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Role of biomarkers in monitoring antiblastic cardiotoxicity

Novo, Giuseppina; Cadeddu, Christian; Sucato, Vincenzo; Pagliaro, Pasquale; Romano, Silvio; Tocchetti, Carlo G.; Zito, Concetta; Longobardo, Luca; Nodari, Savina; Penco, Maria

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Journal of Cardiovascular Medicine: May 2016 - Volume 17 - Issue - p e27-e34
doi: 10.2459/JCM.0000000000000379
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Abstract

Introduction

Anticancer drug-induced cardiotoxicity (CTX) is a major health problem that is growing because of the wider use of antineoplastic therapies within the last few decades.

CTX includes a broad spectrum of cardiac effects, such as arrhythmias, thromboembolism, and cardiomyopathy. Its true incidence is unclear; however, some researchers have reported it to be as high as 50–65% of survivors.1,2

Many drugs may cause an impairment of heart function; in particular, anthracyclines are potent antitumour agents that are used in a large spectrum of malignancies. Other cytotoxic drugs that determine CTX include 5-fluorouracil, capecitabine, mitoxantrone, cisplatin, taxoids paclitaxel, and docetaxel. Newer biological drugs that can induce CTX are the monoclonal anti-ErbB2 antibody trastuzumab and tyrosine-kinase inhibitors (TKI).3–7

Anticancer drug-induced CTX are traditionally distinguished as ‘acute CTX’, in which damage can develop at any time from the initiation of antineoplastic treatments up to 2 weeks after termination of treatment, and ‘chronic CTX’, which can be categorized into two types based on the timing of the onset of clinical symptoms: early chronic, within 1 year from the termination of chemotherapy, and late chronic CTX, after 1 year.

The most common form of antineoplastic drug-induced CTX is left ventricular (LV) dysfunction, which may be subclinical (or asymptomatic), but can also lead to severe heart failure.8–14 Based on its severity and reversibility, two classes of anticancer drug-induced CTX have been proposed: type 1 CTX, consisting of a microstructural lesion of cardiomyocytes, can result in cell death by necrosis or apoptosis and is mostly considered irreversible and classically attributed to anthracyclines15; type 2 CTX relates to cardiac dysfunction without significant microstructural lesions16–19 and can be resolved after completion of therapy or sometimes during its continuation, and it is attributed to biological drugs that are designed to target-specific proteins that regulate cancer cell proliferation. This CTX occurs because the same target proteins are expressed in the cardiovascular system and are necessary for the maintenance of cardiovascular homeostasis.

Nevertheless, these two forms of toxicity may overlap; for example, trastuzumab, an anti-ErbB2 antibody, can result in irreversible myocardial injury in patients who were previously treated with anthracycline (ANT).20

The primary objective for cardiologists and oncologists is the early identification of patients at risk of CTX to personalize cancer therapy and arrange preventive interventions. Thus, there is growing interest on the most recent diagnostic tools, which are noninvasive and suitable for the early identification of patients at risk of CTX. The 2011 document by the Translational Research Committee of the heart failure Association of ESC emphasizes the urgent need to identify and validate reliable biomarkers for the prediction and recognition of CTX from chemotherapeutic agents.21

Currently, the most studied biomarkers for the early detection of myocardial damage induced by chemotherapy are cardiac troponins (cTns) and natriuretic peptides.

Cardiotoxicity induced by anticancer therapies

Knowledge of the biochemical bases of CTX by anticancer drugs is essential to identify the biochemical markers of its presence and intensity. Thus, we will provide information toward the cardiotoxic mechanisms of each class of drugs, referring to more specific manuscripts for a detailed argumentation.

Anthracyclines, type 1 chemotherapeutic agents, are widely used in breast cancer, as well as in haematological cancers22; their CTX, in particular LV dysfunction and heart failure, has historically been the most important and extensively studied.15

In the past few years, the overproduction of reactive oxygen species (ROS), which are free radicals derived from oxygen inside the cardiomyocyte, particularly in mitochondria,23 represents the prevailing hypothesis of anthracycline-induced CTX. In addition, the ANT forms a complex with ferric iron (ANT-Fe3+), originating from the free radical ANT-Fe2+,24 which is capable of reducing molecular oxygen and generating the superoxide radical O2. High levels of ROS overwhelm cellular antioxidant defence systems, deregulating the cell signalling pathways and inducing damage at the ultrastructural level: loss of myofibrils, dilation of the sarcoplasmic reticulum, and vacuolization of the cytoplasm.25 In particular, ROS can lead to lipid peroxidation, resulting in damage to the membrane and DNA, and can trigger apoptotic pathways of cell death.26

