Cardiac toxicity associated with HER-2 targeted agents

Cancer patients receiving HER-2 directed agents are at an increased risk of developing cardiotoxicity, typically manifesting as an asymptomatic decrease in the left ventricular ejection fraction (LVEF) and less commonly congestive heart failure (CHF).

Definition

Cardiotoxicity is a well recognised complication of trastuzumab therapy. However, this risk appears to be lower with the newer HER-2 directed agents (trastuzumab emtansine and pertuzumab), as well the mixed HER tyrosine kinase inhibitors (neratinib and lapatinib), although experience with these agents is limited. Mechanistically distinct from anthracycline-induced cardiotoxicity, it typically manifests as an asymptomatic decrease in the LVEF and less commonly as CHF.

HER-2 is an important mediator of unregulated cell growth and cell survival, with adult myocardium expressing HER-2 and HER-4, but not HER-3.^rrr During periods of myocardial stress, neuregulin (released by endothelial cells) binds to HER-3 and HER-4, while recruiting HER-2 as a co-receptor, in order to increase expression of intracellular survival pathways. Blocking HER-2, HER-3 or HER-4 subsequently leads to increased cellular apoptosis and reduces myocardial proliferation.^r

Incidence/prevalence

Cochrane systematic review for trastuzumab^r

A systematic review from the Cochrane collaboration including 8 randomised controlled trials and 11,991 patients reported on the safety and efficacy of trastuzumab use in early breast cancer.

• CHF: Trastuzumab significantly increased the risk of CHF (RR 5.11; 90% CI 3.00 to 8.72). Definitions of CHF in these trials included NYHA class III-IV, severe CHF, symptomatic CHF and confirmed CHF. CHF was reported in 2.5% of 5471 patients receiving trastuzumab with chemotherapy and 0.4% of 4810 patients receiving chemotherapy alone.
• LVEF decline: Trastuzumab significantly increased the risk of LVEF decline (RR 1.83; 90% CI 1.36 to 2.47, p=0.0008). Definitions of LVEF decline varied across the trials. LVEF decline was seen in 11.2% of 4147 patients in the trastuzumab plus chemotherapy group and 5.6% of 3792 patients in the chemotherapy alone group.

The incidence of cardiac toxicities seemed higher in regimens where trastuzumab was given for more than 6 months than in those where trastuzumab was administered for less time. Cardiac toxicity was not significantly different in studies with concurrent administration of trastuzumab versus those with sequential administration. However subgroup analysis was limited by the small number of studies and further trials are required to confirm these results.

Of note, all 8 trials required normal heart function (many required LVEF >55%) for inclusion and patients with cardiovascular disease of any grade were excluded. Because of this the risks may be higher in routine clinical practice.

Elderly patients, usually underrepresented in clinical trials, have a higher prevalence of cardiovascular risk factors and are at a higher risk of cardiotoxicity. Two large population based studies in the older population have shown that the incidence of cardiotoxicity is substantially higher in older patients.^rr In one study, of the 2203 patients receiving trastuzumab, the rate of CHF was 29.4% compared to 18.9% of the 7332 patients who did not receive trastuzumab (hazard ratio 1.95; 95% CI 1.75 to 2.17).^r

With longer follow-up of patients treated with trastuzumab, there does not appear to be an increase in the incidence of cardiac events over time. This is demonstrated by the persisting low rates of cardiotoxicity reported in the updated analyses of the large adjuvant trials.^rr

Pertuzumab

The Cleopatra trial of 808 patients randomly assigned to trastuzumab and docetaxel plus either pertuzumab or placebo revealed that the pertuzumab group was not at any increased risk of cardiotoxicity, with a rate of left ventricular (LV) dysfunction of 3.3% in the placebo arm versus 1.5% in the pertuzumab arm.^r The TRYPHAENA study included 3 arms, with 2 different regimens of FEC + trastuzumab + pertuzumab followed by docetaxel, versus carboplatin + docetaxel + trastuzumab + pertuzumab.  The incidence of symptomatic LV dysfunction occurred in up to 2.7%. Decline in LVEF ≤10% at baseline to <50% was between 3.9 and 5.6% across all 3 arms.^r

