Precision medicine has revolutionized oncology patient care where tumor genetics have re-defined tumor classification and dictate cancer treatment algorithms. As a result, targeted oncology therapies, which specifically interfere with pathways affected by genetic mutations, have heralded a personalized approach to the clinic and have improved survivorship for many cancer types. In some cases, cancer is a chronic disease. However, both traditional and novel cancer treatments are associated with diverse cardiovascular complications with the overall improvement of the underlying cancer, making short-term and long-term cardiovascular issues relevant clinically. Whereas older therapies (such as anthracyclines) or even early targeted therapies (like trastuzumab) caused cardiomyopathy and clinical heart failure, many of the newer cancer therapies are associated with vascular and metabolic complications. The complexity of the vascular complications that are encountered in a cardio-oncology clinic is underscored by the heterogeneity of drug targets leading to very diverse (and often poorly defined) events.

In 2019, the American Heart Association released a statement highlighting this new vascular and metabolic dimensions of cardio-oncology.¹ New cancer therapies can lead to acute vascular complications such as hypertension and thrombosis, as well as more chronic sequelae such as metabolic syndrome and atherosclerosis. The latter becomes even more consequential because some novel cancer therapies are life-long treatments and allow patients to live as long as normal life expectancy. What has been problematic is that the vascular approach for patients has been less personalized and is not cancer or cancer-treatment specific.

Precision cardio-oncology is a solution to the need for patient-specific treatment in cardio-oncology. Precision cardio-oncology considers the specifics of the following three factors in the individual's cardiovascular management: the cardiovascular risk of the individual, the cancer, and the cancer treatments (Figure 1). Although it is not genome specific like cancer therapy, precision cardio-oncology provides individualized algorithms based on these three factors. Here we discuss the roles of these three factors in the management of the cardio-oncology patient.

Figure 1: The Foundation of Precision Cardio-Oncology

The first part of precision cardio-oncology is the cardiovascular risk of the patient with cancer. This includes screening and management of traditional cardiovascular risk factors including hypertension, hypercholesterolemia, diabetes mellitus, and tobacco use. Additionally, discussing family history, diet, and exercise are integral to understanding the patient's cardiovascular risk. Beyond these traditional risk factors, it is important to identify whether a person has had a known coronary artery disease or a myocardial infarction, prior transient ischemic attacks or cerebral vascular accidents, history of congestive heart failure or arrhythmias, and history of prior deep vein thrombosis or pulmonary embolism. Although cardiovascular risk prediction models (i.e., CHA₂DS₂-VASc score and ASCVD Risk Calculator) may be used in the initial evaluation of these patients, they are not specific for patients with cancer, and none have been extensively externally validated in this group. Thus, any use of these models should be done with caution due to uncertain model performance in the oncology population. Primary care physicians and cardiologists should feel comfortable and be capable of managing this portion of the precision cardio-oncology triad.

The next part of precision cardio-oncology is understanding the treatment risks from oncologic care. This is varied and ever evolving but includes hypertension, vascular disease, thrombosis, and cardiovascular disease such as arrhythmia, myocarditis, and heart failure. For instance, in the treatment of chronic myeloid leukemia, there are a number of tyrosine kinase inhibitors available for treatment that have varying side effects. Although imatinib remains relatively safe from a cardiovascular standpoint, ponatinib has a high incidence of vascular events including limb loss.² Dasatinib, another drug in this class, is associated with sometimes fatal pulmonary arterial hypertension along with pleural and pericardial effusions.³ These side effects vary from those seen in vascular endothelial growth factor signaling pathway inhibitors, which are used in the treatment of renal cell carcinoma. Vascular endothelial growth factor signaling pathway inhibitors have a number of cardiovascular side effects including hypertension, vascular disease, and cardiomyopathy.⁴ Therapies such as immune checkpoint inhibitors introduce another level of complexity with cardiovascular effects including myocarditis, pericarditis, vasculitis, and arrhythmias.⁵ Due to the varied presentation among therapies, a cardio-oncologist should have a good understanding of the therapy-specific cardiovascular risks. Additionally, there is an effort to identify genetic markers that may help predict risk of cardio-toxicity for specific therapies, although further research is needed in this field.⁶ Moreover, with the shifting of standard of treatment in cancers from single agent to combination therapy using multiple classes, a broad range of cardiovascular complications has arisen.

Although therapy-specific risks are often considered the cornerstone of cardio-oncology, the last portion of precision cardio-oncology concerns the cancer-specific risks of cardiovascular disease along with the expected survival. For instance, the venous thromboembolism risk is different depending on cancer type, with pancreatic and uterine cancer having higher rates than prostate or breast cancer.¹ By understanding the various risks of the cancer, cardio-oncologists can focus their screening and treatment. Additionally, life expectancy should factor into the care of these individuals. If the expected survival is less then 6 months, then long-term risk factor modification such as anti-hypertensive medications and statin therapy may serve less of a role in their treatment. Whereas with prostate cancer, where individuals have a long survival curve and high risk for cardiovascular disease, prevention is key to management. Thus, factoring in cancer-specific risks completes the third side of the precision cardio-oncology paradigm.

With the complexity of modern cancer therapies and the improved prolonged survival among once-deadly diseases, cardiovascular care will continue to be an important part of cancer care. By understanding the patient's risk, cardiovascular effects of the cancer treatment, and cardiovascular risk of the individual cancer, the cardio-oncologist will be prepared to manage the individual with cancer. Future steps will include providing optimal treatment protocols for hypertension, diabetes mellitus, and hyperlipidemia to ensure that the cardiovascular therapies do not interfere with the oncologic treatments with the goal of improving long-term cardiovascular outcomes.

References

1. Campia U, Moslehi JJ, Amiri-Kordestani L, et al. Cardio-Oncology: Vascular and Metabolic Perspectives: A Scientific Statement From the American Heart Association. Circulation 2019:139:e579-e602.
2. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood 2018;132:393-404.
3. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128-37.
4. Herrmann J, Yang EH, Iliescu CA, et al. Vascular Toxicities of Cancer Therapies: The Old and the New--An Evolving Avenue. Circulation 2016;133:1272-89.
5. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018;19:1579-89.
6. Serie DJ, Crook JE, Necela BM, et al. Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial. Pharmacogenet Genomics 2017;27:378-85.

Clinical Topics: Cardio-Oncology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Nonstatins, Novel Agents, Statins

Keywords: Cardio-oncology, Cardiotoxicity, Anthracyclines, Ischemic Attack, Transient, Antihypertensive Agents, Cardiovascular Diseases, Risk Factors, American Heart Association, Metabolic Syndrome, Vascular Endothelial Growth Factor A, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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