Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC g59GFsyXm9TSCL8zn6GBrJw S0066-782X2016004000040 S0066-782X2016005016102 10.5935/abc.20160084 Original Articles A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients Matos Erika 1 Jug Borut 2 Blagus Rok 3 Zakotnik Branko 1 Institute of Oncology Ljubljana Division of Medical Oncology Slovenia Institute of Oncology Ljubljana - Division of Medical Oncology - Slovenia University Medical Centre Ljubljana Department of Vascular Diseases Slovenia University Medical Centre Ljubljana - Department of Vascular Diseases - Slovenia University of Ljubljana Institute for Biostatistics and Medical Informatics Slovenia Institute for Biostatistics and Medical Informatics - University of Ljubljana - Slovenia Mailing Address: Erika Matos, Institute of Oncology Ljubljana - Zaloska, 2. Postal Code 1000, Moste, Ljubljana - Slovenia. E-mail: ematos@onko-i.si

Author contributions

Conception and design of the research and Critical revision of the manuscript for intellectual content: Matos E, Jug B, Blagus R, Zakotnik B; Acquisition of data, Analysis and interpretation of the data and Writing of the manuscript: Matos E, Jug B, Blagus R; Obtaining financing: Matos E.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 10 06 2016 07 2016 107 1 40 47 23 09 2015 19 10 2015 23 02 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background:

Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended.

 Objectives:

The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction.

 Methods:

In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF).

 Results:

92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant.

 Conclusions:

Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant.

 Keywords: Trastuzumab / adverse effects Trastuzumab / therapeutic use Breast Neoplasms / therapy Cardiotoxicity Cohort Studies Introduction

Adjuvant trastuzumab significantly reduces mortality and the risk of relapse in human epidermal growth factor receptor-2 (HER-2) positive breast cancer patients.1-6 However, trastuzumab therapy is associated with significant cardiotoxicity and trastuzumab-related cardiac dysfunction has been recognized as an important side effect and the main reason for premature therapy discontinuation.1,7

High blood pressure (HBP), age over 50 years, increased body mass index (BMI), exposure to anthracyclines and borderline baseline left ventricular ejection fraction (LVEF) are known risk factors for trastuzumab-related cardiotoxicity, derived from randomized adjuvant trials.8 Regarding the other possible predictive factors for trastuzumab-related cardiotoxicity, such as N-terminal pro-brain natriuretic peptide (NT-proBNP)9-11 and some echocardiographic measurements, like left ventricular end-systolic volume (LVESV), peak systolic wave velocity at septal mitral position in tissue Doppler imaging (Sm wave), early diastolic wave velocity at septal mitral position in tissue Doppler imaging (Em wave), left atrial area (LA) and E to A wave velocity ratio in mitral inflow pulse Doppler (E/A), either evidence is weak or have not been studied extensively.12-15 It is known that deterioration of LVEF is a relatively late stage of ventricular dysfunction, as the myocardium has exhausted its considerable functional reserve. However, diastolic impairment of left ventricle occurs and can be echocardiographically demonstrated before the fall in LVEF in different pathologies, like anthracycline-mediated cardiotoxicity, coronary artery disease, diabetes, or HBP. Therefore, to demonstrate the earliest and subtle cardiac changes during adjuvant trastuzumab treatment looking at diastolic function seems reasonable. The currently available data in this patient population are scarce and not uniform.15-18 Natriuretic peptides, released during hemodynamic stress, are widely used in the early detection of heart failure and have already been shown to be sensitive markers of left ventricular dysfunction and powerful markers of morbidity and mortality in heart failure setting. Increased levels of NT-proBNP have also been detected in some studies evaluating cardiotoxicity due to anthracycline treatment. However, the ability of NT-proBNP to predict early cardiac dysfunction in trastuzumab-treated patients remains unconfirmed with most studies yielding disappointing results.11,13,19

Previous studies reported that changes in serial echocardiographic measurements (especially in the first three months after therapy initiation) predict trastuzumab-related cardiac dysfunction. However, they did not focus on possible predictive value of baseline measurements derived by two-dimensional Doppler echocardiography and pulse wave tissue Doppler imaging.13,20 Studies have demonstrated that two-dimensional echocardiographic techniques are reliable in the detection of difference in LVEF close to 10% and therefore can be used as an indicator of cardiotoxicity in the absence of symptoms.21

In the present prospective study, we assessed age, HBP, BMI, LVEF, LVESV, Sm and Em wave, LA, E/A and NT-proBNP level as possible predictors of trastuzumab-related cardiac dysfunction in HER-2 positive breast cancer patients undergoing post-anthracycline adjuvant trastuzumab therapy.

 Methods

This was a prospective cohort study with serial clinical, echocardiographic and neurohumoral assessment in HER-2 positive breast cancer patients undergoing adjuvant therapy with trastuzumab at the Institute of Oncology in Ljubljana, Slovenia, from October 2011 to November 2013. The study was approved by the National Ethics Committee (No. 110/04/10) and all participants gave informed consent prior to study entry.

Patients were considered eligible if baseline systolic cardiac function was normal (LVEF > 50%). All patients were pretreated with anthracycline-based adjuvant chemotherapy (3-4 cycles). Besides anthracyclines, taxane-based adjuvant chemotherapy was given according to current international guidelines, concomitantly with trastuzumab.22 Patients were treated with trastuzumab for one year, altogether 18 infusions every three weeks. Radiotherapy to the breast or mammary region was delivered after adjuvant chemotherapy, when on treatment with adjuvant trastuzumab, if indicated according to current clinical guidelines.22

At baseline, and after 4, 8 and 12 months during trastuzumab treatment, clinical examination and comprehensive transthoracic echocardiography were performed, and plasma levels of NT-proBNP were determined.

Patients underwent thorough cardiovascular evaluation and were diagnosed with heart failure in the presence of signs and symptoms, and structural heart disease according to the European Society of Cardiology guidelines.23

Regarding co-morbidities, we were specially focused on HBP, dyslipidaemia and diabetes mellitus. High blood pressure was defined as history of arterial hypertension with appropriate antihypertensive medical management, or as a > 140 mmHg systolic and/or > 90 mmHg diastolic blood pressure on two separate measurements. Dyslipidaemia and diabetes mellitus were defined as history of either disease with appropriate medical management, or as laboratory findings (LDL-C > 3, TC > 5 mmol/L or fasting blood glucose level > 7 mmol/L, respectively). Body mass index was calculated based on the following formula: body weight in kilograms divided by height in meters squared. Coronary artery disease was defined as history of myocardial infarction or revascularization procedures, presence of coronary stenosis on invasive or computed tomographic angiography or presence of ischemia on myocardial perfusion imaging. Valvulopathy was defined as a history of valvular repair/replacement, or by significant (> mild) structural or functional valve impairment on cardiac imaging.

Transthoracic echocardiography was performed with a phased-array imaging system equipped with a transducer with second harmonics capability. Images were obtained in the parasternal long- and short-axis and apical views, with the subject lying in the left lateral position. Tissue Doppler imaging, standard M-mode, two-dimensional Doppler and pulse wave tissue Doppler recordings were acquired. All measurements were made according to the recommendations of the American Society of Echocardiography (ASE) and the European Association of Echocardiography (EAE).18,24 Each assessment was analysed for at least three consecutive cycles (or at least five in any rhythm other than regular sinus rhythm), avoiding post-ectopic beats. Left ventricular ejection fraction was assessed on two-dimensional apical four- and two-chamber views, using the biplane Simpson method. If biplane apical views were not available at baseline and/or follow-up, the analysis was conducted using the apical four-chamber view. No echocardiographic measurement was excluded from the study because of poor image quality. Transmitral pulsed Doppler was recorded in the apical four-chamber view in order to measure early (E) and atrial (A) peak velocities (m/s), peak velocity E/A ratio and E velocity deceleration time (ms). Pulsed tissue Doppler was performed at the level of the lateral mitral annulus and septal mitral annulus in order to measure peak systolic (Sm), and early (Em) and late (Am) diastolic velocities. All tissue Doppler parameters were obtained as the average of the values of the lateral and septal mitral annulus. The ratio of Doppler transmitral E peak velocity and average Em peak velocity (lateral Em + septal Em/2) was calculated as an index of left ventricular filling pressure.

