Trastuzumab Cardiotoxicity: Mechanism and Management

Abstract

Trastuzumab, a therapeutic drug for patients with breast cancer, is one of the most effective and commonly used anticancer drugs for breast cancer. However, its adverse effects include cardiotoxicity, and there is a risk of developing conditions such as arrhythmia, cardiomyopathy, and heart failure. The adverse cardiac effects associated with trastuzumab are now widely recognized, and their mechanisms are beginning to be partially understood. One of the mechanisms has been suggested to be related to the suppressive action of trastuzumab on the erythroblastic oncogene B2 receptor, which acts protectively on the myocardium. Diagnosis can be made by assessing cardiac function with echocardiography, as well as measuring serum troponin I and N-terminal pro-B-type natriuretic peptide levels as biomarkers, and magnetic resonance imaging diagnosis may be helpful for early detection. As for therapeutic and prophylactic drugs, β-blockers and angiotensin-converting enzyme inhibitors, which are used to treat heart failure, have been shown to be effective, while recently, angiotensin receptor/neprilysin and sodium–glucose cotransporter 2 inhibitors are expected to be effective. Furthermore, the cardioprotective effects of proprotein convertase subtilisin/kexin type 9 inhibitors, which are used to treat lipid disorders, have also been attracting attention. This review will summarize the mechanisms, diagnostic methods, and treatment/preventive methods of cardiotoxicity associated with antihuman epidermal growth factor receptor 2 therapies, including trastuzumab.

1. INTRODUCTION

Trastuzumab, a therapeutic drug for patients with breast cancer, is one of the most effective and commonly used anticancer drugs for breast cancer.^1,2)

Human epidermal growth factor receptor 2 (HER2)/neu protein is a 185 kDa transmembrane cytoplasmic tyrosine kinase. Amplification of the HER2 gene or overexpression of the HER2 protein is found in 10–34% of breast cancer cases³⁾ and anti-HER2 therapies inhibit tumor cell growth, differentiation, and survival by disrupting the normal regulatory function of the HER2 receptor.⁴⁾

Anti-HER2 therapies, such as trastuzumab, pertuzumab, and ado-trastuzumab emtansine, are used in adjuvant, neoadjuvant, and palliative therapies to improve outcomes for patients with HER2-overexpressing breast cancer.^5,6)

However, their adverse effects include cardiotoxicity, and there is a risk of developing conditions such as arrhythmia, cardiomyopathy, and heart failure.^2,7,8)

To date, numerous large-scale clinical trials of trastuzumab have been conducted in the United States and Europe and have reported that asymptomatic cardiac dysfunction occurs in 3–17% of patients treated with trastuzumab, and symptomatic cardiac dysfunction in 1–11%.^9–12) Cardiotoxicity during breast cancer treatment often leads to treatment interruption or discontinuation,⁸⁾ after which cardiac function, as measured by left ventricular ejection fraction (LVEF), is reported to be restored in approximately 80% of cases.¹³⁾ However, a small number of deaths from heart failure have been reported among patients who have discontinued the treatment. Risk factors for trastuzumab cardiotoxicity include prior anthracycline or taxane therapy for cancer, underlying cardiac disease, advanced age, and low LVEF prior to trastuzumab administration.¹⁾ Suppression of the ErbB2 receptor, which protects the myocardium, has also been reported to contribute to trastuzumab cardiotoxicity.^14–16) The mechanisms of trastuzumab-induced cardiotoxicity are thought to involve a decrease in cardiac function due to increased production of reactive oxygen species (ROS)¹⁷⁾ or mitochondrial dysfunction. Although most trastuzumab-induced myocardial damage is reversible, irreversible and severe cases have been suggested to be strongly associated with myocardial fibrosis.¹⁸⁾ The diagnosis of cardiotoxicity is usually made based on the assessment of cardiac function by echocardiography and the measurement of serum troponin I and N-terminal (NT) pro-B-type natriuretic peptide (BNP) levels as predictive markers of the development of cardiotoxicity.^6,19)

However, since the diagnostic methods have not yet been established, elucidating the mechanism of cardiotoxicity will make it possible to select patients for whom drugs are likely to be effective to provide effective treatment, and will also lead to the development of treatments for patients who present with cardiotoxicity.

