Part I
Advances in early diagnosis, as well as the development of treatments in breast cancer have led to improvements of disease-free and overall survival over the last decade. Complications of antineoplastic treatments can occur and should be carefully evaluated. Aromatase inhibitors are associated with an increased risk of osteoporosis, tamoxifen is associated with uterine cancer and chemotherapy is associated with myelodysplasia and secondary leukemia. Furthermore, long-term cardiac toxicity is an important issue in breast cancer patients. Chemotherapy-induced cardiotoxicity is concerning. Certain antineoplastic treatments like anthracyclines and targeted therapies are known to be cardiotoxic(1-5).
Cardiovascular side effects can impact the quality of life and survival. Cardiac risk factors should be assessed when deciding on adjuvant/neoadjuvant treatment regimens for breast cancer. The most common side effects of antineoplastic treatment include vasospastic and thromboembolic ischemia, arterial hypertension, arrhythmia, cardiac dysfunction and heart failure(1-5).
There are two types of cardiotoxicity: type I cardiotoxicity, seen with anthracyclines (caused by free radical formation that leads to oxidative stress and myofibrillar disorganization), that is dose-related and considered irreversible, and type II cardiotoxicity, seen with the use of trastuzumab, that does not include ultrastructural abnormalities and is considered reversible with treatment discontinuation and does not relate to doses. The difference between type I and type II is complicated. Studies have shown improvement in anthracycline-induced cardiac dysfunction with heart failure (HF) therapy, while other studies have shown irreversible fibrosis on magnetic resonance imaging in patients treated with trastuzumab(1-5).
Cardiovascular risk factors are the history of hypertension, diabetes, known coronary artery disease and cardiotoxicity of anticancer therapy. Known risk factors for trastuzumab-associated cardiac toxicity include a lower screening left ventricle ejection fraction (LVEF) and a lower post-anthracycline LVEF. Alternative less cardiotoxic regimens should be considered, if the patient presents a high cardiac risk, with frequently monitoring cardiac function when cardiotoxic drugs cannot be avoided(2,5).
Risk factors for cardiac toxicity include genetic predisposition, very young or old age, female gender, higher single dose, intravenous bolus administration, previous or concurrent mediastinal radiation therapy, and combination with alkylating or antimicrotubule chemotherapeutics. Patients with underlying traditional cardiac risk factors such as hypertension, diabetes mellitus, hyperlipidemia, smoking history and known coronary artery disease also have increased risk(3,5) (Figure 1).
Type I cardiotoxicity
Anthracyclines, like doxorubicin and epirubicin, are used in the treatment of breast cancer. They are antitumor agents and their mechanism includes intercalation into nuclear DNA to impair protein synthesis, production of reactive oxygen species and inhibition of topoisomerase II to inhibit DNA repair. Approximately 10% of the patients receiving anthracyclines will develop dose-dependent cardiac complications(3,5,11).
Anthracyclines cause DNA damage and formation of reactive oxygen species, they induce the intracellular accumulation of iron and form complexes with it, further inducing the production of free oxygen radicals. These mechanisms can lead to other cellular alterations (changes in calcium homeostasis and abnormalities of the contractile apparatus). Doxorubicin can cause death of cardiac cells and thus affecting cardiac structure and function. The alteration of cardiac fibroblasts activity and the turnover of the myocardial extracellular matrix is a hypothesis sustained by the presence of fibrosis that has been observed in hearts that had been exposed to doxorubicin(3,5,11). In a multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy, Marty M et al. showed that patients treated with dexrazoxane experienced significantly fewer cardiac events (39% versus 13%, P<0.001) and a lower and less severe incidence of congestive heart failure (11% versus 1%, P<0.05) compared with those receiving anthracycline alone, without compromising the antitumor efficacy of the chemotherapeutic regimen(6). In an article by Oliveira PJ et al., it was concluded that the cardioprotective effects of carvedilol against doxorubicin-induced mitochondrial cardiotoxicity are due to its inherent antioxidant activity and not to its beta-adrenergic receptor antagonism, by demonstrating that carvedilol inhibits oxidative stress, mitochondrial dysfunction and histopathological lesions in the cardiac tissue caused by doxorubicin. In contrast, atenolol (AT), a beta-adrenergic receptor antagonist lacking antioxidant properties, preserved phosphate energy charge, but failed to protect against any of the indexes of doxorubicin-induced oxidative mitochondrial toxicity(7).
Taxanes, such as paclitaxel and docetaxel, used in the treatment of advanced breast cancer, are antimicrotubule agents that bind to tubulin, inhibiting cell division, and have been associated with early LVD and HF. Paclitaxel causes massive histamine release that may lead to conduction disturbances and arrhythmias. Heart failure incidence associated with taxanes is relatively low(3,5,11).
