Breast cancer represents the most common type of malignancy in women, with an annual incidence of 1.7 million cases, comprising 25% of all neoplasia and 12% of all new cancer cases.1 The combination of new techniques for the diagnosis of breast cancer and introduction of chemotherapy, radiotherapy, and surgery improved the outcome of the patients, making this disease curable and increasing life expectancy.2 Although highly efficient, chemotherapy has many side effects that alter the quality of life, increasing morbidity and mortality.3 Cardiotoxicity represents the most feared adverse reaction of chemotherapy, with a growing incidence, due to increased number of patients receiving combination of cytotoxic and biological drugs with significantly higher cumulative doses.4 Thus, up to 30% of patients receiving chemotherapy can develop a cardiac side effect during their life.5
Cardiotoxicity varies from clinical unapparent forms, such as electrocardiographic changes to cardiomyopathy with severe heart failure and even death.6 It might depend on the cumulative dose of chemotherapeutic drugs, consecutively requiring its reduction and thus favoring the decrease in their efficiency.7,8 However, there is a risk of cardiotoxicity that cannot be predicted by the total dose. Echocardiography is a wide available, noninvasive, and cost-effective method for the assessment of patients with breast cancer before, during, and after cancer therapy. Currently, the measurement of left ventricular ejection fraction (LVEF) is the standard parameter used to assess the occurrence of cardiotoxicity.9 Recent studies, including our own research,4 suggested that new eco parameters, such as tissue velocity imaging and myocardial deformation by speckle tracking echocardiography, might be more accurate for the early detection of cardiotoxicity. Among serum biomarkers, cardiac troponin I and N-terminal pro-brain natriuretic peptide, markers of myocardial injury and high-filling pressures, respectively, were suggested to be accurate tools for an early diagnosis of myocardial dysfunction after chemotherapy in breast cancer survivors.9 Early detection of cardiotoxicity might be also important to start potential preventive measures because, recently, several studies had suggested a possible cardioprotective role of beta-blockers, angiotensin receptors antagonists, or spironolactone, concomitantly administered with chemotherapy.10–12
Cardiotoxicity has multifactorial determinants, resulted from the interplay between phenotypic and genetic factors. Even if clinical and demographic factors can predispose selected patients to greater severity of cardiotoxicity, there is also an idiosyncratic nature of this reaction, leading to significant interindividual variation.13 Therefore, genetics may provide additional information, for understanding the mechanisms and identifying genetic biomarkers for the early detection of cardiotoxicity. Furthermore, identifying genetic variants associated with cardiac alteration determined by different chemotherapeutic drugs might indicate patients at the risk, who can benefit from early therapeutic measures.
This review will focus on the mechanisms of chemotherapy-induced cardiotoxicity in breast cancer patients and will discuss the role of genetic susceptibility for cardiac dysfunction.
Definition and classification
Cardiotoxicity was identified since 1960s, after treatment with anthracyclines, representing “toxicity that affects the heart.”14 In 2014, a consensus for multimodality imaging evaluation during chemotherapy defined cardiac dysfunction as a decrease in LVEF of more than 10% points to a value of <53%, evaluated at 2–3 weeks after the initiation the therapy.9 Cardiac dysfunction can be reversible (with LVEF arising back to within ±5% points of baseline), partially reversible (with LVEF improving by more than 10% but remaining more than 5% points below baseline), and irreversible (with LVEF deteriorating or improving by less than 10%).9 According to the time of onset of symptoms, cardiotoxicity can be acute, subacute, or chronic.9 Acute cardiotoxicity occurs within 2 weeks after the initiation of therapy; subacute cardiotoxicity appears 2 weeks after starting the treatment9; chronic cardiotoxicity appears in the first year (early chronic cardiotoxicity) or more than 1 year after the completion of chemotherapy (late chronic cardiotoxicity), leading to diastolic and/or systolic dysfunction, usually with irreversible heart failure or death.15
Cardiovascular side effects due to chemotherapy can be classified into direct toxic effect on the heart, associated with cardiomyopathy and cardiac dysfunction; cardiac ischemia; arrhythmias; hypertension; and effect on the coagulation system. All these effects and the relationship with the development of cardiac dysfunction or heart failure are presented in Figure 1.
