhythmias, heart failure and sudden death) and
           diabetes may play a pivotal role, because it contributes importantly both to total
           mortality and to breast cancer specific mortality among breast cancer survivors.

           Comorbidity at breast cancer diagnosis is an independent adverse prognostic factor. In
           Denmark, comorbidity was present in 26% of breast cancer patients diagnosed 2006-2008,
           and the presence of comorbidity increased the risk of dying from breast cancer as well
           as from other causes with adjusted hazard ratios for all-cause mortality of 1.45 and
           breast cancer-specific mortality 1.30. Most studies have, however, used a summary
           measure of comorbidity such as the Charlson Comorbidity Index Score, and only few
           studies have assessed the individual effects of specific comorbidities on the mortality
           among breast cancer patients. These few studies universally demonstrate that CVD and
           diabetes are associated with decreased overall survival. Thus, Patnaik et al showed that
           among breast cancer patients, women with the following comorbidities were more likely to
           die as a result of other causes: CVD (59.2%), COPD (52.2%), diabetes (47.8%) and
           previous cancer (43.8%) Fully adjusted relative hazards of the effects of comorbidities
           on breast cancer-specific mortality was 1.24 for CVD and 1.10 for diabetes, and among
           the total study population of breast cancer patients, CVD was the primary cause of death
           (15.9%), followed closely by breast cancer (15.1%). In a meta-analysis of studies of
           overall survival in breast cancer patients with preexisting diabetes, Barone et al found
           that preexisting diabetes was associated with an increased mortality with a hazard rate
           (HR) of 1.61; (95% CI, 1.46-1.78).

           Metabolic syndrome (MS) is a cluster of disorders including hypertension, type II
           diabetes, dyslipidemia and obesity, and certain aspects of the MS are well described in
           relation to breast cancer. It has been shown that obesity is associated with an
           increased risk of developing breast cancer among postmenopausal women, obese patients
           present with more advanced cancers, and women who are overweight or obese at the time of
           breast cancer diagnosis or gain weight after diagnosis are at increased risk of cancer
           recurrence and death compared with leaner women. One study have shown that the effects
           of adjuvant therapy is less in obese breast cancer patients. An association between
           diabetes and breast cancer has also been observed. Other components of the MS, including
           low HDL-cholesterol, high triglycerides, hypertension, and serum testosterone are,
           however, less well described, but may be associated with an increased breast cancer risk
           and a worse breast cancer prognosis. A recent study showed that patients with MS present
           with more aggressive tumors. In patients with metastatic disease, response to
           chemotherapy appears to be inferior when the patient is diagnosed with MS, as well.
           Emerging evidence suggest that the MS may be quite prevalent among patients with breast
           cancer.

           In our study the metabolic syndrome will be defined in accordance with the definition of
           the National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATPIII). A
           diabetic FPG level is defined as FPG >7 mmol/l; impaired fasting glycemia is defined as
           FPG between 6.1 and 7.0 mmol/l according to World Health Organization criteria.

           Endothelial cells line the internal lumen of all the vasculature and serve as an
           interface between circulating blood and vascular smooth muscle cells (VSMCs). Apart from
           being the key participant during the process of angiogenesis, these dynamic structures
           can actively regulate basal vascular tone and vascular reactivity in physiological and
           pathological conditions. They respond to mechanical forces and neurohumoral mediators by
           releasing a variety of relaxing and contracting factors such as nitric oxide (NO) and
           prostacyclin. The balance between the vasodilatation and vasoconstriction is maintained
           by the endothelium, and the disruption of this balance leads to endothelial dysfunction
           and causes damage to the arterial wall. Endothelial cells are also responsible for the
           maintenance of blood fluidity and restoration of vessel wall integrity (when injured) to
           avoid bleeding. Endothelial cell-derived factors are also critical mediators of VSMC
           growth and inflammation.

           Several cytotoxic regimens have been shown to cause endothelial cell damage and vascular
           toxicity by various mechanisms. Thus, anthracyclines and taxanes (which forms the
           cornerstone of breast cancer treatment) together with cytotoxics as alkylating agents,
           bleomycin, vinca alkaloids and antimetabolites have been associated with endothelial
           cell apoptosis, oxidative stress, inflammation, coagulation disorders/thrombotic state,
           endothelial cell proliferation-migration, effects on VEGF, and impaired
           endothelial-dependent vasodilation in vitro and in vivo, although the exact mechanisms
           are not known. Changes in endothelial function hasten the development of micro- and
           macro-angiopathy and endothelial dysfunction is an important surrogate marker of
           atherosclerotic activity. Endothelial dysfunction has been implicated in the
           pathogenesis and clinical course of all known cardiovascular diseases and is associated
           with future risk of adverse cardiovascular events.

           Endothelial dysfunction is closely related to the MS, and a deficiency of
           endothelial-derived NO is believed to be the primary defect that links insulin
           resistance and endothelial dysfunction. It is not known whether worsening of endothelial
           dysfunction aggravates elements of the MS.

        2. Objective

      The aim of this research program is to study the changes of endothelial function and
      metabolic parameters in patients receiving chemotherapy for early stage breast cancer, and to
      compare these parameters with healthy age matched controls.

      Our theory is that cytotoxic therapy can induce endothelial cell damage and vascular toxicity
      causing endothelial dysfunction. The investigators believe that endothelial dysfunction is a
      mediator in the MS and predisposes to later cardiovascular disease, thus rendering patients
      receiving cytotoxic therapy at risk of these conditions.