All echocardiographic evaluations were performed by one experienced cardiologist in one institution. Method reproducibility was assessed at the echocardiography laboratory using 20 recordings analysed twice (intra-reader variability); intra-class correlation coefficient was good (for LVEF intra-reader, 0.97). Method reliability was assessed by comparing LVEF derived from echocardiography with multigated acquisition scan (MUGA) in 20 patients; inter-class correlation coefficient was good (for LVEF inter-method, 0.87).

Serum levels of NT-proBNP were determined by electrochemiluminescence immunoassay (ECLIA) on Cobas e411 analyser (Roche Diagnostics GmbH, Mannheim, Germany).

Trastuzumab-related cardiac dysfunction was defined as clinical signs and/or symptoms of heart failure or a decline in LVEF of at least 10% from baseline in asymptomatic patients throughout the adjuvant trastuzumab treatment.3,16

According to the literature, the expected incidence of LVEF decline of 10% or more in patients on trastuzumab adjuvant therapy was 15%.16 For a desired probability level of 0.05 and statistical power of 0.80 to detect a 10% decline in the range of normal LVEF values (70% to 60%), we needed 12 patients with this feature, thus we have calculated that we needed to include 90 patients.

Normally distributed continuous variables were described as mean ± standard deviation (SD), non-normally distributed continuous variables were described as median and interquartile range and categorical variables were described as numbers and/or percentages. Baseline characteristics and echocardiographic parameters of patients with and without trastuzumab-related cardiac dysfunction at follow-up were compared with logistic regression; odds ratios (OR) and their 95% confidence intervals (CI) are reported. Multiple logistic regression analysis was performed to determine the independent predictors for a decline in LVEF of at least 10% from baseline using the significant univariate predictors. A two-tailed p value < 0.05 was considered significant. Goodness-of-fit of the models was estimated with Akaike information criterion (AIC)25 and Hosmer-Lemeshow goodness-of-fit test;26 none of the models reported in this paper exhibited a statistically significant misfit. Analyses were performed using IBM SPSS v.22 software and R language for statistical computing (R v.3.0.3.).27

Results

A total of 92 patients gave informed consent and were included. None of the patients who gave informed consent was lost to follow-up and none of the patients died. One patient was excluded from analysis because her baseline echocardiography (post-anthracycline) suggested right ventricular overload and suspected pulmonary embolism, which was confirmed by CT angiography. All the remaining patients received the whole one year of adjuvant trastuzumab by plan. There were no temporary discontinuations from the therapy. All patients were female with a mean age of 53.6 years (range 35.0-75.5). All were pretreated with anthracyclines (3 or 4 cycles of epidoxorubicin 90 to 100 mg/m2 or 4 cycles of doxorubicin 60 mg/m2) and 82 (89.1%) patients received also taxane-based chemotherapy. In total, there were 288 echocardiographic measurements and 297 NT-proBNP measurements. Left ventricular ejection fraction decline has been determined for 78 patients, who have had both, baseline and at least one additional measurement. Certain echocardiographic parameters could not be assessed at baseline for all patients.

Sixty-five (70.7%) patients had radiotherapy and 60 (65.2%) patients had adjuvant endocrine therapy concomitantly with trastuzumab. Co-morbidities were recorded from patients' charts: HBP in 27 (29.3%) patients, diabetes mellitus in 4 (4.3%) patients, and dyslipidaemia in 9 (9.8%) patients. There were 25 patients treated for HBP before study entry. Out of them, 12 patients were treated with monotherapy: ACE inhibitor (5 patients), angiotensin receptor blocker (2 patients), beta-blocker (4 patients), and calcium channel blocker (1 patient). In the remaining 13 patients, HBP was treated with the combination of two or three drugs, one being most commonly diuretic, and the other: ACE inhibitor (5 patients), angiotensin receptor blocker (3 patients), ACE inhibitor and beta-blocker (2 patients), ACE inhibitor and calcium channel blocker (2 patients). One patient was receiving inappropriate combination of ACE inhibitor and angiotensin receptor blocker and this has been modified during the treatment. In 2 patients with known history of HBP (both of them were refusing treatment before), therapy with ACE inhibitor was introduced. Detailed patients and treatment characteristics are summarized in Table 1. None of the patients developed symptomatic heart failure during follow-up; however, echocardiographic assessment revealed a decline of LVEF (≥ 10%) during treatment in 22 (23,9%) patients. Out of these, 11 (50%) experienced a decline during the first 4 months since baseline, 7 (31.8%) between 4 and 8 months since baseline, and 4 (18.2%) between 8 and 12 months since baseline (Figure 1). All these patients were additionally referred to a cardiologist for follow-up during treatment.

Patients and treatment characteristics
No. 92 100%
Age / years
Mean (SD) 53.6 (9.0)
Range 35.0-75.5
Breast cancer side
Left 46 50%
Right 46 50%
BMI / kg/m2
Mean (SD) 26.1 (4.9)
Range 17.9-40.1
No. of patients with BMI 25-29.9 kg/m2 30 32.6%
No. of patients with BMI ≥ 30 kg/m2 16 17.4%
Co-morbidities
HBP 27 29.3%
DM 4 4.3%
Dyslipidaemia 9 9.8%
Treatment
Cumulative dose of anthracycline
Doxorubicin (mean) / mg/m2 240 10.9%
Epidoxorubicin (mean) / mg/m2 304 89.1%
RT 65 70.7%
ET 60 65.2%
Taxane-based chemotherapy 82 89.1%

BMI: body mass index; HBP: high blood pressure; DM: diabetes mellitus; RT: radiotherapy; ET: endocrine therapy; SD: standard deviation.

Incidence of cardiotoxicity during trastuzumab treatment.

In the univariate model only baseline LVEF and LVESV were found to predict significant decline in LVEF of 10% or more during adjuvant trastuzumab treatment (Table 2). The mean baseline LVEF was 70.7% and 64.8% for those with and those without trastuzumab-related cardiac dysfunction. The difference for LVEF as well as for LVESV was statistically significant; in multivariate analysis, only LVEF retained statistical significance (Table 3). There was no significant impact of age, BMI, HBP, baseline NT-proBNP level between patients with and without significant decline in LVEF. None of the Doppler ultrasound and tissue Doppler derived parameters of systolic or diastolic function approached statistical significance (Table 2).