This review aims to summarize clinical characteristics, pathophysiology, and clinical management of cardiotoxicity associated with anti-HER2 therapies for breast cancer.

2. BREAST CANCER TREATMENT

Several different molecular subtypes of breast cancer are defined based on gene expression patterns.²⁰⁾ The gene expression patterns will determine the mode of treatment for patients. The main subtypes of breast cancer have three tumor markers, namely estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. The most common subtype is hormone receptor (ER or PR)-positive, consisting of the luminal A and luminal B subtypes. The luminal A subtype is strongly hormone receptor-positive and HER2-negative, with a low expression of Ki-67. The luminal B subtype is hormone receptor-positive and HER2-positive or highly expressed Ki-67. Furthermore, the luminal B subtype and triple-negative tumors (ER⁻/PR⁻/HER2⁻), as well as HER2-overexpressing tumors (ER⁻/HER2⁺), are known to be clinically more progressive and have a poorer prognosis compared to luminal A tumors.^21–23)

3. HER2

The HER2 gene is an oncogene with a structure similar to the epidermal growth factor receptor (EGFR) gene. The HER2 protein encoded by the HER2 gene is a membrane-localized receptor with tyrosine kinase activity and is involved in epithelial cell proliferation and differentiation. HER2 gene amplification or protein overexpression is observed in 15–25% of invasive breast cancers, and the prognosis of patients with invasive breast cancer that has HER2 gene amplification or protein overexpression is poor if anti-HER2 therapies are not performed.^24,25) HER2 proteins are targets of anti-HER2 therapies such as trastuzumab.²⁶⁾

4. MECHANISMS OF CARDIOTOXICITY INDUCED BY ANTI-HER2 THERAPIES

The mechanisms by which HER2 inhibitors cause cardiotoxicity have not been fully elucidated, but various physiologically active pathways are involved.

HER2 is overexpressed in 20–25% of human breast cancer cases.²⁷⁾

The HER receptor is activated in vivo by several ligands, including EGF (HER-1) and neuregulin (NRG, HER-3, and HER-4).²⁸⁾ HER-2 per se is an orphan receptor, but it forms heterodimers with other types of ErbB receptors, activating the receptors.²⁹⁾ Additionally, HER-2 homodimers are homeostatically active on the surface of cells overexpressing HER-2, such as breast cancer cells.³⁰⁾

ErbB downstream signaling involves the activation of several important pathways, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and endothelial nitric oxide synthase (eNOS), all of which contribute to cell survival and proliferation, mitochondrial function, and sarcoplasmic reticulum calcium uptake.^31–33)

In the heart, these pathways play an important role in homeostasis and are activated primarily via HER-4. So, when trastuzumab inhibits HER2 molecules in cardiomyocytes, it interferes with normal ErbB signaling by forming dimers with members of the HER/ErbB family or with each other. It is also believed to impair cardiomyocytes by inhibiting the PI3K/AKT MAPK and Src/FAK signaling pathways that protect cells from death and contribute to cardiomyocyte proliferation.^34,35)

Another mechanism is thought to be that trastuzumab causes mitochondrial dysfunction. Suppression of HER2 leads to eNOS downregulation, resulting in decreased antioxidant levels and ROS accumulation, and ROS accumulation leads to mitochondrial damage and dysregulation.³⁶⁾

High ROS concentration also decreases antioxidant activity. Additionally, anthracyclines directly reduce the activity of antioxidant enzymes, resulting in increased oxidative stress and amplifying the detrimental effects of ROS.³⁷⁾ Furthermore, inhibition of the HER2 and PI3K/Akt pathways causes an upregulation of the pro-apoptotic Bcl-2 family protein Bcl-xS and downregulation of the anti-apoptotic protein Bcl-xL, activating the mitochondrial apoptotic pathway, resulting in mitochondrial damage and cellular energy impairment.^38,39)

Mitochondrial dysfunction then leads to reduced myocardial contractility and cardiomyocyte damage, resulting in heart failure. Moreover, inhibition of HER2 downregulates the cMLCK, MEK/Erk, and Src/FAK pathways, resulting in the disruption of myocardial structure, leading to cardiac hypertrophy and ventricular remodeling.^40,41) Another proposed mechanism is that HER2 inhibition triggers the Erk/mammalian target of rapamycin (mTOR) signaling cascade, leading to autophagy suppression and ROS accumulation^42–44) (Fig. 1).