More recently, the main pathogenic mechanism of ANT-induced CTX was attributed to inhibition of the nuclear topoisomerase (Top)IIβ. In humans, there are two types of Top II enzymes: TopIIα and TopIIβ. Top IIα is expressed in proliferating cells, is necessary to unwind DNA strands during DNA replication and transcription27 and is a target of the ANT anticancer effect. TopIIβ is expressed in resting cells, such as cardiomyocytes; its inhibition by ANT causes DNA double-strand breaks and transcriptomic changes, which are responsible for defective mitochondrial biogenesis and the formation of ROS.28 It follows cell dysfunction and death.

A recent meta-analysis showed that 6% of patients treated with anthracyclines experience clinically overt CTX, whereas 18% of patients develop subclinical CTX,29 which indicates that they have a five-fold increased risk of heart failure.30 Myocardial damage from anthracyclines appears to be dose-dependent, and the risk and severity of post-toxic cardiomyopathy proportionally increases with the cumulative dose.31

Taxanes are a chemotherapeutic class that causes interference with the formation of microtubules that are necessary for cellular division. This drug may cause conduction diseases, such as bradycardia, which is usually asymptomatic and does not require intervention.32,33

Trastuzumab is a monoclonal antibody targeting ErbB2 (overexpressed in 25–30% of breast cancers), whose CTX ranges from asymptomatic left ventricular ejection fraction (LVEF) decline to congestive heart failure. The anti-ErbB2-induced CTX is attributed to the blockade of cardiac action of neuregulin-1, which stimulates pathways of stress protection. Consequently, trastuzumab can make the myocardium more vulnerable to all types of harmful stimuli. Trastuzumab-related CTX is usually considered to be transient and reversible. However, ErbB2 inhibition may trigger irreversible cardiac damage in patients with preexisting cardiovascular risk factors or diseases, including systemic hypertension, obesity, advanced age, or LV dysfunction. Once blocked, the repair mechanisms related to ErbB2 blockade involve oxidative damage induced by anthracyclines proceeds without control.34–36 Consistently with these findings the combination of trastuzumab with anthracyclines elicits a greater CTX. Other anti-ErbB2 agents that are currently in use are the monoclonal antibody pertuzumab and the TKI lapatinib, which appear to produce less CTX compared with trastuzumab.

Antiangiogenic drugs, which inhibit vascular endothelial growth factor (VEGF) signalling, interfere with the integrity of coronary and systemic circulation, as well as cancer vascularization.37–40 VEGF blockade may result in hypertension, thromboembolism, LV dysfunction, and heart failure. The antibody bevacizumab, which is currently approved for the treatment of advanced carcinoma of the lung, breast, and colon-rectum, only interferes with VEGF binding to the VEGF receptor (VEGFR).41,42 The TKIs, sunitinib and sorafenib, may induce cardiovascular toxicity by inhibiting the VEGFR and other on-target and off-target kinases that are involved in the maintenance of the cardiovascular balance. Sunitinib has been shown to be more cardiotoxic, eliciting LV dysfunction in up to 28% of patients.43–46

Hypertension is one of the most common side-effects of VEGF signalling pathway inhibitors. Its incidence ranges from 19 to 47% and appears to have a key role in the pathogenesis of subsequent LV dysfunction.47 Mechanisms of hypertension include a decrease in NO signalling, increase in endothelin-1 production, and capillary rarefaction in the endothelium, which may worsen ventricular-arterial coupling.48

Cardiac troponin

cTn, a complex of three units (Tn I, T, and c), is involved in the contraction of the myocardium, and units I and T (cTnI, cTnT) are sensitive and specific biomarkers of myocardial damage.49 cTns are potentially the best characterized biomarkers for the evaluation of chemotherapy-induced CTX. Currently, most of the available scientific data on CTX involve treatment with anthracyclines, with uncertain applicability to a broader range of anticancer drugs.

In 2004, the Food and Drug Administration stated that cTnI and cTnT are specific and reliable biomarkers of CTX and are suitable for the recognition and quantification of myocardial injury.50,51 Among the troponins, cTnI proved to have better predictive value than cTnT, with a greater sensitivity in detecting minimal anthracycline-induced cardiac lesions.52 The cTns have been incorporated in the National Cancer Institute classification of CTX during cancer therapy, and their role has become particularly important, with evidence that their elevation may precede the perceptible changes observed in myocardial function.