Baseline characteristics and echocardiographic parameters of patients with and without trastuzumab-related cardiac dysfunction at follow-up – univariate model
Parameter All patients LVEF decline ≥ 10% [No.] LVEF decline < 10% [No.] OR 95% CI p
Age (years) 53.6 ± 9.0 53.2 ± 9.4 [22] 52.6 ± 9.0 [56] 1.008 0.954 – 1.065 0.7753
BMI (kg/m2) 26.1 ± 4.9 25.2 ± 5.2 [22] 26.5 ± 5.4 [56] 1.001 0.902 – 1.112 0.9805
LVESV (ml) 21.8 ± 8.0 17.8 ± 5.0 [22] 22.6 ± 6.6 [56] 0.858 0.774 – 0.950 0.0033
LVEF (%) 66.3 ± 5.8 70.7 ± 4.4 [22] 64.8 ± 5.5 [56] 1.284 1.128 – 1.462 0.0002
Sm (cm/s) 8.5 ± 1.8 8.1 ± 1.9 [22] 8.6 ± 1.8 [54] 0.945 0.717 – 1.242 0.6847
NT-proBNP (pg/ml) 79 (45-133) 113 (61–165) [22] 83 (53–114) [54] 1.003 0.996 – 1.009 0.3920
Em (cm/s) 8.5 ± 2.7 8.4 ± 2.5 [22] 8.5 ± 2.8 [54] 1.000 0.834 – 1.200 0.9992
LA (cm2) 15.8 ± 3.4 15.6 ± 2.9 [22] 16.1 ± 3.1 [51] 0.945 0.800 – 1.116 0.5067
E/A 1.0 ± 0.3 1.0 ± 0.3 [22] 0.99 ± 0.2 [52] 1.194 0.226 – 6.299 0.8349
HBP (%)* 27/92 (29.3%) 7/17 (41.1%) (22] 20/75 (26.7%) [56] 1.892 0.672 – 5.329 0.2273

Prevalence of hypertension is presented as number (proportion) of patients. NT-proBNP levels are presented as median and interquartile range. All other data are presented as mean ± SD.

LVEF: left ventricular ejection fraction(Simpson biplane method); BMI: body mass index; LVESV: left ventricular end systolic volume; Sm: peak systolic wave velocity at septal mitral position in tissue Doppler imaging; Em: early diastolic wave velocity at septal mitral position in tissue Doppler imaging; LA: left atrial area; E/A: E to A wave velocity ratio in mitral inflow pulse Doppler; HBP: high blood pressure; NT-proBNP: N-terminal pro-brain natriuretic peptide; OR: odds ratio; No.: number of patients.

 Multivariate predictors of trastuzumab-related cardiac dysfunction
Parameter Estimate SE OR 95% CI p
Intercept -15.0019 5.8521 0.000 0.000 – 0.029 0.0104
LVEF (%l) 0.2207 0.0755 1.247 1.075 – 1.446 0.0035
LVESV (ml) -0.0422 0.0589 0.959 0.854 – 1.076 0.4739

LVEF: left ventricular ejection fraction; LVESV: left ventricular end systolic volume; SE: Standard Error; OR: odds ratio.

 Discussion

In the present study, we found that classic risk factors (age, HBP, BMI), NT-proBNP, echocardiographic measurements (Sm and Em wave, LA, E/A) are not predictors of trastuzumab-related left ventricular dysfunction in HER-2 positive breast cancer patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. Patients with higher baseline LVEF values (70.7% vs 64.8%) were found to have a statistically significant but clinically irrelevant LVEF decline of 10% or more during treatment.

The age, incidence of HBP and BMI of our patients were comparable to reported adjuvant studies.2,4,5 In our study patients' age was not found as an important predictive factor, which is in contrary to the results of both North American prospective randomized clinical studies.2,5 On the other hand, there are studies that could not confirm its predictive value, among them the HERA study.4 In addition, some studies including patients from daily clinical practice could not demonstrate the impact of patients' age in predicting cardiac dysfunction when on trastuzumab adjuvant treatment.14,28 High blood pressure, the most extensively studied co-morbidity in this patient population, is a generally accepted risk factor and its importance was confirmed in several studies.5,29 But the results are not uniform and there are also studies that could, like ours, not demonstrate its predictive role.2,30,31 In the HERA study,2 BMI was found to be an important risk factor, however this was not demonstrated or not extensively studied in another two randomized studies.5,29 In our study, BMI did not emerge as important.

The majority of studies aimed to demonstrate the utility of NT-proBNP level in predicting trastuzumab cardiotoxicity were disappointing.10,19,32 However, due to its wide availability and low cost, NT-proBNP is still very attractive and a matter of several studies. In our study, it was not found useful to identify patients at risk for cardiac dysfunction. All patients had normal baseline levels, and, during one year of trastuzumab treatment, in the majority of patients NT-proBNP level remained within normal level (less than 300 pg/mL). No patient showed a progressive increase. Nevertheless, we will probably have to wait for the results of clinical study CATS (Cardiotoxicity of Adjuvant Trastuzumab) to get more firm data on predictive value of this serum biomarker.33

Of the echocardiographic measurements, the diagnostic and predictive value of tissue Doppler imaging and its role in detecting cardiotoxicity in patients on trastuzumab therapy has so far not been studied extensively. In our study, we did not identify baseline peak systolic tissue Doppler velocity (Sm wave) as an important predictive factor of trastuzumab-related cardiotoxicity. Tissue Doppler velocities represent an easy measurable and reproducible alternative to LVEF to prediction early cardiac dysfunction in different cardiac diseases.34 Measurements are highly reproducible and reliable, and also less prone to intra- and inter-observer variability than any two-dimensional echocardiographic assessment of LVEF.35 Moreover, Sm wave velocity decline early in the course of trastuzumab therapy has been proposed as a marker of trastuzumab-related cardiac dysfunction that can be detected before a hemodynamic increase of cardiac volumes or a decrease in LVEF.13,20 In our study, we could also not demonstrate any baseline diastolic parameter (namely, LA area, Em wave and E/A ratio) as statistically significant predictive factors for trastuzumab-related cardiotoxicity. It is well known that diastolic dysfunction precedes systolic dysfunction, but may be present alone.34 Previous studies have yielded inconclusive and mixed results about a possible role of diastolic dysfunction as a predictor of anthracycline-related cardiotoxicity.13,36 Consequently, Doppler-derived diastolic indices are not deemed useful for early detection of anthracycline-related heart failure.18 With trastuzumab, Cochet et al.16 have reported that diastolic dysfunction (assessed by MUGA-derived time to peak rate of left ventricular filling) independently predicts trastuzumab-mediated cardiotoxicity. Conversely, in a small study with 42 patients on adjuvant trastuzumab treatment, early decline of tissue Doppler derived diastolic indices failed to predict trastuzumab-related cardiac dysfunction.13 Diastolic dysfunction indeed represents an early stage in the process of cardiac damage; it remains however present in late (systolic) stages as well. In our study, based on baseline diastolic function parameters, we could not identify patients with a LVEF decline of at least 10% from baseline during one year of adjuvant trastuzumab treatment. This is probably because all baseline values were in high-normal ranges. Due to enormous ability of cardiac reserves that have not been exhausted after a relative low cumulative dose of anthracyclines (patients in our study received from 300 to 400 mg/m2 epidoxorubicin or 240 mg/m2 doxorubicin), adaptive response has been able to fully compensate for toxicities and therefore over shaded predictive impact of otherwise very sensitive diastolic dysfunction indices. Although in our study we could not identify predictive value of any tissue Doppler derived measurements of either systolic or diastolic dysfunction, it is generally believed that serial measurements of tissue Doppler echocardiographic parameters (namely, Sm wave) could represent a feasible and reliable additional tool for early detection of threatening LVEF decline in patients receiving cardiotoxic oncologic therapy.18

