Everolimus as cancer therapy: Cardiotoxic or an unexpected antiatherogenic agent? A narrative review

Abstract

Everolimus (EVE) is now approved by many agencies for the treatment of variable neoplasms. The risk for adverse events with this agent is not adequately defined. The purpose of this review is to summarize the EVE-induced cardiotoxic effect as an antineoplastic factor on patients who received the specific drug and to evaluate any possible antiatherogenic effects due to systemic use of the drug. Articles were searched on PubMed until August 2017. Articles included an expanded-access clinical trial, as well as phase 2 or 3 clinical trials (most of them were randomized). Three experimental studies that provided evidence for the possible antiatherogenic action of EVE were also included. In addition, only studies that evaluated the systemic use of the drug were included. To be eligible for inclusion, trials should have evaluated patients with malignancy, treated by EVE, or assessed the antiatherogenic effect of the systemic use of EVE through clinical or experimental studies. Only articles written in English language were included. No direct cardiotoxic adverse effects (arrhythmia, acute coronary event, heart failure, and echocardiography pathologic findings) were reported. Patients appeared to have a risk of developing adverse events that could be associated with the risk factors of cardiovascular disease. In all clinical studies, patients suffered hyperglycemia, and in most of them, hyperlipidemia was observed. Fewer studies have reported the incidence of hypertension. Finally, there is evidence claiming that EVE has an antiatherogenic action. Three experimental studies have shown that the systemic use of EVE in mice or rabbits with atherosclerotic lesions led to the reduction in atheromatous plaque growth. However, we could not find any clinical study that showed similar results in patients with cancer. To sum up, the only reported cardiac adverse event of EVE treatment in patients with cancer is indirect. They are associated with the risk factors of cardiovascular disease (hyperglycemia, hyperlipidemia, and hypertension), which are mainly mild and easily manageable. Further research and data that support the antiatherogenic action of EVE are needed.

Oral Oncolytics and Cardiovascular Risk Management and Monitoring

“…The proposed pharmacologic mechanism and associated oral cancer therapies are reviewed below and further outlined in Table 1. [14][15][16][17][18][19][20][21][22][23][24][25]…”

“…14,31 Mechanisms contributing to bradycardia vary based on the oral oncolytic and are described in Table 1. [14][15][16][17][18][19][20][21][22][23][24][25] The primary mechanism for bradycardia with oral oncolytics is the inhibition of hyperpolarization-activated cyclic nucleotide-gated channel 4 activity. Hyperpolarizationactivated cyclic nucleotide-gated channel 4 activity plays a significant role in the sinoatrial node to set and regulate the intrinsic heart rate, specifically the lower limit of the heart rate range, and protects the stability of the sinoatrial node during autonomic nervous system activity.…”

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

“…Everolimus (RAD001) is a rapamycin analog with a similar function to rapamycin, as a protein kinase inhibitor of the mTOR serine/threonine kinase signal transduction pathway. Everolimus has been approved for the treatment of pancreatic neuroendocrine tumors (p-NETs), advanced renal cell carcinoma (RCC), subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC), and in combination with exemestane for advanced hormone-receptor (HR)-positive, HER2-negative breast cancer [31,32]. In 2019, Taylor et al discovered in a phase I/II study of everolimus and bevacizumab in advanced solid tumors (e.g., ovarian, peritoneal, and fallopian tube cancers) that this proved to be a promising combination treatment [33].…”

Prevention, Detection, and Management of Heart Failure in Patients Treated for Breast Cancer

“…Mammalian target of rapamycin (mTOR) inhibitors may be used in combination with exemestane in selected postmenopausal breast cancer patients with metastatic disease and have shown improved progression free survival compared with exemestane alone [ 26 , 27 ]. mTORs can exhibit an indirect effect on cardiovascular health by metabolic changes, i.e., glucose and lipid metabolism, but are generally well tolerated [ 28 ]. Overall, the cardiovascular tolerability of endocrine therapy is high.…”