Cardiotoxicity in medical breast cancer treatment
Chemotherapy based on anthracycline and antibody therapy with trasuzumab in HER2 positive breast cancer have significantly improved survival, but the treatment has potentially critical cardiac side effects and increases the risk of developing heart failure.
This study will describe the epidemiology of heart failure related to treatment with anthracycline and trastuzumab for breast cancer. In a prospective study HER2 positive breast cancer patients will be offered advanced echocardiography, test of bio-markers and genetic markers for the purpose of investigating if early identification of patients in particular risk of developing heart failure is feasible.
Breast cancer is the most common type of cancer among women in Denmark. A cornerstone in the management of breast cancer is anthracycline based chemotherapy, which has improved survival, but has potentially serious cardiac side effects and has been associated with increased risk of developing heart failure. The injury is most often considered irreversible and when present associated with a poor prognosis. The actual clinical incidence of heart failure related to anthracycline is uncertain, since observational studies indicate a higher incidence than originally reported from controlled clinical trials. Furthermore, the development of cardiac toxicity and of symptomatic heart failure may be delayed several years after exposure to antracycline. Thus a substantial under-reporting is expected in studies without long term follow-up.
Up to 20% of breast cancer patients have a subtype of cancer with expression of the Human Epidermal Growth Factor Receptor 2 (HER2), which is associated with accelerated tumor growth, early metastasis and thus a poor prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2, and adjuvant therapy with trastuzumab has improved survival for HER2 positive breast cancer patients. However as for antracycline, cardiac toxicity with impairment of left ventricular (LV) systolic function and development of heart failure is also a potential risk with trastuzumab. The adverse effect of trastuzumab is considered in contrast to the anthracycline associated myocardial injury to be reversible. Thus, if impairment of LV function is detected early and treatment is interrupted temporarily or permanently the LV function may recover.
The first randomized trials with trastuzumab, which mainly included younger women without overt cardiac disease and low cardiac risk profile, reported a statistically significant 5-fold increased risk of cardiac toxicity with development of symptomatic heart failure in 1-2% of the trastuzumab treated patients. However, new observational studies suggest that the problem is even larger in the clinical unselected breast cancer population, where up to 20% of patients treated with trastuzumab has been reported to develop heart failure.
Treatment with trastuzumab is monitored and includes recording of possible clinical side effects and repeated isotope Multi Gated Acquisition (MUGA) scans with measurements of LV ejection fraction (LVEF). However, LVEF is a relatively crude measure of LV systolic function. In addition, systolic dysfunction primarily affecting subendocardial longitudinal myocardial fibers may be unnoticed by LVEF, which mainly reflects function of the circular oriented muscular fibers located in the middle of the myocardium. Impairment of these fibers is typically preceded by a decreased function of the subendocardial fibers. Abnormalities in longitudinal LV function may be detected reproducible using cardiac ultrasound (tissue Doppler imaging (TDI) and speckle tracking echocardiography). In patients with ischemic heart disease, hypertension and restrictive cardiomyopathy myocardial deformation may be severely impaired despite apparently normal LVEF. In these circumstances 2D speckle tracking contributes with independent prognostic information about mortality and hospitalization due to heart failure. In addition, these methods also provide information about LV diastolic function, which in a range of heart disease is impaired before the systolic dysfunction becomes manifest. The value of these echocardiographic methods for early detection of myocardial injury in patients treated with trastuzumab treatment is not fully clarified.
This study will describe the epidemiology of heart failure related to treatment with anthracycline and trastuzumab for breast cancer in Denmark.
Description of the cohort
Breast cancer patients treated with antracycline and trastuzumab registered in Denmark and for a subgroup analysis at Odense University Hospital will comprise the cohorts for the description of the epidemiology of heart failure related to treatment with anthracycline and trastuzumab for breast cancer in Denmark.
70 HER2 positive breast cancer patients scheduled for trastuzumab treatment at Odense University Hospital will be offered to participate in the prospective study.
Data and biological material
The description of the epidemiology patients are identified from the Danish Breast Cancer Cooperative Group (DBCG) database. Development of heart failure is the primary endpoint. Data is obtained from the National Patient Register, Register of Medicinal Product Statistics, Social Security Register and Cause of Death Registry.
In a prospective study, HER2, positive breast cancer patients will be clinically examined including ECG and blood pressure. They will be offered advanced echocardiography, test of bio-markers and genetic markers for the purpose of investigating if early identification of patients in particular risk of developing hart failure is feasible.
Collaborating researchers and departments
Department of Cardiology, Odense University Hospital
- Professor Jacob Eifer Møller, MD, DMSc
- Jordi Sanchez Dahl, MD, PhD
- Lars Melgaard Videbæk, MD, PhD
- Professor Jens Mogensen, MD, DMSc
Department of Cardiology, Herlev Hospital
Department of Cardiology, Gentofte University Hospital
- Professor Gunnar H. Gislason, MD, DMSc
Department of Oncology, Odense University Hospital
- Professor Marianne Ewertz, MD, DMSc
- Søren Cold, MD, PhD
Department of Clinical Biochemistry, Odense University Hospital
- Professor Lars Melholt Rasmussen, MD, DMSc
Department of Cardiology, University Hospital Copenhagen, Rigshospitalet
- Professor Lars Køber, MD, DMSc