In our study, only baseline systolic function emerged as the only independent statistically significant predictor of trastuzumab-related cardiac dysfunction. However, unexpected and contrary to the results of some previous studies with different cardiotoxicity definitions,2,4,5 we found that the risk was proportional and not inversely proportional to the patient's baseline LVEF; i.e. the chance of a LVEF decline ≥ 10% was significantly higher in patients with a higher baseline LVEF and the finding is therefore clinically not important. The average baseline LVEF of patients included in our study was high: 70.7% for those with a decline of 10% or more and 64.8% for those without it. In the randomized adjuvant clinical trials that used different cardiotoxicity definitions, a decline of 10% or 15% from baseline to below 50% or 55% was regarded as a cardiac event in asymptomatic patients. Looking at these trials, in all HERA37,38 and both American trials2,5 baseline LVEF was found as an important inversely proportional predictive factor for trastuzumab-related cardiotoxicity. In the American trial, patients with baseline LVEF ranging from 50% to 54% had 12-times higher risk compared to those with LVEF of 65% or more.29 Nevertheless, not all studies have shown baseline LVEF level to be important. In one of the first and biggest studies performed by Cardiac Review and Evaluation Committee including over 100 patients with proven trastuzumab-related cardiac dysfunction, baseline LVEF was not recognized as important predictor.39 Our patients, apart from HBP, had no cardiovascular disease, had normal heart function and were exposed to low doses of cardiotoxic anthracyclines, having, therefore, preserved high-normal LVEF. One possible explanation for an unexpected significantly higher chance of LVEF decline in patients with higher baseline LVEF could be in recruitment of compensatory mechanisms. It is well known that cardiomyocytes have a tremendous ability to preserve sufficient cardiac output. In patients with really high baseline LVEF, the LVEF decline of 10% of cardiac output is probably not compromised at all and adaptive response is activated with a delay. On the contrary, in patients with lower baseline LVEF, but still within normal range, adaptive response is activated earlier, thus further decline is opposed. The other possible explanation is that 10 percentage points represent a relatively higher value in patients with lower than higher baseline LVEF measurement. Nevertheless, according to the results of our study, a LVEF decline of ≥ 10% in patients with high-normal baseline level, although statistically significant, is not clinically relevant and predictive of cardiac dysfunction.

We have identified some limitations in our study. Our study employed standard transthoracic two-dimensional echocardiographic assessment. According to recommendations of ASE and EAE,18 echocardiography is suitable for serial evaluation of left ventricular structure and function in adult patients during and after cancer therapy; nevertheless, applying advanced echocardiographic methods, such as strain and strain-rate or the use of three-dimensional echocardiography, would strengthen the scientific accuracy of our results. However, standard echocardiography accompanied by tissue Doppler imaging used in our study is readily available in the clinical setting. Thus, our results provide wider applicability into the current clinical practice of cardio-oncology surveillance of breast cancer patients on adjuvant trastuzumab therapy. Additionally, our study was powered to detect a significant decline in LVEF, but not new-onset heart failure, which has almost a 5-fold lower incidence than asymptomatic cardiac dysfunction.1 We did not detect any case of new-onset heart failure; therefore it should be emphasized that this may be simply due to a small sample size.

