Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies
2017; Wiley; Volume: 6; Issue: 9 Linguagem: Inglês
10.1161/jaha.117.006915
ISSN2047-9980
AutoresRoberta Florido, Karen L. Smith, Kimberly Cuomo, Stuart D. Russell,
Tópico(s)Cancer Treatment and Pharmacology
ResumoHomeJournal of the American Heart AssociationVol. 6, No. 9Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBCardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies Roberta Florido, MD, Karen L. Smith, MD, MPH, Kimberly K. Cuomo, NP and Stuart D. Russell, MD Roberta FloridoRoberta Florido Division of Cardiology, Johns Hopkins University, Baltimore, MD , Karen L. SmithKaren L. Smith Breast and Ovarian Cancer Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD , Kimberly K. CuomoKimberly K. Cuomo Division of Cardiology, Johns Hopkins University, Baltimore, MD and Stuart D. RussellStuart D. Russell Division of Cardiology, Johns Hopkins University, Baltimore, MD Originally published22 Sep 2017https://doi.org/10.1161/JAHA.117.006915Journal of the American Heart Association. 2017;6:e006915IntroductionBreast cancer is the most commonly diagnosed cancer in women and the second‐leading cause of death among women with cancer.1 Whereas outcomes for many breast cancers are favorable, human epidermal growth factor receptor‐2 (HER2)‐positive breast cancers may have an aggressive clinical course and are associated with higher rates of disease recurrence and mortality.2, 3 Such tumors are characterized by overexpression of HER2 and/or amplification of the ERBB2 gene.2, 4 Development of the monoclonal antibody that targets the extracellular domain of HER2, trastuzumab, revolutionized the care of these patients, leading to large improvements in disease‐free and overall survival.5 In addition, development of newer anti‐HER2 therapies has led to further improvements in cancer outcomes for this population.6, 7, 8, 9HER2 targeted therapies, such as trastuzumab, are generally well tolerated. They do not have significant myelosuppressive side effects nor do they cause typical symptoms associated with chemotherapy, such as emesis and alopecia. However, the safety of therapies directed at HER2, in particular trastuzumab, has been questioned by concerns regarding cardiotoxic effects.10Clinical PresentationCardiac adverse effects from trastuzumab therapy involve decreases in the left ventricular systolic function with or without clinical signs and symptoms of heart failure (HF). Decreases in left ventricular ejection fraction (LVEF) typically manifest during the course of treatment and long‐term follow‐up data up to 10 years do not show evidence of late‐onset cardiac dysfunction associated with HER2 targeted therapy.11, 12, 13 Additional key features that differentiate cardiotoxicity associated with trastuzumab use from that associated with anthracycline therapy, which may occur late and be irreversible, are lack of ultrastructural changes in endomyocardial biopsy specimens, and possible reversibility of cardiac dysfunction.14, 15Although various groups have proposed a set of criteria to define cardiotoxicity from cancer therapies (Table 1), none have been uniformly accepted.16, 17, 18, 19 The use of various definitions for cardiac adverse events in the trastuzumab trials makes direct comparison of these studies difficult and limits our understanding of the true clinical burden of cardiotoxicity associated with HER2 targeted therapies.Table 1. Definitions of Cardiotoxicity Used by Different OrganizationsNational Cancer Institute Common Terminology Criteria for Adverse Events (HF) version 418Grade 1Grade 2Grade 3Grade 4Grade 5Asymptomatic elevation in biomarkers or imaging abnormalitiesSymptoms with mild‐to‐moderate exertionSymptoms with minimal exertion or at restLife‐threatening consequencesDeathCardiac Review and Evaluation Committee (CREC)19LVEF decrease >5%, to less than 55%, that is either global or more severe in the septum, with or without symptoms or HFAmerican Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI)17LVEF decrease >10%, to less than 53%, confirmed on