It has been shown that the increase in cTn allows discrimination between patients with a low risk of developing chemotherapy-induced CTX and those at high risk, which required more rigorous cardiac monitoring.53 In children treated with high doses of doxorubicin for acute lymphoblastic leukaemia, cTnT increased in approximately 30% of cases, and the amount of such an elevation was predictive of a variety of cardiac abnormalities, as detected by echocardiography during follow-up.54,55 cTnI has been proposed as a valuable tool to monitor chemotherapy-related CTX. A persistent release of cTnI was associated with a probability of up to 85% of major cardiac events within the first year of follow-up.56,57 Serial troponin measurements in patients with haematologic malignancies treated with anthracyclines showed a significantly greater reduction of LVEF in individuals with elevated enzyme levels during follow-up compared with patients without cTnI elevation.58

Cyclophosphamide is an anticancer agent that is commonly used for the treatment of neoplastic and autoimmune diseases.32 Coadministration of cyclophosphamide and anthracycline causes an earlier cTn peak compared with anthracyclines alone, without altering the absolute peak of the enzyme, or the outcome.33

Patients with a late increase in cTnI showed a greater reduction in LVEF. Serial measurements of cTn showed a peak of the substance 3 weeks after the administration of chemotherapy, foreshadowing the degree and severity of future LV dysfunction.26 In contrast, in the absence of a cTn increase, a low probability of myocardial insufficiency in the follow-up was apparent.

However, most studies investigated the ability of cTn elevation to identify individuals who would develop a LVEF reduction during follow-up and enrolled patients treated with high-dose anthracyclines. Conversely, in patients treated with low doses of anthracyclines, cTn proved to not be effective in detecting early or minimal heart damage, with occasional increases that were not statistically related to the amount of myocardial impairment.59–61

Increasing evidence confirms the important role of cTn in anticipating the occurrence of a clinically significant LV dysfunction in patients treated with the most recent anticancer therapies.62,63 Importantly, trastuzumab-induced CTX occurs more frequently in patients with low LVEF or cTnI elevation at baseline or during treatment with trastuzumab in metastatic disease. Patients previously treated with other drugs, such as taxanes and anthracyclines, are more vulnerable to trastuzumab-related CTX. Elevated cTnI is an important indicator of a higher incidence of cardiac events and a lower likelihood of recovery in these conditions.64

The role of cTnI and cTnT has been evaluated in patients with metastatic solid tumours treated with TKI, demonstrating an increase in TnI values in 11–12% of patients.65,66

The enzyme could be measured on each cycle and 1 month after the end of treatment: the increase in cTn at the end of chemotherapy is a rare event, but is indicative of a high risk of heart failure or LV dysfunction.57

The advantages of cTn as a biomarker includes ease of use, wide availability, low cost compared with imaging, and extensive use of troponin in other pathological conditions.67 Nevertheless, there are some uncertainties that still remain unresolved, including the optimal timing of assessing, frequency of cTn evaluations, optimal cut-off point for positivity with the highest level of specificity, and comparison of different assays of troponin.

In conclusion, despite the evidence of that cTn has the ability to identify anthracycline-induced cardiac damage and patients at risk of LV dysfunction or heart failure,68,57 many experts believe that its practical use has yet to be definitively proven, and serial cTn measurements are not recommended by recent european society of medical oncology guidelines for the early detection of CTX in clinical practice.69

The use of ultrasensitive cTnI could overcome some of these issues, increasing the accuracy of the test. It has been shown that among patients with breast cancer undergoing anthracycline or trastuzumab regimens, an elevation of the ultrasensitive cTnI along with a decrease in global longitudinal strain (GLS) of at least 19% demonstrated an increased specificity to detect CTX (of 93%) and a increased negative predictive valued (of 91%).26 Based on these recent data, the european association of cardiovascular strain expert consensus document proposed an integrated approach for early CTX detection: a cTn measurement at baseline and every 3 weeks during trastuzumab therapy together with echocardiography, comprehensive of GLS, at baseline and every 3 months.70 However, further studies are required to strengthen the validity of this approach.

