Cardiotoxic Effects of Cancer Therapy

Cancer Therapeutics–Related Cardiac Dysfunction

Historically, the term cardiotoxicity was used to describe the development of LVD in the setting of the administration of cardiotoxic chemotherapeutic regimens. However, the term is nonspecific, as chemotherapeutic agents may affect the heart in ways different from LVD, including pericardial disease, hypertension, pulmonary hypertension, and QT prolongation. The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) defined in their expert consensus the term cancer therapeutics–related cardiac dysfunction (CTRCD) as a decrease in the LVEF of greater than 10 absolute points to a value less than 53%. In 2016, the American Society of Clinical Oncology published its clinical practice guidelines on prevention and monitoring of cardiac dysfunction in survivors of adult cancers. The guidelines state that the existing American College of Cardiology/American Heart Association guidelines for management of stage B disease recommend initiation of pharmacotherapy for individuals with reduced LVEF regardless of cause. They make the point that the exact absolute reduction of ejection fraction (EF) points is irrelevant as long as there is adjudication of stage B heart failure demonstrating the presence of a reduced LVEF.

Anthracycline–Mediated Cardiac Dysfunction

Although a comprehensive discussion of all cancer therapeutics associated with CTRCD is beyond the scope of this review, we will focus on two of the most commonly encountered and historically important agents: anthracyclines and trastuzumab. CTRCD secondary to anthracyclines has long been attributed to the production of reactive oxygen species (ROS). However, in the past decade, considerable evidence supports the role of the enzyme topoisomerase 2. There are two topoisomerase 2 isoenzymes in mammalian species: Top2α and Top2β. It has been demonstrated that the antitumoral effect of doxorubicin is mediated by the formation of a ternary complex consisting of Top2α, doxorubicin, and DNA. Top2α is expressed only in cells with a high mitotic rate, such as neoplastic cells, which explains the high efficacy of anthracyclines. In contrast, Top2β is expressed in normal tissue, including cardiac cells. The role of Top2β in anthracycline cardiotoxicity was demonstrated in a Top2β knockout animal. Formation of the ternary complexes leads to DNA fragmentation. The resultant overproduction of ROS and defective mitochondrial biogenesis ultimately leads to apoptosis of myocardial cells. The incidence of heart failure, which is the major complication of anthracycline-mediated cardiotoxicity, fluctuates between 2.2% and 5.1% depending on the series. The curves of cardiotoxicity with doxorubicin showed an incidence of heart failure that was appreciably low until the cumulative dose reaches 450 mg/m ² . This finding promoted the common belief that CTRCD was unlikely with doxorubicin doses lower than 450 mg/m ² . Nevertheless, there was evidence of a rate of 26% of mild left ventricular (LV) dysfunction at 6 months (EF <50% by cardiac magnetic resonance imaging [CMRI]) in patients who were treated with doses previously thought to be benign (50–375 mg/m ² ).

The pathophysiology of CTRCD secondary to anthracyclines involves early and cumulative dose-dependent myocyte damage, which is mediated largely by cellular apoptosis. Overall, anthracycline cardiomyopathy, which includes doxorubicin, epirubicin, and idarubicin, has been linked to a poor prognosis, with 2-year mortality rates up to 60%. These agents are now considered to have increased potential for long-term cardiac dysfunction and increased morbidity and mortality and, as a result, warrant a higher level of long-term scrutiny. ^,

Trastuzumab–Associated Cardiac Dysfunction

In contrast to anthracyclines, a number of agents, such as trastuzumab, do not directly cause myocyte apoptosis at the time of administration in a cumulative dose-dependent fashion. The typical anthracycline-induced cell damage seen in cardiac biopsies is not seen in patients treated with these agents. In many instances, these agents have been continued for decades without the progressive cardiac dysfunction that would be expected with anthracyclines. Functional recovery of myocardial function is frequently seen after their interruption. Nevertheless, recent data recognize a cohort of patients that would have higher risk of trastuzumab-related CTRCD (older adult patients, patients with more than two traditional cardiovascular risk factors, patients with borderline baseline LVEF and combination chemotherapy and/or radiotherapy).

The amplification of the HER2/neu (ErbB2) gene represents an essential process in this subgroup of breast cancer and is associated with a more malignant behavior and prognosis. Trastuzumab (Herceptin) is a humanized monoclonal antibody that targets the HER2 protein acting as an inhibitor of the tyrosine kinase receptor encoded by the ErbB2 gene. The development of this monoclonal antibody, approved in 1998, was one of the most significant breakthroughs in the history of translational research. Multiple large-scale studies have proven that trastuzumab significantly reduces the risks of recurrence and early death in patients with HER2 -positive breast cancers. An incidence of heart failure has been reported in up to 12% of treated patients.

Combined Chemotherapy

The addition of trastuzumab to anthracyclines therapy increases the toxicity risk. Slamon and colleagues compared three chemotherapy protocols in patients with metastatic HER2 -positive breast cancer, reporting a rate of 27% of LVD in the group of combined trastuzumab–anthracycline compared with 13% in the trastuzumab paclitaxel protocol and 8% in the trastuzumab-free group. The incidence of severe cardiac dysfunction with New York Heart Association class III or IV was the highest at 16%, among the patients who received trastuzumab and anthracycline, compared with 3% in patients who received anthracyclines without trastuzumab and 2% among those who received trastuzumab and paclitaxel. Animal studies done with a model of cardiac stress mediated by anthracyclines and hemodynamic overload showed that ErbB2 knockout mice were significantly more susceptible to cardiac toxicity and heart failure. These findings support the crucial role of the ErbB2 gene in the activation of cardioprotective pathways to permit myocyte survival during acute stress signaling activation. A reduction in these cardioprotective pathways after trastuzumab treatment probably facilitates myocyte loss after exposure to anthracyclines. This premise is consistent with clinical findings evidencing increased cardiotoxicity after exposure to trastuzumab in patients with underlying myocardial disease in whom the cardiac stress signals are presumably already activated. In the American Society of Clinical Oncology Clinical Practice Guideline, patients treated even with low-dose anthracycline (<250 mg/m ² , epirubicin <600 mg/m ² ) followed by trastuzumab are considered at increased risk of developing cardiac dysfunction, and routine surveillance with echocardiography as the modality of choice can be considered even in asymptomatic patients.