Cardiovascular side effects of small molecule therapies for cancer: Table 1

Targeted therapies such as monoclonal antibodies and small molecule inhibitors of protein kinases, have improved the prognosis for patients with a wide range of cancers. Several of these classes of therapies are associated with cardiovascular and metabolic sequelae. These include heart failure or an asymptomatic decline in ejection fraction, peripheral and cardiac ischemic events, pulmonary hypertension, arrhythmias and QT-prolongation. This review will focus on the following targeted therapies: BCR-Abl tyrosine kinase inhibitors (TKI), vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors as well as mitogen activated protein kinase (MEK) inhibitors and mammalian target of rapamycin complex (mTOR) inhibitors. The HER2/ErbB2 inhibitors trastuzumab and pertuzumab are important targeted therapies used in the treatment of breast cancer that have been reviewed in detail elsewhere and will not be discussed in this review.1 Table 1 summarizes the cardiovascular side effects of small molecule therapies for cancer.2 Cardiovascular Side effects of Small Molecule Therapies for Cancer 1VSP inhibitors are all associated with arterial thrombotic events; the association with venous thrombosis is less certain. Arterial thrombotic event for VSP inhibitor agents include stroke, TIA, angina and myocardial infarction. LV dysfunction can be seen in patients treated with any of the VSP inhibitor therapies. 2Bevacizumab HF reported in trials in which it was given with anthracycline or paclitaxel in metastatic breast cancer (no longer approved for this indication). Cardiovascular Side effects of Small Molecule Therapies for Cancer 1VSP inhibitors are all associated with arterial thrombotic events; the association with venous thrombosis is less certain. Arterial thrombotic event for VSP inhibitor agents include stroke, TIA, angina and myocardial infarction. LV dysfunction can be seen in patients treated with any of the VSP inhibitor therapies. 2Bevacizumab HF reported in trials in which it was given with anthracycline or paclitaxel in metastatic breast cancer (no longer approved for this indication). BCR-Abl tyrosine kinase inhibitors are an important advance in the treatment of chronic myelogenous leukemia (CML) and the cardiovascular side effects have been extensively reviewed by Moslehi et al.3 Imatinib, a first generation TKI was followed by the second generation TKIs nilotinib, dasatinib and bosutinib and the third-generation agent ponatinib. Imatinib has a low incidence of cardiomyopathy and heart failure, with sequential imaging studies demonstrating rates of left ventricular dysfunction comparable to expected population incidence.4 The heart failure and cardiomyopathy rates for dasatinib were similar to imatinib in the landmark DASISION study, aside from frequent pleural effusions.5 However, the risk of pulmonary arterial hypertension (PAH) was substantially increased (3% on dasatinib versus 0% on imatinib), results that were confirmed in the French Pulmonary Hypertension Registry.5,6 Nilotinib demonstrated a 5-15 millisecond prolongation in corrected QT interval in a subset of patients in the ENESTnd study7,8 without evidence of increased ventricular arrhythmias or left ventricular dysfunction. Numerous studies support an increase in peripheral and cardiac ischemic events (but not venous thrombosis), including data from long-term follow-up of the ERESTnd trial.9 Given that there was also an increase in hyperglycemia, hyperlipidemia and BMI, it was hypothesized that the increase in events is mediated through accelerated atherosclerosis. Bosutinib cardiotoxicity also appears similar to imatinib on the basis of the BELA trial.10 Significant cardiovascular toxicity of ponatinib has led to a restriction of its indication to patients with T315I mutation or in whom other TKI are not indicated. Pontainib demonstrated an increased risk of cardiotoxicity including 10% cardiovascular, 7% cerebrovascular and 7% peripheral adverse events in the PACE study at 28 months follow-up; hypertension developed in 26%, a predictable side-effect given ponatinib’s VEGFR inhibition11. The majority of events were arterial (14% arterial and 3% venous) and cardiovascular risk factors predisposed patients to events. Nilotinib and dasatinib are approved for first-line treatment, while bosutinib is approved for second line treatment. All TKIs approved for CML therapy share activity for BCR-Abl, but have different potencies and activities against other kinases. VEGF signaling pathway (VSP) inhibitors target tumor angiogenesis in a variety of tumors. As a class, all VSP inhibitors are