 Conclusions

Identifying women at risk of developing trastuzumab-related cardiac dysfunction when starting adjuvant trastuzumab treatment continues to be an ongoing challenge. In this prospective cohort study, we have found that age, HBP, BMI, baseline LVEF, LVESV, Sm and Em wave, LA, E/A and NT-proBNP are not predictors of trastuzumab-related cardiac dysfunction in HER-2 positive breast cancer patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. In these patients, we found a high-normal baseline echocardiographically determined LVEF. A LVEF decline of ≥ 10% in patients with high-normal baseline level although statistically significant is not clinically relevant and predictive of cardiac dysfunction.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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Matos E Zakotnik B Kuhar CG Effectiveness of adjuvant trastuzumab in daily clinical practice Radiol Oncol 2014 48 4 403 407 7 Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009;117(2):357-64. Wadhwa D Fallah-Rad N Grenier D Krahn M Fang T Ahmadie R Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study Breast Cancer Res Treat 2009 117 2 357 364 8 Harbeck N, Ewer MS, De Laurentiis M, Suter TM, Ewer SM. Cardiovascular complications of conventional and targeted adjuvant breast cancer therapy. Ann Oncol. 2011;22(6):1250-8. Harbeck N Ewer MS De Laurentiis M Suter TM Ewer SM Cardiovascular complications of conventional and targeted adjuvant breast cancer therapy Ann Oncol 2011 22 6 1250 1258 9 Kutteh LA, Hobday T, Jaffe A, LaPlant B, Hillman D, Kaufman P, et al. A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer. [Abstract]. J Clin Oncol. 2007;185(20 Suppl):579. Kutteh LA Hobday T Jaffe A LaPlant B Hillman D Kaufman P A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer. [Abstract] J Clin Oncol 2007 185 20 Suppl 579 579 10 Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63(8):809-16. Ky B Putt M Sawaya H French B Januzzi JL Jr Sebag IA Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab J Am Coll Cardiol 2014 63 8 809 816 11 Goel S, Simes RJ, Beith JM. Exploratory analysis of cardiac biomarkers in women with normal cardiac function receiving trastuzumab for breast cancer. Asia Pac J Clin Oncol. 2011;7(3):276-80. Goel S Simes RJ Beith JM Exploratory analysis of cardiac biomarkers in women with normal cardiac function receiving trastuzumab for breast cancer Asia Pac J Clin Oncol 2011 7 3 276 280 12 Di Lisi D, Bonura F, Macaione F, Peritore A, Meschisi M, Cuttitta F, et al. Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. Anticancer Drugs. 2011;22(5):468-72. Di Lisi D Bonura F Macaione F Peritore A Meschisi M Cuttitta F Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction Anticancer Drugs 2011 22 5 468 472 13 Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, Fang T, et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol. 2011;57(22):2263-70. Fallah-Rad N Walker JR Wassef A Lytwyn M Bohonis S Fang T The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy J Am Coll Cardiol 2011 57 22 2263 2270 14 Piotrowski G, Gawor R, Bourge RC, Stasiak A, Potemski P, Gawor Z, et al. Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study. Pharmacol Res. 2013;78:41-8. Piotrowski G Gawor R Bourge RC Stasiak A Potemski P Gawor Z Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study Pharmacol Res 2013 78 41 48 15 Dores H, Abecasis J, Correia MJ, Gandara F, Fonseca C, Azevedo J, et al. Detection of early sub-clinical trastuzumab-induced cardiotoxicity in breast cancer patients. Arq Bras Cardiol. 2013;100(4):328-32. Dores H Abecasis J Correia MJ Gandara F Fonseca C Azevedo J Detection of early sub-clinical trastuzumab-induced cardiotoxicity in breast cancer patients Arq Bras Cardiol 2013 100 4 328 332 16 Cochet A, Quilichini G, Dygai-Cochet I, Touzery C, Toubeau M, Berriolo-Riedinger A, et al. Baseline diastolic dysfunction as a predictor factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat. 2011;130(3):845-54. Cochet A Quilichini G Dygai-Cochet I Touzery C Toubeau M Berriolo-Riedinger A Baseline diastolic dysfunction as a predictor factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer Breast Cancer Res Treat 2011 130 3 845 854 17 Fouad FM, Slominski JM, Tarazi RC. Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function. J Am Coll Cardiol. 1984;3(6):1500-6. Fouad FM Slominski JM Tarazi RC Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function J Am Coll Cardiol 1984 3 6 1500 1506 18 Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-39. Plana JC Galderisi M Barac A Ewer MS Ky B Scherrer-Crosbie M Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging J Am Soc Echocardiogr 2014 27 9 911 939 19 Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5(5):596-603. Sawaya H Sebag IA Plana JC Januzzi JL Ky B Tan TC Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab Circ Cardiovasc Imaging 2012 5 5 596 603 20 Lange SA, Ebner B, Wess A, Kogel M, Gajda M, Hitschold T, et al. Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy. Clin Res Cardiol. 2012;101(6):415-26. Lange SA Ebner B Wess A Kogel M Gajda M Hitschold T Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy Clin Res Cardiol 2012 101 6 415 426 21 Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popovic ZB, Marwick TH. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol. 2013;61(1):77-84. Thavendiranathan P Grant AD Negishi T Plana JC Popovic ZB Marwick TH Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy J Am Coll Cardiol 2013 61 1 77 84 22 National Comprehensive Cancer Network (NCCN). NCCN guidelines for treatment of cancer [Accessed in 2015 Apr 09]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp National Comprehensive Cancer Network NCCN guidelines for treatment of cancer 2015 Apr 09 Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp 23 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-847. Erratum in: Eur Heart J. 2013;34(2):158. McMurray JJ Adamopoulos S Anker SD Auricchio A Bohm M Dickstein K ESC Committee for Practice Guidelines ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC Eur Heart J 2012 33 14 1787 1847 Erratum in: Eur Heart J. 2013;34(2):158. 24 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440-63. Lang RM Bierig M Devereux RB Flachskampf FA Foster E Pellikka PA Chamber Quantification Writing Group American Society of Echocardiography's Guidelines and Standards Committee European Association of Echocardiography Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 2005 18 12 1440 1463 25 Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control. 1974;19(6):716-23. Akaike H A new look at the statistical model identification IEEE Transactions on Automatic Control 1974 19 6 716 723 26 Hosmer DW, Lemeshow S. (editors). Applied logistic regression. New York: Wiley; 2000. Hosmer DW Lemeshow S Applied logistic regression New York Wiley 2000 27 Team RD. (editor). R: A language and environment for statistical computing. Vienna (Austria): R Foundation for Statistical Computing; 2009. Team RD R: A language and environment for statistical computing. Vienna (Austria): R Foundation for Statistical Computing 2009 28 Naumann D, Rusius V, Margiotta C, Nevill A, Carmichael A, Rea D, et al. Factors predicting trastuzumab-related cardiotoxicity in a real-world population of women with HER2+ breast cancer. Anticancer Res. 2013;33(4):1717-20. Naumann D Rusius V Margiotta C Nevill A Carmichael A Rea D Factors predicting trastuzumab-related cardiotoxicity in a real-world population of women with HER2+ breast cancer Anticancer Res 2013 33 4 1717 1720 29 Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, et al. Seven-year segment assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30(31):3792-9. Romond EH Jeong JH Rastogi P Swain SM Geyer CE Jr Ewer MS Seven-year segment assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer J Clin Oncol 2012 30 31 3792 3799 30 Xue J, Jiang Z, Qi F, Lv S, Zhang S, Wang T, et al. Risk of trastuzumab-related cardiotoxicity in early breast cancer patients: a prospective observational study. J Breast Cancer. 2014;17(4):363-9. Xue J Jiang Z Qi F Lv S Zhang S Wang T Risk of trastuzumab-related cardiotoxicity in early breast cancer patients: a prospective observational study J Breast Cancer 2014 17 4 363 369 31 Fried G, Regev T, Moskovitz M. Trastuzumab-related cardiac events in the treatment of early breast cancer. Breast Cancer Res Treat. 2013;142(1):1-7. Fried G Regev T Moskovitz M Trastuzumab-related cardiac events in the treatment of early breast cancer Breast Cancer Res Treat 2013 142 1 1 7 32 Grover S, Leong DP, Chakrabarty A, Joerg L, Kotasek D, Cheong K, et al. Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers. Int J Cardiol. 2013;168(6):5465-7. Grover S Leong DP Chakrabarty A Joerg L Kotasek D Cheong K Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers Int J Cardiol 2013 168 6 5465 5467 33 Cardiotoxicity of Adjuvant Trastuzumab (CATS). Clinical Trials. [Accessed in 2015 Apr 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT00858039 Cardiotoxicity of Adjuvant Trastuzumab Clinical Trials 2015 Apr 10 Available from: https://clinicaltrials.gov/ct2/show/NCT00858039 34 Tassan-Mangina S, Codorean D, Metivier M, Costa B, Himberlin C, Jouannaud C, et al. Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr. 2006;7(2):141-6. Tassan-Mangina S Codorean D Metivier M Costa B Himberlin C Jouannaud C Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study Eur J Echocardiogr 2006 7 2 141 146 35 Park YS, Park JH, Ahn KT, Jang WI, Park HS, Kim JH, et al. Usefulness of mitral annular systolic velocity in the detection of left ventricular systolic dysfunction: comparison with three dimensional echocardiographic data. J Cardiovasc Ultrasound. 2010;18(1):1-5. Park YS Park JH Ahn KT Jang WI Park HS Kim JH Usefulness of mitral annular systolic velocity in the detection of left ventricular systolic dysfunction: comparison with three dimensional echocardiographic data J Cardiovasc Ultrasound 2010 18 1 1 5 36 Walker J, Bhullar N, Fallah-Rad N, Lytwyn M, Golian M, Fang T, et al. Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol. 2010;28(21):3429-36. Walker J Bhullar N Fallah-Rad N Lytwyn M Golian M Fang T Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging J Clin Oncol 2010 28 21 3429 3436 37 Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12(3):236-44. Gianni L Dafni U Gelber RD Azambuja E Muehlbauer S Goldhirsch A Herceptin Adjuvant (HERA) Trial Study Team Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial Lancet Oncol 2011 12 3 236 244 38 de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol. 2014;32(20):2159-65. de Azambuja E Procter MJ van Veldhuisen DJ Agbor-Tarh D Metzger-Filho O Steinseifer J Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01) J Clin Oncol 2014 32 20 2159 2165 39 Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215-21. Seidman A Hudis C Pierri MK Shak S Paton V Ashby M Cardiac dysfunction in the trastuzumab clinical trials experience J Clin Oncol 2002 20 5 1215 1221 Artigos Originais Estudo Prospectivo de Coorte sobre Cardiotoxicidade na Terapia Adjuvante com Trastuzumabe em Pacientes com Câncer de Mama Matos Erika 1 Jug Borut 2 Blagus Rok 3 Zakotnik Branko 1 Institute of Oncology Ljubljana - Division of Medical Oncology - Slovenia University Medical Centre Ljubljana - Department of Vascular Diseases - Slovenia Institute for Biostatistics and Medical Informatics - University of Ljubljana - Slovenia Correspondência: Erika Matos, Institute of Oncology Ljubljana - Zaloska, 2. Postal Code: 1000, Moste, Ljubljana - Slovenia. E-mail: ematos@onko-i.si

Contribuição dos autores

Concepção e desenho da pesquisa e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Matos E, Jug B, Blagus R, Zakotnik B; Obtenção de dados, Análise e interpretação dos dados, Análise estatística e Redação do manuscrito: Matos E, Jug B, Blagus R; Obtenção de financiamento: Matos E.

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

Cardiotoxicidade é um importante efeito colateral da terapia com trastuzumabe, recomendando-se vigilância cardíaca.

 Objetivos:

Avaliar prospectivamente as características basais de pacientes, nível de fração N-terminal do pró-peptídeo natriurético cerebral (NT-proBNP) e parâmetros ecocardiográficos como possíveis preditores de disfunção cardíaca relacionada ao trastuzumabe.

 Métodos:

Em um estudo clínico prospectivo de coorte, realizou-se avaliação ecocardiográfica e neuro-humoral basal, aos 4, 8 e 12 meses em pacientes com câncer de mama submetidas a terapia adjuvante com trastuzumabe após antraciclina (3-4 ciclos). Definiu-se disfunção cardíaca relacionada ao trastuzumabe como uma redução na fração de ejeção ventricular esquerda (FEVE) ≥ 10%.

 Resultados:

Este estudo incluiu 92 pacientes (idade média, 53,6 ± 9,0 anos). Pacientes que desenvolveram redução na FEVE ≥ 10% (20,6%) relacionada ao trastuzumabe durante tratamento tinham FEVE basal significativamente maior (70,7 ± 4,4%) do que aqueles sem (64,8 ± 5,5%) (p = 0,0035). Todos os demais parâmetros basais medidos (idade, índice de massa corporal, hipertensão arterial, nível de NT-proBNP e outros parâmetros ecocardiográficos) não foram identificados como significativos.

 Conclusões:

Nossos achados sugerem que as características basais das pacientes, nível de NT-proBNP e parâmetros ecocardiográficos, contanto que dentro da variação normal, não são ferramentas confiáveis para predição precoce de disfunção cardíaca relacionada ao trastuzumabe em pacientes submetidas a terapia adjuvante com trastuzumabe após baixa dose de antraciclina. Uma redução na FEVE em pacientes com FEVE basal alta-normal, ainda que estatisticamente significativa, não é clinicamente relevante.