repeat imaging, with or without symptoms of HFEuropean Society of Cardiology (ESC)20LVEF decrease >10%, to less than 50%, with or without symptoms or HFTrastuzumab labelingLVEF decreased ≥16% from baseline or LVEF decrease ≥10% to institutionally defined normalHF indicates heart failure; LVEF, left ventricular ejection fraction.The Benefits of HER2 Targeted TherapiesThe evidence indicating increased rates of cardiotoxicity with the use of HER2 targeted therapies needs to be taken in the context of the significant cancer‐related benefits.Trastuzumab was the first approved HER2 monoclonal antibody (approved by the US Food and Drug Administration in 1998). Initial trials showed it was well tolerated and produced durable response in patients who had failed first‐ and second‐line chemotherapy.21, 22, 23 Subsequent large, phase III trials showed significant improvements in time to treatment failure and overall mortality in patients with progressive metastatic breast cancer.5 A systematic review published in 2014 concluded that trastuzumab led to 18% and 39% improvements in overall and progression‐free survival in this population (hazard ratio, 0.82; 95% confidence interval [CI], 0.71–0.94; P=0.004; and hazard ratio, 0.61; 95% CI, 0.54–0.70; P<0.00001, respectively).24In 2005, results of 3 large phase III clinical trials were published showing high efficacy of adjuvant trastuzumab in combination with poly‐chemotherapy for patients with early breast cancer (node positive or high‐risk node negative). In a joint analysis from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trial B‐31 and NCCTG (North Central Cancer Treatment Group) trial N9831, the addition of trastuzumab to standard chemotherapy was associated with 33% and 50% improvements in overall and disease‐free survival,25 which persisted at 10 years of follow‐up.26 Similar results were reported from the HERA (Herceptin Adjuvant) trial.27 The BCIRG (Breast Cancer International Research Group) 006 trial extended these findings by showing benefit from trastuzumab regimens both with and without anthracyclines.28 Most recently, extremely low risk of recurrence was demonstrated with the use of trastuzumab and a single chemotherapy agent (paclitaxel) in patients with small, node‐negative, early‐stage breast cancer.29Three additional HER2‐directed therapies have been approved for use in patients with breast cancer: lapatinib, pertuzumab, and ado‐trastuzumab emtansine. In the recent CLEOPATRA (A Phase III, Randomized, Double‐blind, Placebo‐controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2‐positive Metastatic Breast Cancer) trial, the addition of pertuzumab to trastuzumab and chemotherapy led to dramatic improvements in overall and progression‐free survival of patients with metastatic HER2‐positive breast cancer.8 Additionally, pertuzumab is approved for use in the neoadjuvant setting in patients with early breast cancer, and a large trial evaluating its use in the adjuvant setting in combination with trastuzumab has recently reported favorable outcomes.30, 31, 32 The use of lapatinib and ado‐trastuzumab emtansine is restricted to patients with disease progression on trastuzumab in the metastatic setting.33 The addition of lapatinib lead to a 51% decrease in the risk of progression in women with advanced breast cancer that had previously progressed after treatment with trastuzumab.8 In the EMILIA (A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2‐positive Locally Advanced or Metastatic Breast Cancer) trial, ado‐trastuzumab prolonged overall and progression‐free survival of patients with advanced breast cancer who had been previously treated with trastuzumab.9The Cardiac Risks of HER2 Targeted TherapiesThe first signal for cardiotoxicity associated with trastuzumab did not appear until the first phase III trial of the monoclonal antibody in patients with metastatic breast cancer published in 2001. In this study, risk of symptomatic or asymptomatic cardiac dysfunction was highest among individuals who received trastuzumab in combination with anthracycline and cyclophosphamide, followed by those who received the monoclonal antibody in combination with paclitaxel, as compared with either chemotherapeutic regimen alone (incidence, 27% versus 13% versus 8% versus 1%, respectively).5 Additionally, a significant proportion of these patients developed New York Heart Association class III or IV HF (incidence; 16%, 2%, 3%, and 1%, respectively).5 Such differences in the rates of cardiac dysfunction with the use of different chemotherapeutic regimens raised suspicion for a synergism between trastuzumab and anthracycline. Given these unexpectedly high rates of HF, subsequent trials of trastuzumab adopted stringent criteria for patient enrollment excluding those at increased risk for cardiac adverse events. Exclusion criteria have included: history of uncontrolled hypertension, arrhythmias, valvular disease, coronary artery disease, HF, or asymptomatic left ventricular systolic dysfunction. Enrollment of a lower‐risk population, implementation of strict protocols for monitoring of cardiac function, and changes in chemotherapeutic regimens so that anthracyclines were not given concurrently with trastuzumab or were omitted, likely explain the lower rates of cardiotoxicity observed in the subsequent trials of the monoclonal antibody.Rates of severe HF, defined as New York Heart Association class III or IV symptoms, were 0.8% and 4.1% in the placebo and trastuzumab groups of the NSABP trial B‐31.34, 35 Similar rates were reported in the NCCTG trial N9831, whether trastuzumab was administered concomitantly or sequentially with adjuvant chemotherapy.13, 36 Although lower rates were reported in the HERA (Herceptin Adjuvant) trial with administration of the monoclonal antibody after completion of chemotherapy,37 these likely reflect differences in timing of randomization of the trials, with the latter only reporting events that occurred following completion of adjuvant chemotherapy. In the HERA and PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure) trials, longer duration of therapy was associated with higher rates of cardiotoxicity.12, 38, 39 Rates of cardiotoxicity appear to be similar when trastuzumab is added to chemotherapy containing epirubicin as opposed to doxorubicin.40, 41, 42, 43 In a meta‐analysis of adjuvant trastuzumab trials published by the Cochrane group in 2012, there were 135 cases (2.5%) of HF of 5471 patients in the trastuzumab groups compared with 20 cases (0.4%) of 4810 in the control groups, yielding a statistically significant relative risk of 5.1 for development of HF in patients treated with the monoclonal antibody. Additionally, 11.2% of patients in the trastuzumab group had a decline in the LVEF as compared with 5.6% in the control group (relative risk, 1.83; 95% CI, 3.0–8.72).44Rates of cardiotoxicity appear to be significantly lower when trastuzumab is used with regimens that do not include anthracyclines. In the BCIRG006 trial, docetaxel administered with carboplatin and trastuzumab showed similar efficacy to an anthracycline‐based regimen, while having significantly less cardiac adverse events (0.4% symptomatic HF).45 Similar rates of cardiac adverse events were reported in a recent single‐arm study of paclitaxel plus trastuzumab for small, node‐negative, HER2‐positive breast cancer (0.5% symptomatic HF).46The combination of pertuzumab and trastuzumab does not appear to increase the risk of cardiotoxicity beyond that expected with trastuzumab alone.8 Similarly, data suggest that lapatinib has a more‐favorable cardiac risk profile than trastuzumab7, 47 and the combination of both does not appear to be more cardiotoxic than the use of trastuzumab alone.6 Trials of ado‐trastuzumab suggest low rates of cardiotoxicity during follow‐up to date.9A summary of key trastuzumab trials, cardiac monitoring schema used in each trial, and reported rates of cardiotoxicity are provided in Table 2.Table 2. Summary of Key Trastuzumab Trials Including Treatment Protocols, Strategies for Monitoring for Cardiac Dysfunction, and Reported Rates of Cardiac Adverse EventsStudyStudy ArmsMonitoring ProtocolRates of Cardiac Adverse EventsModalityFrequencySlamon et al, NEJM, 20015 1. AC±Tras 2. Pac±Tras Not specifiedNot specified NYHA class III or IV, or death from HF: 1. 3% vs 16% (with Tras) 2. 2% vs 1% (with Tras) Any cardiac dysfunction: 1. 8% vs 27% 2. 1% vs 13% NSABP trial B‐3125, 26, 34, 35, 36AC+Pac±Tras (concurrent with paclitaxel) for 1 yMUGAStudy entry, after completion of doxorubicin and cyclophosphamide, and at 6, 9, and 12 mo after randomization 19% discontinued the medication for cardiac adverse events NYHA class III or IV, or death from HF: 0.8% vs 4.1% (with Tras) NCCTG trial N983113, 25, 34, 36, 48 AC+Pac±Tras: 1. Sequential, for 1 y 2. Concurrent with Pac, for 1 y MUGA or echocardiographyStudy entry, after completion of doxorubicin and cyclophosphamide and at 6, 9, and 12 mo after randomization NYHA class III or IV, or death from HF: 0.3% vs 2.8% (sequential Tras) vs 3.3% (concurrent Tras) HERA trial12, 27, 37, 49 Surgery+adjuvant and/or neoadjuvant chemotherapy (94% anthracycline; 26% taxane)±radiation±sequential Tras for: 1. 2 y 2. 1 y MUGA or echocardiographyAt baseline, 3, 6, 12, 18, 24, 30, 36, and 60 mo after randomization Asymptomatic decrease in LVEF ≥10%, or to 15% decrease in LVEF at any point: 6% vs 3.5% PACS‐0440 1. FEC±sequential Tras for 1 y 2. ET±sequential Tras for 1 y MUGA or echocardiographyAt mo 1, 2, 5, 8, and 12 during trastuzumab administration, and at 6 mo and 5 y after completion of trastuzumab Asymptomatic declined in LVEF >15% to 10%: 17% vs 24.5% (with Tras) Symptomatic HF: 0% vs 1.7% (with Tras) BCIRG00645 1. ACT±concurrent Tras for 1 y 2. TCH MUGA or echocardiographyLVEF assessment after doxorubicin+cyclophosphamide, after the second dose of docetaxel, at the end of chemotherapy, and 3, 12 and 36 mo after randomization Asymptomatic decrease in LVEF >10%: 1. 11.2% vs 18.6% (with Tras) 2. 9.4% Grade 3 or 4 HF (According to NCI criteria): 1. 0.7% vs 2% (with Tras) 2. 0.4% PHARE38, 39Standard chemotherapy (89% received anthracycline and 84% taxane)+6 mo of Tras±6 additional mo of TrasMUGA or echocardiographyEvery 3 mo during the first 2 y and then every 6 mo afterwardsSymptomatic or asymptomatic decrease in LVEF: 1.9% vs 5.7%Tolaney et al, NEJM, 201529, 46Pac+Tras for 1 yMUGA or echocardiographyAt baseline, 12 wk, 6 mo, and 1 ySymptomatic, grade 3 or 4 HF: 0.5% Aymptomatic decline in LVEF that lead to discontinuation of therapy: 3.2%AC indicates doxorubicin+cyclophosphamide; ACT, doxorubicin+cyclophosphamide+docetaxel; HF, heart failure; FEC, fluorouracil, epirubicin, cyclophosphamide; LVEF, left ventricular ejection fraction; MUGA, Multigated Acquisition Scan; NCI, National Cancer Institute; NYHA, New York Heart Association; Pac, paclitaxel; TCH, docetaxel+carboplatin+trastuzumab; Tras, trastuzumab.Risk of Cardiotoxicity Outside of Clinical TrialsExperience outside of clinical trials suggests higher risks of cardiac toxicity associated with trastuzumab compared with that reported in clinical trials.50 In a retrospective analysis of older women with early‐stage breast cancer, compared with patients who did not receive either adjuvant chemotherapy or trastuzumab, use of trastuzumab alone or the combination of trastuzumab and anthracycline were associated with absolute increases in the adjusted incidence rate of HF or cardiomyopathy of 14% and 23.8%.51 Similarly, in a retrospective analysis of women treated for metastatic breast cancer at the MD Anderson where 5% had a history of cardiovascular disease (CVD), 26.5% of those who received HER2 targeted therapies had symptomatic HF, which was reversible in the majority of cases.52 Data from the health maintenance organization Cancer Research Network reported the cumulative incidence of HF at 1 and 5 years was 6.2% and 20.1% for women who received a combination of anthracycline and trastuzumab and 3.6% and 12.1% for women who received trastuzumab alone.50 Such cumulative incidence increased significantly, with increasing age at cancer diagnosis being as high as 40.7% among women who were aged ≥75 years and received