Fig. 1. Mechanism of Trastuzumab Cardiotoxicity

MAPK = mitogen activated protein kinase, PI3K = phosphatidylinositol-3-kinase Akt = Ak transforming factor, mTOR- = mammalian target of rapamycin RAS = Ras GTPase, RAF = Raf-1, ERK = extracellular signal-regulated kinase NOS = endothelial nitric oxide synthase, NO = nitric oxide, ROS = reactive oxygen specie

5. CONCOMITANT USE WITH ANTHRACYCLINES

According to a meta-analysis, the incidence of LVEF decline and congestive heart failure in patients taking trastuzumab was 7.5 and 1.9%, respectively.⁴⁵⁾ Trastuzumab is associated with LVEF decrease and increased risk of developing heart failure and may lead to more severe heart failure and significantly reduced LVEF when concomitantly used with anthracyclines. For trastuzumab-based anthracycline chemotherapy agents, the incidence of LVEF decrease ranged from 4.0 to 18.6%, and the incidence of severe heart failure of class III or class IV as defined by the New York Heart Association (NYHA) ranged from 0.4 to 4.1%. Patients treated with trastuzumab had a lower risk of developing cardiotoxicity without anthracyclines, with a 3.2% decrease in asymptomatic LVEF and a 0.5% decrease in symptomatic heart failure. The incidence of cardiotoxicity with trastuzumab monotherapy ranged from 2 to 7%.⁴⁶⁾

As mentioned in the above reports, concomitant use with anthracyclines amplifies the cardiotoxicity induced by trastuzumab.^47,48) As an amplification mechanism, anthracyclines stimulate cardiac stress pathways through various mechanisms, including topoisomerase 2 inhibition and ROS generation.⁴⁹⁾ Additionally, the inhibition of HER2 increases ROS formation, promotes apoptosis, and exacerbates oxidative stress and cell damage. It has also been reported that suppression of HER2 disrupts the HER2/NRG pathway, making cardiomyocytes more vulnerable to stress,⁵⁰⁾ and the combination of anthracyclines and trastuzumab is likely to increase cardiotoxicity.

6. DIAGNOSTIC METHODS FOR CARDIOTOXICITY

6.1. Biomarkers

Elevated troponin I or T is associated with an increased risk of myocardial damage induced by trastuzumab. NT-pro-BNP has also been found to be predominantly increased in patients who have developed myocardial damage compared to those who have not.⁵¹⁾

Guidelines recommend baseline cardiac troponin (cTn) and natriuretic peptide (NP) measurements for all patients treated with drugs that may cause cardiovascular toxicity associated with cancer therapy. For patients with high- and intermediate-risk early-stage HER2-positive breast cancer, NP and cTn monitoring is also recommended before starting therapy, every 3 months during therapy, and every 12 months after completing therapy.⁵²⁾

6.2. Echocardiography

On echocardiography, myocardial damage is defined as a condition where LVEF decreases >10 or >5% if <50%. For low-risk patients receiving anti-HER2 therapies, it is recommended that LVEF and global longitudinal strain be assessed before starting therapy, every 3 months during therapy, and within 12 months after completing therapy.⁵²⁾ There is clear evidence from clinical trials that the heart failure rate in low-risk populations not receiving anthracycline therapy is low and likely no higher than that in the general population.⁵³⁾ Even for patients at low risk of metastatic disease, echocardiography is recommended every 3 months for the first year and every 6 months thereafter. Furthermore, the recommendations do not distinguish between trastuzumab and other therapies, such as pertuzumab and trastuzumab emtansine. These therapies have demonstrated even lower rates of LVEF decrease in trials.⁵⁴⁾

6.3. Global Longitudinal Strain (GLS)

In recent years, GLS has been using the speckle tracking method. GLS can detect myocardial damage more sensitively than LVEF and has been recommended for use not only by cardiovascular system-related guidelines in the United States and Europe^55,56) but also by the American Society of Clinical Oncology guidelines, as an indicator with excellent reproducibility.