 Palavras-chave: Trastuzumab / efeitos adversos Trastuzumab / uso terapêutico Neoplasias da Mama / terapia Cardiotoxicidade Estudos de Coortes Introdução

O tratamento adjuvante com trastuzumabe reduz significativamente a mortalidade e o risco de recidiva em pacientes com câncer de mama positivo para receptor do fator de crescimento epidérmico humano 2 (HER-2).1-6 Trastuzumabe adjuvante, no entanto, acha-se associado a significativa cardiotoxicidade, sendo a disfunção cardíaca a ele relacionada reconhecida como um importante efeito colateral e a principal razão para interrupção prematura do tratamento.1,7

Ensaios randomizados identificaram os seguintes fatores de risco para cardiotoxicidade relacionada ao trastuzumabe: hipertensão arterial (HA); idade superior a 50 anos; índice de massa corporal (IMC); exposição às antraciclinas; e fração de ejeção ventricular esquerda (FEVE) basal limítrofe.8 No entanto, há evidência fraca ou ainda não exaustivamente estudada quanto a outros possíveis preditores de cardiotoxicidade relacionada ao trastuzumabe, como a fração N-terminal do pró-peptídeo natriurético cerebral (NT-proBNP)9-11 e algumas medidas ecocardiográficas, como volume ventricular esquerdo sistólico final (VVESF), pico de velocidade sistólica de onda na posição mitral septal na ecocardiografia com Doppler tecidual (onda Sm), velocidade diastólica precoce de onda na posição mitral septal na ecocardiografia com Doppler tecidual (onda Em), área de átrio esquerdo (AE) e relação entre as velocidades de onda E e A no fluxo mitral no Doppler pulsátil (E/A).12-15 Sabe-se que a deterioração da FEVE é um estágio relativamente tardio da disfunção ventricular, quando o miocárdio já exauriu sua considerável reserva funcional. Entretanto, pode-se demonstrar na ecocardiografia o comprometimento diastólico do ventrículo esquerdo antes da queda na FEVE em diferentes patologias, como cardiotoxicidade mediada por antraciclina, doença arterial coronariana, diabetes, ou HA. Logo, parece razoável utilizar a função diastólica para mostrar as alterações cardíacas mais precoces e sutis que ocorrem durante tratamento adjuvante com trastuzumabe. Os dados disponíveis atualmente para essa população de pacientes são escassos e não uniformes.15-18 Os peptídeos natriuréticos, liberados durante estresse hemodinâmico, são bastante utilizados na detecção precoce de insuficiência cardíaca e já se mostraram marcadores sensíveis de disfunção ventricular esquerda e poderosos de morbimortalidade no contexto de insuficiência cardíaca. Níveis elevados de NT-proBNP foram detectados em alguns estudos avaliando cardiotoxicidade devida ao tratamento com antraciclina. Entretanto, a capacidade do NT-proBNP para predizer disfunção cardíaca precoce em pacientes tratadas com trastuzumabe permanece não confirmada, tendo a maioria dos estudos fornecido resultados desanimadores.11,13,19

Estudos prévios relataram que alterações nas medidas ecocardiográficas seriadas (especialmente nos três primeiros meses após o início da terapia) predizem disfunção cardíaca relacionada ao trastuzumabe. No entanto, não focaram no possível valor preditivo das medidas basais na ecocardiografia bidimensional com Doppler e na ecocardiografia com Doppler tecidual e pulsátil.13,20 Estudos demonstraram que as técnicas ecocardiográficas bidimensionais são confiáveis para a detecção de diferença na FEVE próxima a 10%, podendo ser usadas como indicador de cardiotoxicidade na ausência de sintomas.21

O presente estudo prospectivo avaliou idade, HA, IMC, FEVE, VVESF, ondas Sm e Em, AE, E/A e nível de NT-proBNP como possíveis preditores da disfunção cardíaca relacionada ao trastuzumabe em pacientes com câncer de mama positivo para HER-2, submetidos a terapia adjuvante com trastuzumabe após antraciclina.

 Métodos

Trata-se de estudo prospectivo de coorte com avaliação seriada clínica, ecocardiográfica e neuro-humoral em pacientes com câncer de mama positivo para HER-2 submetidos a terapia adjuvante com trastuzumabe no Instituto de Oncologia em Ljubljana, Eslovênia, de outubro de 2011 a novembro de 2013. Este estudo foi aprovado pelo Comitê de Ética Nacional (No. 110/04/10), tendo todas as participantes fornecido termo de consentimento livre e esclarecido antes de sua entrada no estudo.

Foram consideradas elegíveis as pacientes com função cardíaca sistólica basal normal (FEVE > 50%). Todas as pacientes foram tratadas previamente com quimioterapia baseada em antraciclina (3-4 ciclos). Além das antraciclinas, administrou-se quimioterapia adjuvante com base em taxano conforme as diretrizes internacionais atuais, concomitantemente com trastuzumabe.22 As pacientes foram tratadas com trastuzumabe por um ano, perfazendo um total de 18 infusões a cada três semanas. Radioterapia nas mamas ou região mamária foi realizada após a quimioterapia adjuvante, quando em tratamento com trastuzumabe adjuvante, se indicado, conforme as diretrizes clínicas atuais.22

Exame clínico e ecocardiografia transtorácica foram realizados, assim como os níveis plasmáticos de NT-proBNP foram determinados nas condições basais e após 4, 8 e 12 meses durante tratamento com trastuzumabe.

As pacientes foram submetidas a extensa avaliação cardiovascular, tendo recebido o diagnóstico de insuficiência cardíaca na presença de sinais e sintomas, e de cardiopatia estrutural de acordo com as diretrizes da Sociedade Europeia de Cardiologia.23

Com relação a comorbidades, focou-se especialmente em HA, dislipidemia e diabetes mellitus. Definiu-se HA como história de HA com uso de medicação anti-hipertensiva, ou como pressão arterial sistólica > 140 mmHg e/ou pressão arterial diastólica > 90 mmHg em duas medidas separadas. Dislipidemia e diabetes mellitus foram definidas como história de doença com tratamento medicamentoso apropriado ou achados laboratoriais (LDL-C > 3, CT > 5 mmol/l ou glicemia de jejum > 7 mmol/l, respectivamente). Calculou-se o IMC com base na seguinte fórmula: peso corporal em quilograma dividido pelo quadrado da altura em metros. Doença arterial coronariana foi definida como história de infarto do miocárdio ou procedimento de revascularização, presença de estenose coronariana em angiotomografia computadorizada ou invasiva ou presença de isquemia na cintilografia miocárdica. Valvulopatia foi definida como história de correção/substituição valvar, ou significativo comprometimento (> leve) estrutural ou funcional em exame de imagem cardíaca.