Direct toxic effect on the heart
Current guidelines describe 2 types of chemotherapy-induced cardiomyopathy, based on the the mechanisms of the drug used: type I and type II.9
Type I cardiomyopathy is induced by anthracyclines (doxorubicin, epirubicin) and mitoxantrone.9 Asymptomatic cardiac dysfunction occurs in 57% of patients receiving anthracyclines, whereas heart failure occurs in 16% of patients.16 The main mechanism involved in this type of cardiotoxicity is increased oxidative stress, with high formation of reactive oxygen species (ROS), determining myocyte apoptosis through damage of proteins, lipids, and DNA.9 Other mechanisms incriminated were interaction with topoisomerase-II-β, transcriptional changes in the production of adenosine triphosphate (ATP), decreased contractility by downregulation of messenger RNA for sarcoplasmic reticulum calcium ATPase, mitochondrial DNA damage, and myofibrillar disarray by interaction with neuregulin 1β.6,9,15 Moreover, anthracycline-induced cardiotoxicity correlates with the accumulation of anthracycline alcohol metabolites (doxorubicinol, epirubicinol).17 As a general characteristic, anthracyclines may lead to irreversible cardiomyopathy that is dose dependent, with progressive myocyte loss and LVEF reduction, with progression to heart failure.9
Type II cardiomyopathy is determined by tyrosine kinase inhibitors, typically trastuzumab.9 Trastuzumab is a recombinant DNA–derived humanized monoclonal antibody that binds the extracellular domain of HER2/epidermal growth factor receptor/ErbB2, used to treat metastatic breast cancer with overexpressed HER2.18 HER2 receptor and its ligand are presented in cardiomyocytes, where they determine a protective role on cardiac function, by determining cell growth and protecting from apoptosis (through the activator protein-1 and nuclear factor kB). Inhibition of this pathway can affect mitochondrial function, causing ATP depletion and contractile dysfunction.6,15,19
Trastuzumab-induced cardiotoxicity is often reversible and not dose dependent.9 It appears in 4% of cases when the drug is used alone.18 The addition of trastuzumab to taxanes or anthracycline improves chemotherapeutic response of the cancer, but it is associated with an increased risk of cardiac dysfunction to 13% and 27%, respectively.6,20
Another class of effective chemotherapy in breast cancer is represented by taxanes (paclitaxel, docetaxel).21 Despite the clinical success, their mechanism of action remains elusive, different from type I and II cardiotoxic effects.22 Taxanes-induced cardiotoxicity can be determined not only by polymerization of tubulin, leading to dysfunctional microtubules and altered cell division,6 but also by massive histamine release, resulting in arrhythmias, conduction disturbances, or myocardial ischemia.15,23 Furthermore, taxanes can increase plasma levels of doxorubicin and the formation of doxorubicinol, a toxic metabolite, increasing the risk of cardiotoxicity.6
Chemotherapy-induced cardiotoxicity expressed by myocardial ischemia is rare. Associated with the use of taxanes, this type of cardiotoxicity appears in 5% of cases and includes angina, myocardial infarction, and heart failure.19 Myocardial ischemia was detected in 8% of cases after using antimetabolites, such as 5-fluorouracil (5-FU) and capecitabine, adjuvant cytotoxic drugs for breast cancer.24 This side effect appears due to coronary arteries endothelial dysfunction and vasospasm (Figure 1). Patients with known ischemic heart disease have a higher risk of 5-FU-induced cardiotoxicity.19
Known since 1979, proarrhythmogenic effects of anthracyclines are represented by supraventricular, junctional, and ventricular arrhythmias, often secondary to prolongation of QT interval.19,25 This effect can be explained by the interaction of anticancer drugs with HERG K channels causing rapid decrease in potassium inflow into the cell.23,26 Alkylating agents (cyclophosphamide) and antimetabolites (5-FU) can determine ecocardiographic changes, such as decrease in the amplitude of QRS complexes, ST segment and T-wave changes, tachyarrhythmia, and complete heart block.19,27 Taxanes are proarrhythmogenic drugs, with an effect directly on the Purkinje system or indirectly through histamine release.28 Also, docetaxel, 5-FU, gemcitabine, or corticosteroids can induce atrial fibrillation.15 An important role in triggering atrial fibrillation in patients with cancer might be due to chronic inflammation because 18.3% of patients with the history of cancer had this arrhythmia, associated with a high serum level of C-reactive protein, by comparison with 5.6% of those without cancer.29
Hypertension is a common side effect of chemotherapy, induced by antiangiogenic agents (sorafenib, sunitinib, and bevacizumab) used for the treatment of gastrointestinal, renal, and breast cancer, respectively.6 The mechanism of chemotherapy-induced hypertension involves the inhibition of NO-synthase activity, with a decrease in NO production, increasing vasoconstriction and peripheral vascular resistance (Figure 1).23 The use of chemotherapy exacerbates preexisting hypertension, frequently coexisting in patients with cancer, with long-term cardiac effects, such as left ventricular hypertrophy, increased arterial stiffness, and heart failure.15