Trastuzumab emtansine

Initial trials with trastuzumab emtansine have demonstrated similar results, however all these trials were after prior treatment with other potentially cardiotoxic agents including trastuzumab and docetaxel so cardiotoxicity associated with trastuzumab emtansine is unknown.^r

The TH3RESA trial in metastatic breast cancer patients compared trastuzumab emtansine versus physician’s choice. It showed no increase in cardiac toxicity defined as LVEF ≥15% or absolute decrease in LVEF to <50%.^r

Lapatinib

Geyer et al. (2006) compared lapatinib + capecitabine versus capecitabine and placebo. It did not reveal a difference in the mean LVEF values between the two groups, with no symptomatic cardiac events.^r A subsequent EMILIA trial of 991 patients compared T-DM1 to lapatinib with capecitabine, and showed no increase in mean LVEF between the two groups.^r In the ALTTO trial, 8381 patients were randomly assigned to 1 year of adjuvant trastuzumab, lapatinib, sequential trastuzumab followed by lapatinib, or their combination (trastuzumab + lapatinib).^r The incidence of primary and secondary cardiac events was low in all treatment arms – between 0.25% and 0.97% of patients developed primary cardiac endpoints with 3 fatal cardiac events in the sequential arm, and 1 in each of the other treatment arms.^r

Neratinib

The cardiotoxicity profile of neratinib was favourable in the phase 3 NEfERT-T study in the first-line metastatic setting.^r The only phase 3 trial exploring neratinib in the adjuvant setting reported a low rate of cardiac events.^r

Risk factors

A careful risk benefit assessment should be made before deciding to treat with HER-2 directed agents and referral to a cardiologist may be required prior to initiating treatment.

Risk factors for development of cardiotoxicity include:^rr

• previous or concurrent anthracycline use
• prior treatment with high dose cyclophosphamide
• radiotherapy to the chest area
• age over 60
• history of hypertension
• documented coronary artery disease (increased risk of impaired LV function).

Specific cardiovascular risk factors and suggested treatment targets^r

^* Source www.heartscore.org/en_GB/access

ACE inhibition, angiotensin inhibition and β-blockade appear to prevent the development of left ventricular dysfunction when given prior or during chemotherapy/HER-2 targeted therapy in patients exhibiting early signs of cardiotoxicity.^rr​ However, universal primary prevention with standard heart failure medication is controversial, with only a few small studies demonstrating clinical benefit in high-risk populations.^rrrrr

Symptoms and signs

HER-2 directed therapy related cardiotoxicity most often presents as an asymptomatic decrease in LVEF and less commonly with clinical heart failure. Cardiotoxicity associated with HER-2 directed agents is not dose dependent. It is reversible in many patients if treatment is stopped, and responds to standard treatment for heart failure. Many patients tolerate continued treatment or rechallenge with HER-2 directed agents. Patients who fail to improve following withdrawal of the HER-2 directed agents should be referred to a cardiologist.^r

Investigations and diagnosis

All patients (both adjuvant and metastatic) should have a baseline cardiac assessment including history and physical examination, ECG and assessment of LVEF with either echocardiogram (ECHO) or gated heart pool scan (GHPS). ECHO is the preferred method of measuring cardiac function because of the ability to assess both systolic and diastolic dysfunction. However, limitations include operator dependency, reduced accuracy due to body habitus and variable methods for LVEF assessment. The threshold for monitoring cardiac function may be different for patients treated with curative vs palliative intent and clinician judgement is required especially in palliative settings.

HER-2 directed agents should not be used in adjuvant/neoadjuvant patients with an LVEF <45% and/or symptomatic heart failure; in the metastatic setting when breast cancer is life threatening a HER-2 directed agent may be considered at lower levels of LVEF in consultation with a cardiologist. Current PBS guidelines specify HER-2 directed agents must not be used in patients with a LVEF <45% and/or symptomatic heart failure.

Cardiac biomarkers

The role of cardiac biomarkers, particularly cardiac troponins (cTn) and N-Terminal pro-BNP (NT-proBNP), lies predominantly in the prediction of cardiomyopathy and the early detection of subclinical cardiomyopathy associated with breast cancer treatment.^rr A large analysis of 23 cross-sectional, prospective and retrospective studies confirmed the association of cTn with different biomarkers contributing to the early diagnosis of cardiotoxicity, though evidence is low that cTn is related to a better outcome, though it carries a strong negative predictive value (NPV).^r 

Further, there is no clearly defined optimal biomarker assay, the threshold for risk prediction, the timing of biomarker measurements in relation to chemotherapy, or biomarkers’ prognostic utility with biologic agents whose mechanism of cardiotoxicity may be due to myocardial cell death.

Although biomarkers are an attractive option in the early detection of cardiotoxicity among cancer patients, current recommendations surrounding their role is based on expert consensus opinion internationally, without conclusive studies demonstrating evidence for use of troponin I and NT-pro-BNP.  Appropriately designed prospective trials are required prior to addition of these markers to current clinical guidelines.

Monitoring during treatment

Adjuvant setting

In the adjuvant setting, LVEF should be monitored at 3 monthly intervals during HER-2 directed therapy. Refer to table below for recommended treatment interruptions for asymptomatic decreases in LVEF. If LVEF <45% at baseline, refer to cardiology prior to commencement of adjuvant trastuzumab.

Treatment interruption for asymptomatic decreases in LVEF in adjuvant patients (based on NSABP B-31 and NCCTG N9831 trials)^r

* If treatment is withheld due to a decline in cardiac function (LVEF <45%) consider referral to a cardiologist and commencing an angiotensin converting enzyme inhibitor (ACEI) and/or a beta blocker

When treatment is withheld it may be resumed if:

• the LVEF returns >45% or to <10 percentage points from baseline; if LVEF is between 45% and 50%, continuation can be considered (cardiologist advice is recommended).

HER-2 directed agents should be permanently discontinued, consideration for commencement of an angiotensin converting enzyme inhibitor (ACEI) and/or beta blocker (if not already commenced) and referral to a cardiologist if:

• persistent LVEF decline is observed, or
• symptomatic cardiac dysfunction occurs.

Metastatic setting

The decision to commence a HER-2 directed agent in the metastatic setting for a patient with compromised cardiac function will depend on an assessment of competing risks and the outcome of discussion with patient and family. There is no definitive guideline as to the lower limit of acceptable LVEF to administer HER-2 targeted agents to a patient with metastatic cancer.^r

For patients with metastatic breast cancer, HER-2 directed therapy is continued until disease progression, which may be several years. There have been anecdotal reports of patients continuing trastuzumab for more than 10 years. The recommendations in the adjuvant setting are suitable for monitoring cardiac effects during the first 12 months of therapy. After this, if there are no cardiac complications, frequency of cardiac assessments may be reduced at the discretion of the treating clinician unless there has been recent exposure to anthracyclines.

In the metastatic setting, restarting HER-2 directed therapy after a decline in LVEF or symptomatic cardiac dysfunction, can be considered in consultation with a cardiologist, on a case-by-case basis.

Educate the patient:

• about the risk of developing heart failure
• about the importance of ongoing monitoring
• to immediately report any cardiac symptoms, or changes, to the treating team:
  • any alteration in breathing patterns
  • swelling in the extremities
  • palpitations, chest pain
• to go to the nearest hospital emergency department or call an ambulance if they develop chest pain or shortness of breath at home.

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Bibliography

Berardi, R., M. Caramanti, A. Savini, et al. 2013. "State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review." Crit Rev Oncol Hematol 88(1):75-86.

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Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival, regardless of the oncologic prognosis. Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident months, and sometimes years, after completion of chemotherapy. Cardiotoxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent, that can serve as a tool in the clinical practice.

Bovelli, D., G. Plataniotis, F. Roila, et al. 2010. "Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines." Ann Oncol 21 Suppl 5:v277-282.

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Curigliano, G., D. Cardinale, T. Suter, et al. 2012. "Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines." Ann Oncol 23 Suppl 7:vii155-166.

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Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs, such as anthracyclines or other biological agents, have been implicated in causing potentially irreversible clinically important cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effects are irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-term cardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by various cancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treating cardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention, detection and management, avoiding unintended consequences that can impede development, regulatory approval and patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinary cardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations on CV risk prevention, assessment, monitoring and management during anticancer treatment.

MIMS Point of Care Online: CMPMedica Australia Pty Ltd (accessed 2015)

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O'Hare, M., K. Murphy, F. Mookadam, et al. 2015. "Cardio-oncology Part II: the monitoring, prevention, detection and treatment of chemotherapeutic cardiac toxicity." Expert Rev Cardiovasc Ther 13(5):519-527.

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Cancer treatment has advanced in recent years with new drugs, complex regimes and multiple modalities of treatment; which has improved survival of cancer patients. Cardiotoxicity from chemotherapy is an emerging, important issue. Currently, echocardiographic evaluation of ejection fraction is the most commonly employed diagnostic tool for detecting chemotherapy-induced cardiotoxicity. However, novel echocardiographic techniques assessing myocardial mechanics using strain imaging can detect earlier changes. New imaging techniques and biomarkers can risk stratify patients to identify those requiring closer monitoring. Cardiologists collaborating with oncologists can detect and treat cardiovascular chemotherapeutic complications earlier, reducing morbidity and mortality. While cardiac MRI and multigated acquisition nuclear scanning are alternatives, echocardiography has become the mainstream for assessing cardiac function due to its portability, efficiency and low cost. Current recommendations regarding cardiac monitoring of cancer patients are based on expert consensus opinion. There is a need for prospective controlled trials to support specific guidelines.

O'Hare, M., A. Sharma, K. Murphy, et al. 2015. "Cardio-oncology Part I: chemotherapy and cardiovascular toxicity." Expert Rev Cardiovasc Ther 13(5):511-518.

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Cancer and cardiovascular disease are the most common causes of mortality in the US, causing approximately 1.2 million deaths annually. The incidence of cancer is expected to increase as the population ages. The prognosis of cancer patients has improved over the last few decades primarily because of newer chemotherapeutic drugs; however, many of these drugs have cardiotoxic side effects. The short-term cardiovascular toxicities of more established drugs are well described; however, understanding of the underlying pathogenesis is increasing. The delayed cardiotoxic effects of cancer treatments have become an important issue contributing to mortality and morbidity as cancer survivorship increases. Chemotherapy-induced cardiotoxicity can manifest in many ways, from asymptomatic decreases in left ventricular ejection fraction to congestive heart failure. Hypertension is commonly seen both as a co-morbidity and a side effect of chemotherapy. In this article, we discuss the pathogenesis, scope, presentation and potential prevention of these toxicities.

Shank Coviello, J. 2014. "Cardiac side effects of targeted therapies." Semin Oncol Nurs 30(3):175-182.

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OBJECTIVES: To review common cardiac side effects, their clinical presentation, and recommendations for assessment and management of patients receiving molecularly targeted cancer therapies. DATA SOURCES: Peer-reviewed literature. CONCLUSION: Although there is no established guideline for pretreatment cardiac evaluation and monitoring of patients receiving molecularly targeted agents, data currently supports the need for early risk identification and prevention/reduction strategies. IMPLICATIONS FOR NURSING PRACTICE: As nurses, we have a unique opportunity to help improve and maintain the quality of life of cancer survivors. Cardiovascular assessment and prevention/reduction strategies are essential to reduce risk of cardiovascular disease, promote optimal quality of life, and improve survival outcomes in patients receiving molecularly targeted cancer treatment.

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