      The investigators hypothesize that:

        1. Cytotoxic therapy induces endothelial dysfunction in predisposed early breast cancer
           patients.

        2. Metabolic syndrome may be aggravated by cytotoxic therapy, possibly through worsening of
           endothelial dysfunction.

        3. Treatment of early breast cancer (chemotherapy, antihormonal therapy and/or trastuzumab)
           aggravates preexisting CVD and/or metabolic disease and may induce the metabolic
           syndrome.

      3) Methods

      The study is a clinical case-control study with the inclusion of 90 patients divided into 3
      groups as stated below. 30 healthy women with the same age will participate as controls
      (group 4).

      Group 1: Newly diagnosed patients with early breast cancer. Investigated immediately prior to
      start of adjuvant therapy.

      Group 2: Early breast cancer patients, who have received standard treatment. Investigated
      immediately after completion of adjuvant chemotherapy.

      Group 3: Early breast cancer patients, who have received standard treatment. Investigated 1
      year after completed chemotherapy.

      Group 4: Healthy, age-matched controls. Controls will be recruited from an internet resource
      (www.forsoegsperson.dk):

      The test program will consist of the following investigations:

        1. To characterize endothelial function in vivo the effect of vasodilatating substances is
           measured in the forearm circuit. The substances is administered via a thin catheter
           placed in the Brachial artery near the elbow in local anesthesia. Once the vessels
           dilate, the blood flow in the forearm will increase and the flow change is a measure of
           the vasodilatory capacity of that substance. The change is measured with classical
           venous occlusion plethysmography. The method described is established at Aarhus
           University Hospital and has been used for several decades to illustrate the effect of
           vasoactive drugs on the human circulation, meaning it is a proven and well documented
           method.

        2. Applanation tonometry (pulse wave velocity and central blood pressure/arterial
           stiffness): The central blood pressure and the augmentation index is estimated from the
           shape of the radial pulse wave measured with a tonometer.

           Pulse wave velocity (PWV) is calculated from the average difference between the pulse
           pressure wave measured with a tonometer and the R in an ECG recorded simultaneously.

        3. Medical history: A full medical history including use of medication is obtained from
           every subject. Age, smoking status and concurrent medication. For patients tumor
           characteristics and anticancer treatment will also be described.

        4. Clinical examination: A regular objective examination is performed including weight,
           height (BMI) and measurements of hip and waist circumference.

        5. Measurements of body composition: Total body fat and fat free mass is measured by Dual
           Energy X-ray Absorptiometry (DEXA).

        6. Electrocardiography: A conventional 12 lead surface electrocardiogram is recorded.

        7. 24 hour blood pressure measurement

        8. Laboratory tests: Fasting blood tests are drawn from an antecubital placed catheter
           (albumin, ALAT/ASAT, alkaline phosphatase, bilirubin, gammaglutamyl transferase,
           coagulation factors, red and white blood cells, creatinin, potassium, sodium, fasting
           lipids, fasting glucose, hemoglobin A1C, insulin, sex hormones, von Willebrand factor,
           low grade inflammation markers, DNA and RNA for later analyses, including relevant
           coding genes).

           Further more urine samples to determine possible systemic impact of cardiovascular
           disease.

           The investigators will create a biobank containing urine and blood samples from
           participants for future research, provided that the participant gives her permission.

           Responsibility for the biobank lies with the project responsible physician, Anders Bonde
           Jensen.

        9. To characterize the overall risk of cardiovascular death within 10 years, the
           investigators will use a well- established and validated method called SCORE using age,
           gender, smoking status, systolic blood pressure and plasma cholesterol for risk
           stratification.

       10. Every premenopausal woman will be asked about the possibility of her being pregnant. In
           case of doubt the investigators will do a pregnancy test (urine hcg)
    

Intervention name(s): Venous occlusion plethysmography; SphygmoCor; 24hour blood pressure; DEXA scan; Laboratory blood samples
Intervention type(s): Procedure; Procedure; Procedure; Procedure; Biological
Intervention description(s): To characterize endothelial function in vivo the effect of vasodilatating substances is measured in the forearm circuit. The substances is administered via a thin catheter placed in the Brachial artery near the elbow in local anesthesia. Once the vessels dilate, the blood flow in the forearm will increase and the flow change is a measure of the vasodilatory capacity of that substance. The change is measured with classical venous occlusion plethysmography. The method described is established at Aarhus University Hospital and has been used for several decades to illustrate the effect of vasoactive drugs on the human circulation, meaning it is a proven and well documented method.; Applanation tonometry (pulse wave velocity and central blood pressure/arterial stiffness): The central blood pressure and the augmentation index is estimated from the shape of the radial pulse wave measured with a tonometer.
Pulse wave velocity (PWV) is calculated from the average difference between the pulse pressure wave measured with a tonometer and the R in an ECG recorded simultaneously.; 24 hour blood pressure measurement; Measurements of body composition: Total body fat and fat free mass is measured by Dual Energy X-ray Absorptiometry (DEXA).; Fasting blood tests are drawn from an antecubital placed catheter (albumin, ALAT/ASAT, alkaline phosphatase, bilirubin, gammaglutamyl transferase, coagulation factors, red and white blood cells, creatinin, potassium, sodium, fasting lipids, fasting glucose, hemoglobin A1C, insulin, sex hormones, von Willebrand factor, low grade inflammation markers, DNA and RNA for later analyses, including relevant coding genes).
Further more urine samples to determine possible systemic impact of cardiovascular disease.
We will create a biobank containing urine and blood samples from participants for future research, provided that the participant gives her permission.
Responsibility for the biobank lies with the project responsible physician, Anders Bonde Jensen.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention