How Target Therapy can Induce Cardiotoxicity: The Onco-Cardiologist Point of View

Joana Espiga de Macedo

Consultant of Medical Oncologist, Department of Medical Oncology, Centro Hospitalar de Entre, Douro e Vouga, PortugalPortugal

DOI: https://doi.org/10.17140/csmmoj-3-119 · Published 2017-06-21 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2017 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Introduction

known to all of us for a long time. How do they act specifically? What are their cardiotoxic ef-

fects at a short and long time period? How can they be monitored? How can they be prevented

Cardiotoxicity can be defined as all damage caused directly or indirectly to the cardiomyocyte.

This is a broad term which affects the cardiovascular system in many ways. The classical

definition refers a reduction in left ventricular ejection fraction and the development of heart

failure.1 However, they can be divided in ten categories: myocardial dysfunction, heart failure,

coronary artery disease, arrhythmias, arterial hypertension, thromboembolic disease, periph-

eral vascular disease, stroke, pulmonary hypertension and pericardial complications (Figure 1).

Figure 1. Cardiovascular Effects of Target Therapies.

First of all, when a patient presents himself with a certain lifestyle risk factors (smok-

cular disease such as heart failure or myocardial infarct. Or he might even, have already have

As mentioned above, the three most important cardio-

toxicities are myocardial dysfunction, heart failure and coronary

artery disease. The mechanisms of action of these target thera-

pies and how they act and their statistical incidence can be anal-

ysed in Tables 1 and 2. However, as already mentioned, in Table

3, we can evaluate the population baseline cardiovascular risk

factors, which may be increased by specific target therapies as

will be explained further on.

Table 2. Coronary Artery Disease.

Therapies Possible mechanisms

Fluoropyrimidines (5-FU, capecitabine)

Platinum salts

VEGF inhibitors

Radiotherapy

Table 3. Factors Associated with Risk of Cardiotoxicity Following Therapeutics with Anti-HER2 and VEGF Inhibitors.

Anti-HER2 compounds

Antibodies • Previous or concomitant anthracycline treatment (short time - Trastuzumab between anthracycline and anti-HER2 treatment) - Pertuzumab • Age (>65 years) - T-DM1 • High BMI > kg/mg

Tyrosine Kinase inhibitors • Arterial hypertension - Lapatinib • Previous radiation therapy

VEGF inhibitors

Antibodies • Pre-existing HF, significant CAD or left side VHD (e.g. mitral - Bevacizumab regurgitation), chronic ischaemic cardiomyopathy - Ramucirumab • Previous anthracycline

Tyrosine Kinase inhibitors • Arterial hypertension - Sunitinib • Pre-existing cardic disease - Pazopanib - Axitinib - Neratinib - Afatinib - Sorafenib - Dasatinib

Human Epidermal Receptor 2 (Her2)

Human epidermal receptor 2 (HER2), is a member of the ErbB

protein family, with an extracellular domain and an intracel-

lular domain. It is overexpressed for example, in patients with

breast cancer. It is an extremely important control centre of un-

regulated cell growth and proliferation. Blocking this protein

by target therapies, leads to inhibitionor downregulation of the

Table 1. Heart Failure and Myocardial Dysfunction.

Agent Incidence (%) Agent Incidence (%)

Doxorubicin 2-48 Pertuzumab <1.5

Epirubicin 1-3.3 Lapatinib <1

Lipsomal A 2 Sunitinib 2.7-19

Cyclophosphamide 7-28 Sorafenib 4-8

Ifosfamide 17 Pazopanib 7-11

Docetaxel 2-13 Imatinib <3

Paclitaxel <1 Everolimus <1

Bevacizumab 1.6-4 Temsirolimus <1

Trastuzumab 1.7-20

Incidence

Myocardial ischemia: 18% Endothelial injury and vasospasm Silent myocardial ischemia: 50%

Procoagulant status; arterial Thrombosis: 2% thrombosis In long-term survivors (8% 20 y testicular cancer)

Procoagulant status; arterial AT with bevacizumab 3.8% thrombosis; endothelial injury

Thrombosis; endothelial injury, plaque rupture In long-term survivors 30 y (13% 30 y Hodgkin lymphoma)

Agent Risk factors

• Previous LV dysfunction

phosphoinositide 3-kinase (P13-Kinase/AKT) and the mitogen-

activated protein kinase (MAPK/ERK1/2) pathways (Figure 2).2

This protein can be inhibited in two places: in the ex-

tracellular domain by trastuzumab, a monoclonal antibody, or in

the intracellular domain by lapatinib, an inhibitor of the recep-

tor of the tyrosine kinase domain. This leads to downregulation

of this pathway. Consequently, leading to impaired myocardial

response to stress, leading to hypertension.