associated with a wide spectrum of cardiovascular toxicities including hypertension, arterial and venous thromboembolism, left ventricular dysfunction and cardiomyopathy. This topic has been reviewed recently by Li et al.12 Hypertension is caused by all commercially available VSPs and is the most common cardiovascular side effect. Risk factors include preexisting hypertension, age over 60 and elevated body mass index.13 Blood pressure elevation can occur as early as the first week of therapy. The mechanism is likely mediated through changes in the normal endothelial homeostasis mediated by nitrous oxide and a reduction in generation of new blood vessels. Interestingly, some studies have demonstrated an association between the development of hypertension and improved antitumor efficacy.14 Both arterial and venous thromboembolic events are increased with VSP inhibition, but data are more consistent for the risk of arterial thrombosis. In a meta-analysis of 20 RCTs, the relative risk of arterial thrombotic events (ATEs), including myocardial ischemia, was 1.44 in patients taking bevacizumab compared to controls.15 In a meta-analysis of 9,387 patients taking either sunitinib or sorafenib, the relative risk of ATEs was 3.03 compared to placebo.16 Myocardial ischemia has been consistently demonstrated with bevacizumab, sunitinib, sorafenib and regorafenib. In a meta-analysis of 7,956 patients the incidence of venous thrombotic events (VTE) was 11.9 (high-grade 6.3%) with a relative risk compared to control of 1.33.17 However, a subsequent study demonstrated no significant increase in VTE.18 Although VSP inhibitors are associated with increased thrombosis, they are also associated with increased risk of bleeding and hemorrhage. Left ventricular dysfunction and cardiomyopathy has been observed in patients receiving any of the VSP inhibitors, but the exact incidence is unknown. For example, it is speculated that as many as 20% of patients have asymptomatic left ventricular dysfunction while on sunitinib.19 In a meta-analysis of 10,647 patients receiving TKI VSP inhibitors, heart failure occurred with a relative risk of 2.69 compared to those receiving no TKI.20 Asymptomatic decline in left ventricular dysfunction occurs more commonly than symptomatic heart failure, and appears to be reversible.21 Many possible mechanisms have been proposed for the VSP inhibitor-associated heart failure including direct VEGF inhibition in the heart. The mitogen activated protein kinase (MEK) inhibitors are used to treat BRAF-mutated melanoma and advanced NSCLC. A meta-analysis of 10 phase II and III randomized control trials of trametinib, selumetinib and cobimetinib including a total of 2704 patients22 used the common terminology criteria for adverse events (CTCAE) to define clinical endpoints. Compared to controls, the grade 3-4 hypertension (including systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg among other definitions) occurred in 2-12% of patients receiving MEK inhibitors with a relative risk of 1.85 (95% CI, 1.01 to 3.40; P = 0.05). An asymptomatic decline in LVEF occurred with a relative risk of 4.92 (95% CI, 2.93 to 8.25; P .001), but the degree of LVEF decline encountered was not specified. The phosphoinositide 3-kinases (PI3Ks)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important intracellular pathway that is frequently mutated in cancers.12 In experimental models, activation of the mTOR pathway likely counteracts fibrosis and cell death and preserves cardiovascular function, providing a plausible mechanism by which mTOR inhibition could potentially cause cardiotoxicity23; however, clinical cardiac dysfunction has not yet been demonstrated. In a clinical trial of everolimus, rates of hypertriglyceridemia, hypercholesterolemia and hyperglycemia were about double that observed in the control group; similar results were seen in temsirolimus.24,25 The epidermal growth factor receptor (EGFR) inhibitors are used in the treatment of lung and gastrointestinal cancers. Overall, cardiotoxicity is very low in this class of agents and pertains mainly to Erlotinib and Osimertinib.26 Lapatinib is a used in HER2 positive breast cancer as an alternate to trastuzumab; it is unclear which agent has superior anti-cancer efficacy. Lapatinib may have lower cardiotoxicity compared to trastuzumab, but skin rash and diarrhea are more common.27 Targeted therapies are integral to modern cancer therapy. Future investigation is needed to understand the mechanism of cardiovascular complications and identify strategies to mitigate and treat cardiovascular sequelae. References are available as supplementary material at European Heart Journal online.