Natriuretic peptides

Natriuretic peptides are hormones that are released from the atrial and ventricular myocardium in response to an increase in wall stress. Brain natriuretic peptides (BNP) and its N-terminal fragment (NT-proBNP) are mainly released from ventricular cardiomyocytes and are involved in many physiological functions, including vasodilation, natriuresis, kaliuresis, and inhibition of the renin–angiotensin–aldosterone system and sympathetic tone. NT-proBNP is used in the diagnosis and prognostic stratification of patients with heart failure.71,72

In recent years, the use of BNP as a screening test for asymptomatic LV dysfunction was found to be useful and reliable in several studies73,74; however, the applicability of BNP and NT-proBNP as early biomarkers for chemotherapy-induced CTX was interpreted with mixed results.

BNP levels were increased during chemotherapy treatment and correlated with the E/A ratio. BNP levels were indicative of CTX diastolic dysfunction.75 Another study showed that at low doses of epirubicin, as an adjuvant chemotherapy for breast cancer, the increase in plasma BNP was significantly correlated with a decrease in LVEF.76

More recent studies observed that plasma levels of NT-proBNP persistently increased during chemotherapy and are associated with the development of cardiac dysfunction.77,78 The finding that anomalies of the BNP are predictive of LV impairment, generally only if sustained over time, can be particularly useful in patients in whom it is difficult to obtain samples to measure cTn in the first hours or days after the initiation of therapy (e.g. outpatients).

In some studies, BNP anomalies were observed in the absence of changes in cTn,61,79,80 which suggested that in patients receiving chemotherapy at low or medium doses and with a predictable reduced myocardial suffering, BNP monitoring could be more useful than cTn.

The levels of NT-proBNP may increase when patients are treated with cyclophosphamide prior to stem cell transplantation for non-Hodgkin lymphoma and multiple myeloma; most likely, this drug can cause temporary cardiac stunning.34–35

The above outlined positive evidence, the limited number of patients studied, the different cut-offs used in the studies and the difficulty of defining BNP high values because they vary in different age groups limit the usefulness of this biomarker in clinical practice.

Oxidative stress and inflammatory parameters

Measurements of cTnI and BNP demonstrated a predictive capacity to mark the CTX in case of high, cumulative anthracycline doses, whereas they are not as valuable for the detection of cardiac abnormalities in early stages or for revealing CTX induced by nonclassical therapeutic agents.

CRP is a nonspecific marker of inflammation that is widely used for the prediction of cardiac risk. It produces very mixed results in anticancer drug-related CTX. A study evaluating women treated with adjuvant trastuzumab showed a correlation between the levels of hs-CRP and the development of subsequent cardiac damage.81

The observation that high sensitivity C-reactive protein levels correlate with LV dysfunction in survivors of childhood cancer who were not exposed to cardiotoxic therapy suggests that they may not be a marker of pharmacological effects but rather the expression of inflammation and tumour burden.82

Other circulating biomarkers tested thus far include cytokine and parameters of oxidative stress. Their elevation in the presence of anticancer therapy meets the dominant pathophysiological hypothesis, specifically represented by the anthracycline-induced CTX of cardiac damage caused by oxidative stress via the generation of ROS. The importance of ROS production as early predictors of chemotherapy-related CTX has been clarified in a recent murine model in which measurements of the temporal evolution of selected biochemical markers after treatment with doxorubicin were made. The most important finding was that an oxidative imbalance preceded the alterations of myofibrillar and mitochondrial bioenergetics.83

Moreover, the role of proinflammatory cytokines in the pathophysiology of dilated cardiomyopathy was also assumed.84 Consistently with these findings, a direct relationship between cytokine levels and functional impairment, in accordance with the heart failure New York Heart Association stages, was observed. Increased circulating levels of interleukin 6 (IL-6) and its soluble receptor (sIL-6R), as well as TNFα and its receptor (TNFα R1), were found to be correlated with cardiomyocyte apoptosis in the failing human heart.85 Furthermore, inflammatory cytokines exert a negative inotropic effect and are involved in the genesis of human-dilated cardiomyopathy.

Consistently with these findings, a significant increase in IL-6, IL-6R, and ROS was observed together with a decrease in the enzymatic antioxidant potential (glutathione peroxidase, GPx), which was associated with an early reduction of longitudinal systolic function, observed using tissue Doppler imaging after the administration of 200 mg/m2 of epirubicin in patients with breast cancer.86 The role of inflammatory markers in the early detection of epirubicin-induced cardiac damage was confirmed in these studies by an inverse significant correlation between the deterioration of systolic parameters and increase in IL-6 and ROS.