By blocking the extracellular domain this inhibitor

starts competing with neuregulin-1 (NRG-1) which is released

by the endothelial cells. It has an autocrine function, stimulat-

ing angiogenesis and vascular homeostasis, and also a paracrine

effect, acting on the myocyte leading to growth, survival and

maintenance of the sarcomere organisation by stimulating the

erbB2 pathway. Together these effects protect the cardiac struc-

ture and function under normal conditions. It has a cardio-pro-

tective effect. However if this pathway is blocked, it induces

apoptosis leading to heart failure. On the other hand, if tyrosine

Figure 2. HER2/ERBB2 – Target Therapies.

signalling is maintained, with constant stimulation by neuregu- 2 2 lin-1, preservation of the myocyte haemostasis is achieved.2

Platelet Derived Growth Factor (Pdgf)

Inhibition of the VEGF may occur in different places along

the signalling pathway. Directly, on the ligand for example as

dose bevacizumaba monoclonal antibody. It blocks its connec-

tion to the VEGF receptor (VEGFR). Secondly, by blocking the

receptor directly as does Sunitinib. It doesn’t allow an adapta-

tive modulation of vascular structure and function, leading to

hypertension and left ventricle disfunction. Sunitinib blocks the

AMP-activated protein kinase (AMPK) pathway disrupting the

regulation of the endothelial metabolism (Figure 3).

PDGF can also be blocked in the intracellular domain

of the PDGF receptor (PDGFR) by Sorafenib, a tyrosine kinase

inhibitor, which causes disruption of the cardiomyocyte haemo-

stasis leading to hypertension.

Monitored, Prevented And Treated?

First of all, a rigorous screening can be done to exclude patients

at unacceptable high cardiovascular risk. This is achieved with a

complete patient’s history, physical examination, alerted to signs

and symptoms of heart failure. Evaluate cardiac co-morbidities

and if it was well medicated and controlled. Also patients should

be questioned regarding previous cancer history and therapies

performed, if any.

Secondly, it is necessary to adapt each treatment to the

patient we have in front, and induce less toxicity as possible in

all areas. Regular screening can be done by echocardiography

with Doppler imaging to evaluate the left ventricle ejection frac-

tion. It is still the standard of care, which best characterizes the

cardiac morphology and function, detects cardiac systolic and

diastolic dysfunction, although it’s operator dependent and time

consuming. On the other hand it doesn’t expose the patient to

radiation as multi-gated acquisition (MUGA). Cardiac magnetic

resonance imaging (MRI) it’s not widely available, causes claus-

trophobia and is expensive comparing theechocardiography with

Doppler imaging.3

Cardiac biomarkers, such as brain natriuretic peptide

(BNP) and troponin I (TNT) have been wildly used in many tri-

als, but have never been validated as true biomarkers.3 However,

it has been demonstrated that TNT early increase and detection,

is predictive of early cardiac dysfunction in oncological patients.

Consequently, early treatment with inhibition of the angiotensin

converting enzyme, may avoid late dysfunction of the left ven-

tricle. When early cardiomyopathy cell death is detected both 4,5 present elevated parameters.4,5

Treatment has long been more beneficial and effective,

when it is started as early as possible with cardioprotective drugs.

The most common used are β-blockers and inhibition of the an-

giotensin converting enzyme pathway (ACE). Also correction

and control of other co-morbidities are also extremely important

to prevent further damage to the cardiomyocyte. Adopt healthy

lifestyle is essential in all medical areas, such as: a healthy diet,

not smoking controlling body weight and above all regular aero-

bic exercise.

Future Orientations

Clinicians have to be more aware of heart disease in oncological

patients and survivors. The aim of this paper was to widen the

view of how these new targeting molecules may act on the car-

diovascular system, what’s the best way to diagnose and prevent and also how to treat. More than ever, efforts between cardiolo-

gists who best know how to deal with cardiovascular disease,

in its differentclinical ways, the oncologist who best deals with

the targeting therapies and its consequences and also, the family

physician who has the best knowledge of the patient’s clinical

history and co-morbidities. It depends on the fusion of these es-

sential practitioners that they can best treat the patient as whole,

with the best quality of life (QoL). Nevertheless, larger prospective studies are needed to validate appropriate methods of mon-

etarization, prevention and treatment of cardiovascular effects of

cancer target therapies.

References

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