a combination of anthracycline and trastuzumab.49 Importantly, there were significant differences in the number of comorbidities of each treatment group, which may reflect treatment selection biases by providers. The increased rates of cardiotoxicity in such observational studies likely reflect the use of trastuzumab in older populations with more‐adverse cardiac risk profiles and reduced cardiac reserve.Risk Factors for Cardiotoxicity Associated With HER2 Targeted TherapyCharacteristics associated with increased risk of cardiotoxicity from trastuzumab use are summarized in Table 3. Past use of anthracyclines, especially at high cumulative doses (>250 mg/m2 of doxorubicin or >600 mg/m2 of epirubicin),53 appears to be the most important risk factor for subsequent cardiac dysfunction.49 In 1 retrospective analysis, past anthracycline use was the only significant predictor of trastuzumab‐induced cardiotoxicity.54 Additionally, concomitant use of anthracycline or short period (3 weeks versus 3 months) between anthracycline use and administration of trastuzumab appear to increase the risk of cardiac adverse events in some studies.14, 55 Given these observations, many cancer centers are now favoring chemotherapeutic regimens that do not contain anthracyclines when HER2 targeted therapies are used.56Table 3. Risk Factors for Cardiotoxicity From HER2 Targeted TherapiesHigh‐Risk CharacteristicsAnthracycline useHeart failureAsymptomatic systolic dysfunction at baseline (LVEF ≤50%)Coronary artery diseaseAtrial fibrillation/flutterHypertensionDiabetes mellitusObesity (BMI ≥30 kg/m2)DyslipidemiaRenal failureAge ≥60 yBMI indicates body mass index; HER2, human epidermal growth factor receptor‐2; LVEF, left ventricular ejection fraction.In the N9831 trial, older age (≥60 years), lower baseline LVEF, and use of antihypertensive medications were associated with increased risk of cardiotoxicity.48 In a late follow‐up of the NSABP B‐31 trial, older age and lower baseline LVEF (50–54%) were associated with trastuzumab‐induced cardiotoxicity.11 Risk of cardiotoxicity appears to increase progressively with increasing age in several studies.11, 48, 50, 57 Higher body mass index has also been shown to significantly increase the odds of cardiac dysfunction associated with anthracycline or sequential treatment with anthracycline and trastuzumab. In a meta‐analysis of 15 studies, a body mass index >25 or >30 kg/m2 was associated with 1.32 (95% CI, 1.06–1.80) and 1.47 (95% CI, 0.95–2.28) times the odds of cardiotoxicity compared with a normal body mass index.58 Cardiac risk scores have been developed to predict the risk of cardiotoxicity associated with trastuzumab, including several risk factors such as age, hypertension, diabetes mellitus, coronary artery disease, atrial fibrillation or flutter, renal dysfunction, and use of adjuvant chemotherapy.11, 57 However, lack of prospective independent validation limits the use of such tools. Importantly, the risk associated with trastuzumab use in patients with pre‐existing HF and systolic dysfunction is largely unknown.Reports on the use of trastuzumab outside of clinical trials, in the "real‐world" setting, have suggested similar risk factors for cardiotoxicity. Among older women exposed to trastuzumab, factors associated with a higher risk of HF included black race, history of CVD, diabetes mellitus, hypertension, and renal failure.51 In the MD Anderson study, lower baseline LVEF and older age (≥60 years) were associated with increased risk of cardiotoxicity.52PathophysiologyHER2 belongs to a family of tyrosine kinase transmembrane receptors (ErbB1‐4) that regulate growth, differentiation, and survival of cells. After ligand binding, ErbB receptors form homodimers or heterodimers, which activate tyrosine kinase function and recruit downstream effectors. Amplification or overexpression of the ErbB2 gene occurs in ≈20% of breast cancer cases and is oncogenic.59 In tumor cells, trastuzumab binds to the subdomain IV of the extracellular domain of HER2, which blocks HER2 cleavage, stimulating antibody‐dependent