Anticancer Treatment of Breast Cancer Related to Cardiotoxicity and Dysfunctional Endothelium

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.