Ecocardiografia transtorácica foi realizada com um sistema de imagem phased-array equipado com transdutor e segunda harmônica. As imagens foram obtidas em cortes paraesternal, longitudinal, transversal e apical, estando a paciente deitada na posição lateral esquerda. Registros de ecocardiografia com Doppler tecidual, modo M, Doppler bidimensional e Doppler pulsátil foram obtidos. Todas as medidas foram feitas de acordo com as recomendações da Sociedade Americana de Ecocardiografia (ASE) e da Associação Europeia de Ecocardiografia (EAE).18,24 Cada avaliação foi analisada por pelo menos três ciclos consecutivos (ou pelo menos cinco em qualquer ritmo que não fosse sinusal regular), evitando-se os batimentos pós-ectópicos. Avaliou-se FEVE em cortes bidimensionais apicais de 4 e 2 câmaras, usando o método biplanar de Simpson. Caso cortes apicais biplanares não estivessem disponíveis nas condições basais e/ou seguimento, a análise foi realizada usando corte apical de 4 câmaras. Nenhuma medida ecocardiográfica foi excluída do estudo por má qualidade de imagem. Doppler pulsátil transmitral foi registrado no corte apical de 4 câmaras para medir as velocidades de pico precoce (E) e atrial (A) (m/s), relação entre as velocidades de pico de onda E e A (E/A) e tempo de desaceleração da onda E (ms). O Doppler pulsátil foi realizado ao nível do anel mitral lateral e septal para medir as velocidades sistólica de pico (Sm) e diastólicas precoce (Em) e tardia (Am). Todos os parâmetros do Doppler tecidual foram obtidos como a média dos valores do anel mitral lateral e septal. No Doppler, a relação entre a velocidade transmitral de pico E e a média da velocidade de pico Em [(Em lateral + Em septal)/2] foi calculada como um índice da pressão de enchimento ventricular esquerda.

Todas as avaliações ecocardiográficas foram realizadas por cardiologista experiente, em uma única instituição. A reprodutibilidade do método foi avaliada no laboratório de ecocardiografia, usando 20 registros analisados duas vezes (variabilidade intra-observador). O coeficiente de correlação intraclasse foi bom (para FEVE intra-observador, 0,97). A confiabilidade do método foi avaliada comparando-se a FEVE obtida na ecocardiografia com ventriculografia radioisotópica (MUGA - multigated acquisition scan) em 20 pacientes. O coeficiente de correlação interclasse foi bom (para FEVE inter-método, 0,87).

Os níveis plasmáticos de NT-proBNP foram determinados com eletroquimioluminescência em analisador Cobas e411 (Roche Diagnostics GmbH, Mannheim, Alemanha).

A disfunção cardíaca relacionada ao trastuzumabe foi definida como sinais e/ou sintomas clínicos de insuficiência cardíaca ou declínio na FEVE de pelo menos 10% do valor basal em pacientes assintomáticos ao longo do tratamento adjuvante com trastuzumabe.3,16

De acordo com a literatura, a incidência esperada de declínio da FEVE de 10% ou mais em pacientes em terapia adjuvante com trastuzumabe é de 15%.16 Para um nível de probabilidade desejada de 0,05 e poder estatístico de 0,80 para detectar 10% de declínio na FEVE normal (70% a 60%), foram necessários 12 pacientes com tal característica; assim, calculamos ter de incluir 90 pacientes.

As variáveis contínuas distribuídas normalmente foram descritas como média ± desvio padrão (DP), as variáveis contínuas não distribuídas normalmente foram descritas como mediana e variação interquartil, sendo as variáveis categóricas descritas como números e/ou porcentagens. As características basais e os parâmetros ecocardiográficos das pacientes com e sem disfunção cardíaca relacionada ao trastuzumabe no seguimento foram comparadas com regressão logística; razão de chance (OR) e seus intervalos de confiança (IC) a 95% são relatados. Realizou-se regressão logística múltipla para determinar os preditores independentes para redução na FEVE de pelo menos 10% da basal, usando-se os preditores univariados que se mostraram significativos. Um valor de p bicaudal < 0,05 foi considerado significativo. Estimou-se a qualidade do ajuste dos modelos com o critério de informação de Akaike25 e o teste de Hosmer-Lemeshow.26 Do ponto de vista de significado estatístico, nenhum dos modelos relatados neste estudo exibiu má qualidade do ajuste. As análises foram realizadas usando-se o programa IBM SPSS v.22 e linguagem R para cálculo estatístico (R v.3.0.3.).27

Resultados

Um total de 92 pacientes assinou o termo de consentimento livre e informado, sendo incluídas no estudo. Não houve perda durante o seguimento e nem morte. Uma paciente foi excluída da análise porque seus achados ecocardiográficos basais (após antraciclina) sugeriram sobrecarga ventricular direita e suspeita de embolia pulmonar, que foi confirmada por angiotomografia computadorizada. Todas as demais pacientes receberam o tratamento de um ano inteiro de trastuzumabe adjuvante. Não houve interrupção temporária da terapia. A amostra foi constituída só por pacientes do sexo feminino, sendo a idade média de 53,6 anos (variação: 35,0-75,5). Todas foram tratadas anteriormente com antraciclinas (3 ou 4 ciclos de epidoxorrubicina, 90 a 100 mg/m2, ou 4 ciclos de doxorrubicina, 60 mg/m2) e 82 (89,1%) pacientes receberam também quimioterapia baseada em taxano. No total, foram realizadas 288 medidas ecocardiográficas e 297 medidas de NT-proBNP. Redução da FEVE foi observada em 78 pacientes, em quem foram tomadas medidas basais e em pelo menos uma outra ocasião. Certos parâmetros ecocardiográficos basais não puderam ser avaliados em todas as pacientes.

Em concomitância com trastuzumabe, 65 (70,7%) pacientes foram submetidas a radioterapia e 60 (65,2%) foram submetidas a terapia endócrina adjuvante. As seguintes comorbidades foram obtidas a partir dos prontuários médicos: HA em 27 (29,3%) pacientes, diabetes mellitus em 4 (4,3%) pacientes, e dislipidemia em 9 (9,8%) pacientes. Antes de entrar no estudo, 25 pacientes foram tratadas para HA. Dessas, 12 pacientes foram submetidas a monoterapia a saber: inibidor da enzima conversora de angiotensina (IECA), 5 pacientes; bloqueador de receptor de angiotensina, 2 pacientes; betabloqueador, 4 pacientes; e bloqueador de canal de cálcio, 1 paciente. Nas outras 13 pacientes, a HA foi tratada com uma combinação de dois ou três fármacos, sendo, na maioria das vezes, um diurético e o outro: IECA, 5 pacientes; bloqueador de receptor de angiotensina, 3 pacientes; IECA e betabloqueador, 2 pacientes; IECA e bloqueador de canal de cálcio, 2 pacientes. Uma paciente estava recebendo uma combinação inadequada de IECA e bloqueador de receptor de angiotensina, o que foi modificado durante o tratamento. Em duas pacientes com história de HA e que haviam recusado tratamento anterior, introduziu-se terapia com IECA. A Tabela 1 detalha as características das pacientes e do tratamento. Nenhuma paciente desenvolveu insuficiência cardíaca sintomática durante o seguimento; entretanto, a avaliação ecocardiográfica revelou redução de FEVE (≥ 10%) durante o tratamento em 22 (23,9%) pacientes. Dessas, 11 (50%) apresentaram a redução nos 4 primeiros meses, 7 pacientes (31,8%) entre 4 e 8 meses, e 4 pacientes (18,2%) entre 8 e 12 meses (Figura 1). Todas essas pacientes foram também encaminhadas para um cardiologista para acompanhamento durante o tratamento.

Características das pacientes e do tratamento
No. 92 100%
Idade / anos
Média (DP) 53,6 (9,0)
Variação 35,0-75,5
Sítio do câncer de mama
Esquerda 46 50%
Direita 46 50%
IMC / kg/m2
Média (DP) 26,1 (4,9)
Variação 17,9-40,1
Pacientes com IMC 25-29,9 kg/m2 30 32,6%
Pacientes com IMC ≥ 30 kg/m2 16 17,4%
Comorbidades
HA 27 29,3%
DM 4 4,3%
Dislipidemia 9 9,8%
Tratamento
Dose cumulativa de antraciclina
Doxorrubicina (média) / mg/m2 240 10,9%
Epidoxorrubicina (média) / mg/m2 304 89,1%
RT 65 70,7%
TE 60 65,2%
Quimioterapia baseada em taxano 82 89,1%

IMC: índice de massa corporal; HA: hipertensão arterial; DM: diabetes mellitus; RT: radioterapia; TE: terapia endócrina; DP: desvio padrão.