cellular cytotoxicity and inhibiting HER2‐mediated mitogenic signaling.60The mechanisms underlying cardiotoxicity from use of trastuzumab are incompletely understood. It has been long known that ErbB2 is expressed in embryonic hearts and has a critical role in cardiac development61 with relatively low expression in adult cardiomyocytes. Subsequent to the clinical trials showing cardiotoxicity from trastuzumab use, emerging research found that HER2 receptors expressed in the membranes of adult cardiomyocytes have an important role in transmitting growth and survival signals.62 In response to the ligand, neuregulin‐1, ErbB2 forms heterodimers that activate cell hypertrophy and survival pathways through activation of the phosphoinositide 3‐kinase and protein kinase A pathways as well as the mitogen‐activated protein kinase cascade.60, 63 In murine models, deletion of ErbB2 leads to development of spontaneous dilated cardiomyopathy and makes these mice more sensitive to triggers of cardiomyopathy such as pressure overload and anthracyclines.64, 65 Taken together, this evidence suggests an important role of ErbB2 in the maintenance of normal cardiac structure and function, especially under stress conditions.A major risk factor for cardiotoxicity associated with trastuzumab is use of anthracycline‐containing chemotherapy. Given the important protective role of ErbB2 in stress conditions, a "2‐hit" model has been postulated as being responsible for the synergism between anthracycline and trastuzumab in causing cardiac dysfunction. In this model, anthracyclines activate cardiac stress pathways through several mechanisms that include generation of reactive oxygen species and oxidative damage of cardiomyocytes,66 and inhibition of topoisomerase 2β leading to double‐stranded breaks in DNA.67 Concomitant ErbB2 inhibition disrupts cardioprotective and prosurvival signaling, diminishing the heart's ability to tolerate noxious stimuli and recover.68, 69, 70, 71 Indeed, preclinical studies showed that activation of ErbB2 by recombinant neuregulin‐1 protected cardiomyocytes from the myofibrillar disarray caused by anthracyclines,72 whereas administration of an ErbB2 antibody increased susceptibility of myofilaments to doxorubicin.73HER2 targeted therapies currently available have different mechanisms of action that might underlie the variable risks of cardiotoxicity. Ado‐trastuzumab emtansine is a combination of trastuzumab with a cytotoxic agent that allows intracellular drug delivery that is specific to HER2‐overexpressing cells and is therefore associated with low rates of cardiotoxicity.9 Pertuzumab is a similar antibody to trastuzumab, but binds to a different HER2 epitope, subdomain II. After binding, it prevents its dimerization with HER3, which causes similar activation of antibody‐dependent cellular cytotoxicity and prevention of HER2 downstream signaling.74 Because trastuzumab and pertuzumab bind to different receptor subdomains, they have complementary mechanisms of action and clinical synergism without increased cardiotoxicity.8, 75 Lapatinib is an oral small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (HER1). Clinical studies have not demonstrated significant cardiotoxicity associated with use of lapatinib.7, 47Monitoring for Cardiac Dysfunction During HER2‐Targeted TherapyThe ideal modality, frequency, and duration of monitoring for cardiac dysfunction during HER2 targeted therapy are unknown. Table 4 summarizes the published recommendations by major societies.17, 20, 53, 76, 77 Clinical trials have used various monitoring protocols, including echocardiography or multigated acquisition (MUGA) scan, none of which has been prospectively validated. Despite that, routine cardiac monitoring with either echocardiogram or MUGA is recommended in the labeling of trastuzumab.Table 4. Recommendations for Surveillance for Cardiac Dysfunction According to Major SocietiesSocietyModality of ChoiceFrequency of MonitoringAmerican Society of Clinical Oncology (ASCO)53Echocardiography; MUGA or MRI if echocardiography is not