GLS is analyzed with the software built into the device or with an analytical computer using the two-dimensional speckle tracking method based on video data from three apical cross-sections (long-axis, luminal, and intraluminal cross-sections) over the cardiac cycle. GLS is the average systolic strain of each of the 18 left ventricular fractions.

Currently, a relative GLS reduction of >15% compared to baseline is the recommended threshold.⁵²⁾ Follow-up every 3 months is recommended during anti-HER2 therapies.⁵²⁾

6.4. Magnetic Resonance Imaging (MRI) Scan

Cardiac MRI assesses ventricular volume and cardiac function and may detect late stages of myocardial damage when combined with echocardiographic assessment of myocardial strain and measurements of biomarkers such as serum BNP and high-sensitivity cardiac troponin.^52,57) However, it is currently difficult to identify myocardial damage caused by cancer treatment at an early stage.

Cardiovascular magnetic resonance (CMR) scans can capture myocardial tissue changes (such as inflammation and edema) and may allow early detection of the risk of cancer treatment-related cardiac dysfunction (CTRCD).⁵⁸⁾ The first method is late gadolinium enhancement (LGE). LGE suggests myocardial fibrosis and edema and helps differentiate cardiomyopathy from other conditions.⁵⁹⁾

Although no specific LGE pattern has been established in drug-induced myocardial damage, it has been reported that in trastuzumab-induced myocardial damage, LGE is distributed in the mid-myocardial layer of the lateral wall.⁶⁰⁾

Recent CMR animal studies suggest that edema may reflect early anthracycline-related myocardial changes that precede LVEF decrease.^61,62) Additionally, although CMR studies in humans may provide an early assessment of the risk of CTRCD, the subject groups, and conditions are limited.^63,64) Among them, native myocardial T1 mapping has recently attracted much attention.

6.5. T1 Mapping

T1 mapping is an imaging method that quantitatively measures the T1 value (T1 relaxation time) of the myocardium, and it has two indices, namely native T1, which is assessed without gadolinium contrast agents, and extracellular volume fraction (ECV), which is assessed using contrast agents. Native T1 quantitatively assesses damage throughout the myocardium (intracellular and extracellular).

ECV quantitatively assesses the expansion of extracellular volume (fibrosis and interstitial expansion). In particular, it allows the assessment of inflammation and fibrosis.⁶⁵⁾

T1 mapping may be more sensitive and accurate than other imaging tests and serum markers in quantifying anthracycline-induced myocardial damage⁶⁶⁾ and may also be able to assess trastuzumab-induced myocaridial damage.

Furthermore, it can diagnose myocardial damage at an earlier stage.^67,68)

6.6. Decision on Dose Reduction, Withdrawal, or Discontinuation

Cardiotoxicity manifests as LVEF decrease with or without symptomatic heart failure. Early studies have reported that the incidence of NYHA Class III and IV cardiotoxicity resulting from the combination of anthracyclines and trastuzumab was as high as 19%, with a prevalence of left ventricular dysfunction at 27%.⁶⁹⁾

However, most trastuzumab-induced myocardial damage can be reversed by withdrawal of the drug.¹⁵⁾ Nevertheless, there have been reports of severe cases, so caution is required.