The usefulness of CTX monitoring using markers of inflammation and oxidative stress was demonstrated in a cardioprotective setting, which used an ATII receptor blocker during epirubicin treatment: the reduction of IL-6 and ROS occurred in correlation with an improvement in the parameters of myocardial function.87,88

Emerging biomarkers of chemotherapy-induced cardiotoxicity

Other potential CTX markers under investigation in oncology are high sensitivity C-reactive protein, heart-type fatty acid-binding protein (H-FABP), glycogen phosphorylase BB (GPBB), and circulating microRNAs.

H-FABP and GPBB are new potential markers in the diagnosis and risk stratification of acute coronary syndromes. H-FABP is a cytosolic protein involved in the oxidation of fatty acids, which is sufficiently specific for cardiac muscle. The plasma levels of H-FABP increase rapidly (2–3 h) above the reference limit after ischaemic myocardial damage and return to normal values within 18–30 h. GPBB is an enzyme that is responsible for glycogenolysis. During ischaemia, GPBB is released into the blood within 2–4 h after myocardial injury and returns to normal levels within 24–36 h.89–91

In a study of patients with non-Hodgkin lymphoma treated with the cyclophosphamide, hydroxydaunomycin, vincristine, Prednisolone protocol (doxorubicin cumulative dose of 300 mg/m2), H-FABP was elevated in patients with LVEF less than 50%, acting as a reliable early predictor of CTX. A GPBB elevation was reported in patients with acute leukaemia treated with the anthracyclines and cyclophosphamide protocol (anthracyclines and cyclophosphamide) before an increase in cTn, suggesting that this is a promising enzyme and that it is of higher quality in the detection of cardiac damage.92,93 However, symptoms, functional cardiac abnormalities and clinical outcomes in the short term and long term after chemotherapy were not evaluated in this study. To confirm the usefulness of GPBB as a CTX biomarker, large prospective multicentre studies are required.94

Chemotherapy-induced CTX is primarily nonischaemic, and thus, the release kinetics of these biomarkers in this setting is still under investigation.

mRNAs are small noncoding RNA molecules involved in the regulation of gene expression. Among the mRNAs, there are those that regulate the response to oxidative stress and cell damage.

After the administration of doxorubicin, microRNA146a (miR-146a) is upregulated in rats. This finding suggests a mechanism by which doxorubicin induces CTX, with increased levels of miR-146A that may provoke a downregulation of ErbB4 and ultimately induce apoptosis of cells. Although studies have examined the role of miR-146a in different forms of human cardiomyopathy, the clinical data available in the chemotherapy-induced CTX setting remain insufficient.95–97

Conclusion

A number of chemotherapeutic agents can cause damage to the cardiovascular system. There is a legitimate confidence that the use of markers may help to identify patients at high risk of CTX before clinical events will be determined.

The dosage of cTn is a sensitive tool to detect chemotherapy-induced CTX in patients in whom myocardial injury has reached a considerable degree of cell suffering. Consistently with these findings, the data published to date propose an integrated approach to anticipate the recognition of CTX, which covers echocardiography with strain imaging analysis combined with the measurement of cTnI levels. Only the future availability of significant prospective data will allow the adoption of this methodology and its extension to a wider range of patients.98

Recent studies have demonstrated the potential usefulness of natriuretic peptides, which clinical application requires, however, stronger evidence of its diagnostic and prognostic capabilities; moreover, a wider standardization is needed.

We await, with confidence, the scientific validation of novel CTX biomarkers, such as H-FABP, GPBB, and mRNAs.

Prevention of CTX or the earliest potential detection of a myocardial insult must meet the priorities of antiblastic therapy. This is ensured by the effective collaboration between the cardiologist and oncologist, maintaining the centrality of the patient and his right to personalized medication management. In summary, the maximum potential protection against unwanted cardiovascular side-effects should not compromise the chance of survival and recovery of the most threatening disease (Tables 1 and 2).

Table 1
Table 1:
Main studies evaluating the usefulness of TnI measurement in the detection of cardiotoxicity
Table 2
Table 2:
Oxidative stress, inflammatory and emerging biomarkers to evaluate cardiotoxicity

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Keywords:

antineoplastic; antiblastic; anticancer drugs; biomarkers; brain natriuretic peptide; cardiac toxicity; troponin

© 2016 Italian Federation of Cardiology. All rights reserved.