available, with MRI preferred over MUGAStrain imaging and biomarkers (BNP, troponin) could be considered in conjunction with routine echocardiography.Frequency of surveillance should be determined by the provider based on patient's clinical characteristics.American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI)17Echocardiography, ideally incorporating 3‐dimensional imaging and global longitudinal strainConsider measuring high‐sensitivity troponin in conjunction with imagingEvery 3 mo during therapy.European Society for Medical Oncology (ESMO)77Echocardiography or MUGAMay consider MRI as an alternative Baseline, 3, 6, 9, 12, and 18 months after initiation of treatment. For patients with metastatic disease, obtain baseline measurement and only repeat if patient develops symptoms of HF. European Society of Cardiology (ESC)20Echocardiography including 3‐dimensional assessment of LVEF and global longitudinal strainMUGA and MRI may be considered as alternatives.Baseline, every 3 mo during therapy, and once after completion.Canadian cardiovascular Society (CCS)76Echocardiography including 3‐dimensional imaging and strain; MUGA and MRI as alternativesConsider concomitant measurement of biomarkers (BNP, troponin)No specific recommendation.Trastuzumab LabelingEchocardiography or MUGABaseline (immediately preceding initiation of trastuzumab), every 3 mo during and upon completion of therapy, and at every 6 mo for at least 2 y following completion of therapy.BNP indicates brain natriuretic peptide; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multigated acquisition.Echocardiography is currently recommended as the modality of choice for routine monitoring and detection of cardiac dysfunction.17, 53 Volumetric assessment of LVEF using 3‐dimentional echocardiography provides a more‐accurate and reproducible measurement of LVEF than 2‐dimentional echocardiography; however, this method is not available at all centers. The biplane method of disks (modified Simpson's rule) is recommended for calculation of LVEF when 2‐dimensional echocardiography is the modality of choice.17 Assessment of LVEF by MUGA has higher accuracy and reproducibility than 2‐dimensional echocardiography.78 Limitations to the routine use of MUGA include patient exposure to radiation, lack of detailed information on right ventricular function, atrial size, valvular, or pericardial disease. Cardiac magnetic resonance is the references standard in the evaluation of cardiac volumes, mass, and function, with high inter‐ and intraobserver reproducibility.79, 80 However, its use is limited because of lesser availability and elevated operational costs. This method can be particularly helpful when echocardiographic images are suboptimal, or when LVEF assessed by other methods is borderline and discontinuation of cancer therapy is being entertained.17, 81A growing body of research is investigating methods for early detection of subclinical cardiotoxicity that would allow for early implementation of therapies to prevent overt cardiac dysfunction and HF. Assessment of LVEF alone by either method appears insensitive to detect subclinical changes and predict subsequent cardiotoxicity. Decreases in myocardial deformation (strain) precede changes in LVEF and have been consistently predictive of cardiac dysfunction from trastuzumab.82, 83 The American Society of Echocardiography recommends global longitudinal strain measured by speckle tracking echocardiography as the modality of choice for detection of subclinical myocardial changes and risk prediction.17 A decrease of <8% from baseline is likely insignificant, whereas a relative drop of more than 15% is likely pathological.82 Importantly, there have been no studies assessing whether interventions based on changes in strain alter outcomes.The prognostic value of several cardiac biomarkers has also been evaluated, yielding conflicting results. Cardiac troponins are well‐established markers of myocardial injury and appear to correlate best with incident cardiac dysfunction
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