Recognizing the cardiac effects of trastuzumab, particularly in regimens involving anthracyclines, cardiac function monitoring, and anthracycline-free regimens are recommended.⁷⁰⁾ For patients who have developed moderate or severe symptomatic CTRCD or severe asymptomatic CTRCD (LVEF <40%) during anti-HER2 therapies, temporary interruption is recommended. In patients with mild symptomatic CTRCD, rather than interrupting HER2-targeted therapies, it is recommended to approach a multidisciplinary team to determine whether or not to continue treatment. In patients with asymptomatic moderate CTRCD (LVEF 40–49%), it is recommended to continue anti-HER2 therapies and initiate cardioprotective therapies (Angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) and β-blockers) in addition to frequent cardiac function monitoring.^71–73) In patients with asymptomatic mild CTRCD (LVEF ≥50%, significant GLS reduction and/or elevated cardiac biomarkers), continuation of anti-HER2 therapies is recommended, and cardioprotective therapies (ACEIs/ARBs and/or β-blockers) should be considered.^71,74–76)

For all patients with CTRCD who continue anti-HER2 therapies and patients who have recovered to LVEF ≥40% after resuming therapies following an interruption due to the development of heart failure, frequent cardiac monitoring with imaging and serum biomarkers is recommended.^71–73) After the resumption of HER2-targeted therapies, echocardiography and measurement of cardiac serum biomarkers are recommended every four cycles of the first therapy, after which the frequency of testing can be reduced if cardiac function and biomarker levels are stable.

7. PREVENTION OF CARDIOTOXICITY WITH ANTI-HER2 THERAPY AND TREATMENT METHODS

7.1. β-Blockers

β-Blockers are expected to be effective against drug-induced myocardial damage.⁷⁷⁾ It has been reported that β-blockers suppressed the onset of heart failure in patients treated with trastuzumab.⁷⁸⁾ The mechanism of action is thought to involve the antioxidant effect of β-blockers. However, despite suppressing LVEF decrease, they did not suppress left ventricular remodeling.⁷⁹⁾

β-Arrestins are intracellular proteins that increase the activation of ERK1/2 and AKT kinases, HER1/EGFR, and signaling mediated by the EGFR, such as HER2, in cardiomyocytes. Carvedilol stimulates β-arrestin-mediated cell signaling and cardioprotective pathways by increasing the action of β-arrestins on cardiac β-adrenergic receptors in vitro,⁸⁰⁾ thereby exerting cardioprotective effects.

7.2. ACEIs, ARBs, or Aldosterone Antagonists

ACEIs and aldosterone antagonists have been shown to suppress left ventricular dilation and improve the prognosis of drug-induced myocardial damage.^81,82)

It has also been reported that ARBs cannot be expected to be effective against drug-induced myocardial damage.⁸³⁾ However, it has also been reported that concomitant treatment with candesartan suppressed the early decline in left ventricular function in patients with early-stage breast cancer who received adjuvant therapy to anthracycline-containing regimens.⁸⁴⁾

The mechanism of action has been established in treating heart failure with reduced LVEF (HFrEF), and it has been shown to improve adrenergic and neuroendocrine dysregulation and suppress left ventricular remodeling.⁸¹⁾

7.3. Angiotensin Receptor/Neprilysin Inhibitor (ARNi)

ARNi is effective in patients with HFrEF.⁸⁵⁾ ARNi administration was shown to be superior to ACEI enalapril in reducing the risk of death from cardiovascular causes in such patients.⁸⁵⁾ Additionally, the efficacy of ARNi against cardiotoxicity was observed in the subgroup of patients with HFrEF.⁸⁶⁾

The cardioprotective effects of ARNi may be due to reduced oxidative stress levels, suppressed myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improved renin–angiotensin–aldosterone imbalance.⁸⁷⁾ However, data on its effect against trastuzumab-induced cardiomyopathy are scarce at present.

7.4. Sodium–Glucose Cotransporter (SGLT2) Inhibitor (SGLT2i)

Originally approved for treating type 2 diabetes, SGLT2i⁸⁸⁾ has demonstrated efficacy in reducing cardiovascular events, particularly heart failure, in patients with and without diabetes.⁸⁹⁾

Various studies have reported the following effects of SGLT2i on drug-induced myocardial damage.