Effect on the coagulation system
Cancer leads to a procoagulant state, and the risk of thrombosis is higher in metastatic forms.6 Chemotherapy favors the occurrence of thromboembolic events, through injury of the endothelial cells, by altering the function of adhesion proteins (integrins, cadherins) and activation of the coagulation cascade (Figure 1).23
Hemorrhage and arterial thromboembolism appear after the use of angiogenesis inhibitors (thalidomide and lenalidomide). Venous thromboembolism was associated with alkylating agents, tyrosine kinase inhibitors, or angiogenesis inhibitors.15 Particularly, cisplatin, an alkylating agent, favors platelets aggregation, by increasing the production of thromboxane and activating arachidonic acid pathway in these cells.30
Summarizing, the main classes of chemotherapeutic agents, their cardiac side effects, and the probable molecular mechanisms of action are presented in Table 1.
CHEMOTHERAPY AND GENETICS
Although there are several predisposing factors for cardiotoxicity, its mechanisms are incompletely understood. Recently, the implication of genetics in cardiotoxicity is studied, leading to a new concept of interdisciplinary medicine in patients with breast cancer, requiring oncologists, cardiologists, pharmacologists, and geneticists.31 This concept is based on the individual response to a specific class of drugs, determined by the interaction between environmental and genetic factors.19 Environmental risk factors are nonmodifiable (extreme ages, female sex, preexistent cardiovascular pathology, longer time since completion of therapy) and modifiable (cumulative dose of chemotherapy, modality of administration, rate of drug infusion, concomitant mediastinal irradiation).6,19,32 Genetic factors are also extremely important because there is a large variation in the severity of cardiotoxicity between individuals receiving the same drug. Current genetic technology might allow the identification of patients at the risk for cardiotoxicity before therapy, who can benefit from early protective measures. Moreover, cardioprotective effects of dexrazoxane could have a genetic determinism. Therefore, we should focus on the advances in genomics, as genetic and epigenetic acquired alterations, that could be associated with increased susceptibility for cardiotoxicity or with cardioprotective effects of specific drugs.
Genetic susceptibility for chemotherapy-induced cardiotoxicity
Cancer represents a genetic disorder19 resulting from sequential changes in DNA due to acquired genetic mutations.33 Catalogue for Somatic Mutations in Cancer, the most important source of information for genomics and cancer, describes 4800 genes and 50,000 genetic mutations in different forms of cancer.34 These mutations can be amplified by the imbalance between damage and repair of the DNA.35
Beside the implication of genetic alteration in cancer etiology and prognosis, drug response and safety have significant genetic variations among patients with breast cancer. Drug pharmacogenetics or pharmacogenomics represents the effect of patient genomic on the specific response to the drug, including cardiotoxicity.36 Genetic variations include nucleotide deletions, substitutions, insertions, or repetitions.36 Single-nucleotide polymorphisms (SNPs) are variations in the DNA sequence, occurring when a nucleotide (adenine, A, guanine, G, cytosine, C, or thymine, T) is altered, and it represent 90% of human genetic variations. These occur in 100–300 bases in the human genome, in the coding and noncoding region of the genome. To be an SNP, the gene alteration must be found in at least 1% of the population. SNPs produce a modification in a specific protein function, leading to a different response to a drug, including the susceptibility for cardiotoxicity.37 Thus, the objective of a pharmacogenomics study is to describe specific alteration, such as SNPs, that can modify protein function, with role in therapy pharmacokinetics, or pharmacodynamics, resulting in different response and toxicity of the drug.36,38 Several tests can be used to identify specific SNPs in patients with breast cancer. However, it is not clear whether these tests should be used in clinical practice and how could be interpreted. In the next part of the review, we will discuss the published data on the pharmacogenomics and their role in predicting cardiotoxicity of the most common drugs used in patients with breast cancer (anthracyclines, trastuzumab, and taxanes), according to the mechanisms through which these chemotherapeutic drugs induces cardiotoxicity, as shown in Table 2. Thus, several studies showed the role of different genetic SNP types involved in carriage (absorption, elimination, intracellular transport), metabolism, cellular cytotoxic effect, and apoptotic sensitivity of antineoplastic drugs that may influence individual response, triggering the occurrence of cardiac dysfunction or favoring a protective role.