Type II cardiotoxicity
Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2)/ErbB2 protein and used for the treatment of breast carcinoma in women whose tumors overexpress the HER2 protein. In HER2-positive breast cancer, the addition of trastuzumab prolongs overall survival in both early stage and metastatic disease. Moderate/severe cardiac toxicity is a serious complication that can lead to dose reductions and premature discontinuation of treatment. In normal cardiac myocytes, the HER2/ErbB2 signaling pathway is responsible for adaptation and response to stress. The interference in this pathway may explain the mechanism of cardiotoxicity. Trastuzumab can cause cardiac dysfunction in a number of patients and is increased when is coadministered with anthracyclines(3,5). The cardiac dysfunction induced by trastuzumab arises from impairment of contractility and not from the death of myocytes. The cardiac function is likely to recover (within 1-3 months) and there is evidence that it is relatively safe to readminister trastuzumab after it has been discontinued and the myocardial function returned to baseline(1,3,5,9,11). The HER2 655 A>G genetic variant has recently been associated with trastuzumab-induced cardiotoxicity in HER2 breast cancer patients. The results of the study published by Gómez Peña validated the role of this polymorphism as a predictor of the cardiac toxicity of trastuzumab in breast cancer patients. The results support the role of the HER2 655 A>G polymorphism as a genetic marker of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients(10).
The results of a study published in 2008 by Edith A. Perez that tried to assess cardiac safety and the potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial showed that cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC(12). The combination of trastuzumab with other agents such as lapatinib and pertuzumab to increase the efficacy comes with the potential of supplementary cardiotoxicity(11).
Pertuzumab is a more recent anti-HER2 antibody that binds to the domain II of the receptor and interferes with the formation of ligand induced HER2 heterodimers. A third HER2-targeting agent is lapatinib, a small molecule inhibitor of the intracellular tyrosine kinase domain of HER2 that affects both ligand triggered and ligand-independent HER2 signaling. Lapatinib seems to be less toxic than trastuzumab. Data about the toxicity of pertuzumab are limited(3,5,13,14). A meta-analysis published by Valachis A provides evidence supporting comparable cardiac toxicity between anti-HER2 combination therapy and anti-HER2 monotherapy - overall incidence results for congestive heart failure in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 0.88% (95% CI: 0.47-1.64%) and 1.49% (95% CI: 0.98-2.23%). The incidence of LVEF decline was 3.1% (95% CI: 2.2-4.4%) and 2.9% (95% CI: 2.1-4.1%), respectively(14).
Trastuzumab emtansine (TDM1) is an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker and trastuzumab. TDM1 has shown clinically relevant activity in the treatment of HER2-positive breast cancer patients after progression on trastuzumab and taxane based therapy, both in the second line treatment setting and after early relapse on adjuvant trastuzumab therapy, with favorable safety and tolerability profile. A new clinical trial with TDM1 showed a median follow-up of 24.6 months, with no prespecified cardiac events or symptomatic congestive heart failures reported. Four patients (2.7%) had asymptomatic LVEF declines (≥10 percentage points from baseline to LVEF<50%), leading to T-DM1 discontinuation in one patient, at a short 2-year follow-up. It wasn’t considered significant(16,17).
The human epidermal growth receptors are tyrosine-kinase receptors and are expressed as four isoforms: HER1, HER2, HER3, and HER4. Neuregulin binds to HER4 receptors which dimerize with HER2 receptors and increase several survival pathways in the myocardium. Cardiotoxicity of HER2-targeting drugs has been related to the inhibition of fundamental actions of neuregulin-1 in the heart. Neuregulin-1 acts on cardiac cells via ErbB4/ErbB4 homodimers and ErbB4/ErbB2 heterodimers to elicit protective pathways in response to stress. By blocking neuregulin-1 effects in the heart, HER2 inhibitors may make it more vulnerable to noxious stimuli, like anthracyclines. Future studies need to determine its therapeutic role for heart failure(1,5).
Breast radiotherapy has changed substantially in recent decades. Radiotherapy has an effect on cell growth and induces oxidative stress and releasing of proinflammatory cytokines with numerous late effects like fibrosis and intimal proliferation in endothelial vasculature. Estimating the cardiac risk includes challenges in length of follow-up and the use of cardiotoxic agents such as evolving systemic chemotherapy and targeted therapies. Risk factors include high radiation dose (>30 Gy), young age, large volume of irradiated heart, longer time of exposure and use of concomitant therapy (chemotherapy and targeted therapies). The usage of high doses of mediastinal radiotherapy can result in pericarditis, accelerated atherosclerosis, valvular dysfunction, clinical heart failure, as well as fatal cardiovascular events. Cardiovascular effects of radiation are observed as late effects, years after exposure, making long-term surveillance critical. Screening depending on risk factors should be performed years after exposure. Modern technologies aim to improve cardiac function preservation such as deep inspiration breath hold, gating, accelerated partial breast irradiation, and use of modern 3-dimensional planning(3,11,15).
Assessment of anticancer drug-related cardiotoxicity before, during, and after treatment is very important. Patients should be strictly monitored by cardiologists and oncologists and should have a baseline evaluation for risk stratification (complete history and examination, with ECG and blood pressure measurement). Studies showed that cardiac biomarkers like troponins and natriuretic peptides may be elevated in cardiotoxicity and heart failure, but are not being performed routinely in patients undergoing cancer treatment. Future studies need to be performed to determine the role of these biomarkers. Monitoring of cardiac function is necessary also at the end of cancer treatments, and echocardiography should be performed to check for late cardiotoxicity. A recent study conducted by Kalay and colleagues has evaluated the use of