7.4.1. Anti-inflammatory Effect

SGLT2i has been shown to reduce cardiac inflammation and fibrosis by modulating the activation of nuclear factor kappa B and NLR family pyrin domain-containing 3 inflammasomes, thereby weakening the synthesis of proinflammatory cytokines. Several studies have demonstrated the protective effect of SGLT2i against anthracycline-induced cardiomyopathy.⁹⁰⁾ The same cardioprotective effect is expected against trastuzumab-induced myocardial damage.

7.4.2. Antioxidant Effect

It is known that oxidative stress is involved in chemotherapy-induced cardiotoxicity,⁹¹⁾ and empagliflozin, in particular, is thought to reduce oxidative stress induced by trastuzumab in vivo⁹²⁾ and suppress myocardial damage.

7.4.3. Alleviation of Endoplasmic Reticulum Stress

ER stress plays an important role in anthracycline-induced myocardial damage. SGLT2i has been shown to have the potential to alleviate ER stress, which is associated with the suppression of cardiovascular events,⁹³⁾ and dapagliflozin has also been reported to protect against diabetes and anthracycline-induced cardiotoxicity by alleviating ER stress.⁹⁴⁾

7.4.4. Inhibition of Ferroptosis

Ferroptosis is an iron-dependent and nonapoptotic type of cell death caused by excess lipid ROS and redox imbalance and is associated with abnormal iron accumulation.⁹⁵⁾ Ferroptosis plays an important role in cardiovascular disease, and maintaining iron homeostasis plays a critical role in maintaining normal cardiac function.

Trastuzumab induces ferroptosis and may contribute to myocardial damage,⁹⁶⁾ thus SGLT2i may have the ability to reduce trastuzumab-induced cardiotoxicity by inhibiting ferroptosis.

7.4.5. Inhibition of Ketone Production

SGLT2i promotes the production of ketone bodies, especially β-hydroxybutyrate, from the liver.⁹⁷⁾ Empagliflozin has been shown to protect against anthracycline-induced cardiomyopathy by increasing β-hydroxybutyrate levels.⁹⁸⁾

As described above, many mechanisms have been elucidated, and clinical data have been reported on the cardioprotective effects of SGLT2i in anthracycline-induced cardiomyopathy. Unfortunately, there are few clinical data reports on trastuzumab-induced cardiomyopathy, but given the common mechanisms of myocardial damage, SGLT2i may be effective against trastuzumab-induced cardiomyopathy.

7.5. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

PCSK9 is a proprotein convertase that binds to and subsequently degrades low-density lipoprotein (LDL) receptors on the surface of hepatocytes. It is a monoclonal antibody that inhibits the normal function of PCSK9, and inhibiting it increases LDL receptors in the liver and increases LDL uptake from the systemic and portal circulation, thereby lowering LDL levels in the blood PCSK9 inhibitors exhibit diverse effects, including an anti-inflammatory effect, ROS downregulation, and endothelial dysfunction improvement.

PCSK9 inhibitors with such effects may be effective against anthracycline-induced myocardial damage.⁹⁹⁾ Trastuzumab-induced myocardial damage, like that of anthracycline, is thought to be caused by mitochondrial dysfunction and ROS production. Moreover, the antioxidant effect,¹⁰⁰⁾ anti-inflammatory effect,¹⁰¹⁾ and mitochondrial protective effect¹⁰²⁾ of PCSK9 inhibitors may be able to suppress trastuzumab-induced myocardial damage.

8. CONCLUSION

This review summarized the molecular mechanisms, diagnostic methods, and treatment methods of cardiotoxicity associated with trastuzumab, an anti-HER2 drug. At present, cardiotoxicity induced by antitumor drugs is managed through early detection, regular monitoring, and empiric therapy, but currently, there are no widely accepted standards. Under a cooperative relationship with oncologists, the role of oncology cardiologists becomes crucial. The development of future treatments for cardiotoxicity induced by targeted drugs will require accumulating and analyzing more clinical data.

Conflict of Interest

The authors declare no conflict of interest.

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