Susceptibility of SNPs in the transport of chemotherapeutic drugs
Studying more than 1900 SNPs for various types of cancer, including breast cancer, Visscher et al39,40 identified that types rs6759892, rs1149222, rs4148350, rs17583889, rs4982753, and rs4149178 encoding proteins involved in anthracyclines absorption, metabolism, and elimination (ATPbinding cassette transporters, anthracycline metabolite glucuronidation) were associated with cardiotoxicity.
Vulsteke et al41 studied the genetic variation of 10 SNPs in 6 most frequent genes involved in the intracellular transport of the cytotoxic drugs (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3). In 877 patients with early breast cancer forms treated with epirubicin, he found that 6 cycles of FEC (5-fluorouracil, epirubicin, and cyclophosphamide) by comparison with 3 cycles, and the SNPs rs246221 encoding a heterozygous carrier of the T-allele in ABCC1 gene by comparison with homozygous carriers of the T-allele, were significantly related to a decrease in LVEF by more than 10% at the completion of treatment.41 Thus, he suggested that this might be mediated by the decrease in the transportation of toxins, including epirubicin, out of the cell, mechanism in which gene ABCC1 is responsible.41
Another study reported that rs45511401 encoding T allele on the same gene ABCC1 and A-allele carriers of rs8187710 on gene ABCC2 are related to the increased risk for anthracyclines-induced cardiotoxicity, through the same mechanism of decrease in depuration of toxins from the cellular level.42
Physiologically, cytochromes P450 hepatic enzymes CYP3A4, CYP3A5, and CYP2C8 catalyze the conversion of taxanes in their metabolites. Then, ABCC1 and ABCC2 carry these metabolites to the bile canaliculi, out of the cells. There are few data showing a potential correlation between the prognosis of the breast cancer treated with taxanes and different genetic polymorphisms of these enzymes.43 Moreover, in patients receiving adjuvant FEC, followed by docetaxel, Vulsteke et al44 demonstrated that expressed form of homozygous carriers of the rs1057910 variant C-allele in CYP2C9 is associated a poor survival.
In metastatic breast cancer, cellular transport of paclitaxel and gemcitabine is also influenced by genetic variants of different carrier enzymes. Thus, Lee et al45 identified that SNP SLC29A1 determines a shorter survival of the patients, but SLC28A3 (rs7867504) is associated with a good prognosis. In addition, Visscher et al39 found a protective role of rs4148350 in ABCC1, encoding human concentrative nucleoside transporter, selective for different cytotoxic drugs, such as doxorubicin, daunorubicin, and gemcitabine, showing better prognosis and survival of the patients.
Susceptibility of SNPs in the metabolism of chemotherapeutic drugs
Blanco et al17 showed that cardiotoxicity due to low doses of anthracyclines (100–150 mg/m2) may be associated with the presence of SNP rs1056892 and rs9024, encoding the homozygosis for variant G allele in carbonyl reductase 3 (CBR3) V244M, a type of cardiac cytosolic carbonyl reductase involved in cytotoxic drugs metabolism. They demonstrated that this genetic variation increased the anthracyclines toxic alcohol metabolites, reaction that is catalyzed by 2 isoforms of cardiac carbonyl reductase, CBR1 and CBR3, leading to augmentation risk for cardiotoxicity. On contrary, they showed no risk for cardiac dysfunction at low doses of anthracyclines for CBR3 heterozygous (GA), and CBR1 homozygous (GG) or heterozygous (GA) forms.17 Also, high doses of anthracyclines (>250 mg/m2) are related with significant risk of cardiotoxicity, independent of the CBR genotype status.17 In another study, SNPs encoding PIK3R1 and INPP4B, involved in tyrosin kinase metabolism pathway, contributed to cell protection from apoptosis generated by cardiotoxicity induced by daunorubicin.46 In a 132 patient group with breast cancer receiving FEC, knowing the fact that epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), the SNP UGT2B7-161 TT correlated with a higher risk of leukopenia, early recurrence of the neoplasia, and possible cardiac dysfunction.47
Susceptibility of SNPs in the cytotoxic effect of chemotherapeutic drugs
Wojnowski et al48 identified a significant correlation between rs4673 NADPH oxidase and acute cardiotoxicity, suggesting that the cytotoxic effect of anthracyclines, generating ROS, might be influenced by genetic polymorphism of NADPH, favoring the occurrence of cardiotoxicity.
