Cardiotoxicity of Targeted Agents in Oncology: A Medical Oncology Perspective

Without question, targeted therapies have revolutionized the treatment of cancer across histologies. Given the prevalence of breast cancer and the fact that the human epidermal growth factor receptor 2 (HER2) alteration was discovered more than 25 years ago, HER2-directed therapies are arguably the best-studied of the biologics in terms of efficacy and cardiac-specific safety. For the ~25% of breast cancers that overexpress HER2, the addition of trastuzumab to chemotherapy has been shown to substantially improve survival in both the adjuvant and metastatic settings.[1-4] More recently, lapatinib, pertuzumab, and the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) have shown substantial activity against HER2-positive breast cancer. Fortunately, these therapies have been generally safe. However, as Bhave and colleagues point out, there is a recognized risk of cardiac toxicity that must be considered carefully. While several risk factors have been linked to the development of cardiotoxicity from HER2-targeted therapies, coadministration with anthracyclines augments this risk significantly.

Bhave and colleagues[5] present a thorough review of the cardiac complications associated with HER2-targeted therapies based on data primarily from the metastatic setting. However, a discussion relating to the use of trastuzumab in the curative setting is lacking. While the risk of cardiac toxicity may be outweighed by the known benefits achieved in patients with metastatic disease, the highest level of caution should be used when treating patients in the adjuvant setting, since a rather substantial proportion of women with early-stage disease are cured by local-regional therapy alone. Distinguishing patients who are cured and do not require systemic therapy from those who have distant micrometastases is still impossible. Consequently, a large number of patients continue to receive systemic therapy, and all the associated toxicities, unnecessarily. Therefore, the choice of an adjuvant treatment regimen should be based not only on efficacy but also on a critical evaluation of the risk of long-term toxicity, including heart damage. One way to mitigate this risk in the HER2-positive setting is to choose a chemotherapy backbone that does not cause additional cardiac toxicity. A nonanthracycline regimen-docetaxel, carboplatin, trastuzumab (TCH)-was tested in the Breast Cancer International Research Group (BCIRG)-006 adjuvant study and shown to confer a 0.4% risk of heart failure.[4] In contrast, 2% of patients in the doxorubicin-cyclophosphamide→docetaxel-trastuzumab (AC-TH) arm of that study developed heart failure, and a higher proportion of patients had a sustained decrease in left ventricular ejection fraction (LVEF) at 48 months. Furthermore, among the 1,073 patients randomly assigned to the AC-TH arm, 23 patients were unable to receive trastuzumab because they developed heart failure while receiving AC, presumably due to type I cardiac toxicity from doxorubicin.[4] Given the significant improvement in progression-free survival and overall survival associated with the addition of trastuzumab to adjuvant chemotherapy, choosing a chemotherapy regimen that maximizes the chances that patients can receive the full course of trastuzumab is critical. Three other studies have evaluated TCH in over 3,400 patients as a therapeutic backbone in the curative setting, providing more support for its safety and efficacy.[6-8]

One question that has arisen is whether the various HER2-targeted agents have differing levels of cardiac toxicity. The authors report a reduced incidence of cardiac events with lapatinib compared with trastuzumab and hypothesize that this is because lapatinib protects cardiomyocytes against apoptosis via induction of AMP-activated protein kinase (AMPK) activity. While this is one possibility, it should be recognized that almost all patients enrolled in the early studies evaluating lapatinib had already been exposed to trastuzumab, an anthracycline, or both.[9-11] Furthermore, to be eligible for study entry, patients had to have normal cardiac function. Therefore, the lower incidence may, in part, be a result of selection bias. Having said that, in the MA-31 study, in which a frontline taxane-lapatinib regimen was compared to a taxane-trastuzumab regimen, up to 3% of the trastuzumab-treated patients experienced a > 20% decrease in LVEF over the course of the study, compared to 0% in the lapatinib arm.[12] Interestingly, use of dual HER2-targeted therapy with pertuzumab and trastuzumab[13] does not appear to increase the risk of cardiac events. Although Bhave and colleagues do not specifically discuss the cardiac data available for the recently approved T-DM1, data from the EMILIA study are reassuring, as there was only a 1.7% incidence of LVEF reduction in T-DM1-treated patients (vs 1.6% in the lapatinib arm) and only 1 case of grade 3 cardiomyopathy (vs none in the lapatinib arm).[14]

Data relating to the cardiac impact of antiangiogenic agents such as bevacizumab, sunitinib, and sorafenib are also reviewed. The authors point out the hypertensive effects, risks of thromboembolic disease, and incidence of congestive heart failure with these biologics. However, they did not include in their review the recent meta-analysis of the safety of bevacizumab reported by Cortes and colleagues that included 3,784 patients enrolled in phase III trials evaluating bevacizumab plus chemotherapy in metastatic breast cancer.[15] The incidence of grade 3/4 left ventricular dysfunction was over 2.2 times more common in patients receiving bevacizumab. This and other serious toxicities, coupled with the lack of demonstration of an overall survival benefit in patients with metastatic breast cancer, led to the withdrawal of FDA approval for bevacizumab in this disease setting, underscoring the need to carefully evaluate the therapeutic index of new agents. Antiangiogenic agents continue to play an important role in the treatment of other cancers; however, appropriate patient selection and clinician awareness of the potential toxicities are key to optimizing the safe use of these therapies.

Bhave and colleagues summarize well many other effective targeted cancer therapeutics currently in use. Many of these carry the risk of infusion reactions and venous thromboembolic events, but their risk of cardiotoxicity per se is less well defined. Additionally, several of the drugs reviewed were tested in patients with preexisting cardiac disease, making it more difficult to gauge the risk of heart toxicity in a low-risk patient. With so many approved biologic options, patients may receive treatment with such agents for years. Careful comparative assessment of toxicity and long-term follow-up are needed to understand the impacts of these therapies, alone or in combination with chemotherapy, on cardiac function.

What is clearly lacking is a consensus statement relating to the appropriate screening, monitoring, and management of the cardiac effects of each of these drugs specifically. That said, the European Society for Medical Oncology has published a rather thorough clinical practice guideline for the management of cardiac toxicity associated with chemotherapy, radiation, and targeted agents.[16] Although Bhave and colleagues do not specifically reference this guideline, they do mention others published by the American College of Cardiology and the American Heart Association. A thorough evaluation and summary statement of the existing guidelines would be most useful to a practicing clinician. In addition, it would be helpful to have a monitoring algorithm for patients who are being treated in the metastatic setting (in some cases for many years) with a targeted agent that is known to have cardiac toxicity. For example, how frequently and for how long should echocardiograms be performed in an asymptomatic patient?

The cardiac impact of biologic therapies is a critically important topic of discussion, not only for the practicing oncologist but also for investigators and scientists, especially as the most effective agents are moved to the adjuvant curative setting. Awareness of the potential side effects, recognition of signs and symptoms, ability to differentiate cardiac from noncardiac causes of side effects, and an understanding of how to intervene are all crucial for providing quality patient care. As the field continues to improve survival outcomes with new and exciting therapies, long-term follow-up not only to determine efficacy but also for safety is needed. Standardized guidelines to ensure consistent, quality care are imperative.

Financial Disclosure:Dr. Hurvitz receives research funding from Genentech/Roche and GlaxoSmithKline (paid to the University of California, Los Angeles), and her travel to conferences at which she was an invited speaker has been reimbursed by Genentech/Roche. Dr. Wong has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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