Trastuzumab, a humanized monoclonal antibody, which binds to HER2 extracellular domain, is the standard treatment for HER2-positive breast cancer.49 The risk of trastuzumab-induced cardiotoxicity is related to an SNP in HER2 gene, influencing the cellular response to this cytotoxic drug.49 The most studied HER2 SNP includes codon 655 (GTC/valine to ATC/isoleucine).50 Although many evidences demonstrated that trastuzumab efficacy is greater in patients who express HER2/Val isoform, cardiotoxicity seems to be highly associated with genotype.49–53 But no cardiac dysfunction was found in Ile/Ile homozygous patients.49–53 Beauclair et al53 studied 61 patients from whom 8.2% developed cardiac dysfunction, defined as a reduction by more than 20% in LVEF. The genetic variation containing Val655Ile genotype was found in all patients who developed cardiotoxicity.
Similarly, Roca et al54 found a significant correlation between the developing of cardiotoxicity and Val655Ile and FCGR2A-131 H/H genotypes, but no cardiac dysfunction associated with FCGR3A-158 Val/Val genotype, in patients with breast cancer treated with trastuzumab. The underlining mechanism is related to the fact that HER2 signaling has a significant role in cardiac function, and this form of SNP might lead to direct alteration of cardiomyocytes depending on the HER2 signal.54 However, other studies did not demonstrate a relation between cardiotoxicity and HER2 Ile655Val polymorphism.55
In vitro models with cardiomyocytes derived from human embryonic stem cells showed that doxorubicin-induced cardiotoxicity is associated with a high gene expression of growth differentiation factor 15, whose activity is regulated by tumor protein p53, tumor necrosis factor, or hepcidin antimicrobial peptide. These biomarkers might be used to predict anthracycline-induced cardiac dysfunction.56 Moreover, in mice experiments, it was demonstrated that Top1mt, which can be affected by anthracyclines, plays an important role in cardiac tolerance and adaptive response to doxorubicin action, and therefore, Top1mt SNPs can be involved in susceptibility of doxorubicin-induced cardiotoxicity.57
Susceptibility of SNPs in the apoptotic sensitivity of chemotherapeutic drugs
McCaffrey et al20 showed that anthracyclines-induced cardiotoxicity may be related to rs11849538, which is correlated with the reduction of T-cell leukemia IA transcripts. This genetic variation can lead to a decrease in multidrug resistance–associated protein 1 and increased cardiac levels of anthracyclines, with increased apoptotic sensitivity of the cardiac cells, partially via high ROS. Recently, it was showed that SNP rs878156 in PARP2, a polymerase cellular enzyme, may contribute to a longer survival of postmenopausal breast cancer survivors, after chemotherapy and radiotherapy.58
Genetics and cardioprotective effects of dexrazoxane in chemotherapy-induced cardiotoxicity
Administration of dexrazoxane in patients with breast cancer, with a high risk of cardiotoxicity determined by anthracyclines or trastuzumab, demonstrated cardiac protective effects in animal models and humans.59 The mechanisms of dexrazoxane, an analogue of EDTA with potent iron-binding capacity and antineoplastic properties, are not fully understood. Several studies investigated the interaction of dexrazoxane with intracellular iron produced by ROS during therapy with anthracyclines.60 Meanwhile, experimental studies on rats suggested that the cardiac protective effects of dexrazoxane might be related with the upregulation of calpain-2, with a genetic determination.61
Despite the high efficacy in curative treatment of breast cancer, chemotherapy associates a significant risk of cardiotoxicity, leading to an increased morbidity and mortality of these patients. This may vary from asymptomatic forms to severe irreducible heart failure and even death. Genetic mutations, encoding various molecules involved in absorption, transport, metabolism, and elimination of cytotoxic drugs, can explain individual variability in drug response and occurrence of cardiotoxicity, but data are still inconsistent. Larger studies on genetic polymorphisms should be performed to identify patients at a risk for developing cardiac side effects, who can benefit from early therapeutic measures.
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