Incidência de cardiotoxicidade durante tratamento com trastuzumabe.

O modelo univariado mostrou que apenas a FEVE basal e o VVESF prediziam redução significativa na FEVE de 10% ou mais durante tratamento adjuvante com trastuzumabe (Tabela 2). As médias da FEVE basal foram 70,7% e 64,8% para pacientes com e sem disfunção cardíaca relacionada ao trastuzumabe. A diferença na FEVE e no VVESF foi estatisticamente significativa. Na análise multivariada, apenas a FEVE manteve significado estatístico (Tabela 3). Não se observou diferença significativa de idade, IMC, HA e nível basal de NT-proBNP entre pacientes com e sem significativa redução da FEVE. Nenhum parâmetro de função sistólica ou diastólica na ecocardiografia com Doppler e com Doppler tecidual apresentou significado estatístico (Tabela 2).

Características e parâmetros ecocardiográficos basais de pacientes com e sem disfunção cardíaca relacionada ao trastuzumabe em seguimento – modelo univariado
Parâmetro Todas as pacientes Redução FEVE ≥ 10% [No.] Redução FEVE < 10% [No.] OR IC 95% p
Idade (anos) 53,6 ± 9,0 53,2 ± 9,4 [22] 52,6 ± 9,0 [56] 1,008 0,954 – 1,065 0,7753
IMC (kg/m2) 26,1 ± 4,9 25,2 ± 5,2 [22] 26,5 ± 5,4 [56] 1,001 0,902 – 1,112 0,9805
VVESF (ml) 21,8 ± 8,0 17,8 ± 5,0 [22] 22,6 ± 6,6 [56] 0,858 0,774 – 0,950 0,0033
FEVE (%) 66,3 ± 5,8 70,7 ± 4,4 [22] 64,8 ± 5,5 [56] 1,284 1,128 – 1,462 0,0002
Sm (cm/s) 8,5 ± 1,8 8,1 ± 1,9 [22] 8,6 ± 1,8 [54] 0,945 0,717 – 1,242 0,6847
NT-proBNP (pg/ml) 79 (45-133) 113 (61–165) [22] 83 (53–114) [54] 1,003 0,996 – 1,009 0,3920
Em (cm/s) 8,5 ± 2,7 8,4 ± 2,5 [22] 8,5 ± 2,8 [54] 1,000 0,834 – 1,200 0,9992
AE (cm2) 15,8 ± 3,4 15,6 ± 2,9 [22] 16,1 ± 3,1 [51] 0,945 0,800 – 1,116 0,5067
E/A 1,0 ± 0,3 1,0 ± 0,3 [22] 0,99 ± 0,2 [52] 1,194 0,226 – 6,299 0,8349
HA (%)* 27/92 (29,3%) 7/17 (41,1%) (22] 20/75 (26,7%) [56] 1,892 0,672 – 5,329 0,2273

Prevalência de hipertensão apresentada como número (proporção) de pacientes. NT-proBNP níveis apresentados como mediana e intervalo interquartil. Todos os outros dados são apresentados como média ± DP.

FEVE: fração de ejeção ventricular esquerda (método biplanar de Simpson); IMC: índice de massa corporal; VVESF: volume ventricular esquerdo sistólico final; Sm: velocidade sistólica de pico no anel mitral na ecocardiografia com Doppler tecidual; Em: velocidade diastólica precoce em posição do anel mitral septal na ecocardiografia com Doppler tecidual; AE: área atrial esquerda; E/A: relação entre as velocidades de onda E e A no fluxo mitral no Doppler pulsátil; HÁ: hipertensão arterial, NT-proBNP: fração N-terminal do pró-peptídeo natriurético cerebral; OR: razão de chance; No.: número de pacientes.

 Preditores de disfunção cardíaca relacionada ao trastuzumabe em análise multivariada
Parâmetro Estimativa EP OR IC 95% p
Intercepto -15,0019 5,8521 0,000 0,000 – 0,029 0,0104
FEVE (%l) 0,2207 0,0755 1,247 1,075 – 1,446 0,0035
VVESF (ml) -0,0422 0,0589 0,959 0,854 – 1,076 0,4739

FEVE: fração de ejeção ventricular esquerda; VVESF: volume ventricular esquerdo sistólico final; EP: erro padrão; OR: razão de chance.

 Discussão

No presente estudo, fatores de risco clássicos (idade, HA, IMC), NT-proBNP e medidas ecocardiográficas (ondas Sm e Em, AE, E/A) não se mostraram preditores de disfunção ventricular esquerda relacionada ao trastuzumabe em pacientes com câncer de mama positivo para HER-2 submetidas a terapia adjuvante com trastuzumabe após baixa dose de antraciclina. Pacientes com valores basais mais elevados de FEVE (70,7% vs 64,8%) apresentaram uma redução de FEVE estatisticamente significativa, ainda que clinicamente irrelevante, de 10% ou mais durante o tratamento.

Idade, incidência de HA e IMC de nossas pacientes foram comparáveis às relatadas em estudos adjuvantes.2,4,5 No nosso estudo, a idade das pacientes não se mostrou um importante preditor, ao contrário dos resultados de dois estudos clínicos randomizados prospectivos norte-americanos.2,5 Por outro lado, alguns estudos, como o HERA,4 não conseguiram confirmar seu valor preditivo. Além disso, estudos incluindo pacientes da prática clínica diária não demonstraram o impacto da idade para predizer disfunção cardíaca relacionada ao tratamento adjuvante com trastuzumabe.14,28 Hipertensão arterial, a comorbidade mais estudada nesses pacientes, é um fator de risco geralmente aceito, tendo sua importância confirmada em vários estudos.5,29 Os resultados, no entanto, não são uniformes, havendo estudos, como o nosso, que não demonstraram seu papel preditor.2,30,31 No estudo HERA,2 o IMC mostrou-se um importante fator de risco, mas isso não foi demonstrado em outros dois estudos randomizados.5,29 No nosso estudo, o IMC não se mostrou importante.

A maioria dos estudos tendo por objetivo demonstrar a utilidade dos níveis de NT-proBNP na predição da cardiotoxicidade do trastuzumabe foi desapontadora.10,19,32 Entretanto, devido à sua ampla disponibilidade e baixo custo, o NT-proBNP ainda é bastante atraente e objeto de vários estudos. No nosso estudo, ele não se mostrou útil para identificar pacientes com risco para disfunção cardíaca. Todas as pacientes tinham níveis basais normais, e, durante um ano de tratamento com trastuzumabe, a maioria delas manteve níveis normais de NT-proBNP (menos de 300 pg/ml). Nenhuma paciente apresentou elevação progressiva. No entanto, aguardamos os resultados do estudo clínico CATS (Cardiotoxicity of Adjuvant Trastuzumab) para obter dados mais robustos sobre o valor preditivo desse biomarcador sérico.33

Com relação às medidas ecocardiográficas, o valor diagnóstico e preditivo da ecocardiografia com Doppler tecidual e seu papel na detecção de cardiotoxicidade em pacientes em tratamento com trastuzumabe ainda não foram exaustivamente estudados. No nosso estudo, não identificamos velocidade sistólica de pico no Doppler tecidual (onda Sm) como importante fator preditivo de cardiotoxicidade relacionada ao trastuzumabe. As velocidades no Doppler tecidual representam uma alternativa à FEVE de fácil medida e reprodutível para a predição de disfunção cardíaca precoce em diferentes doenças cardíacas.34 As medidas são altamente reprodutíveis e confiáveis, além de menos propensas a variabilidade intra- e inter-observador do que a avaliação ecocardiográfica bidimensional da FEVE.35 Além disso, a redução precoce da velocidade de onda Sm no curso da terapia com trastuzumabe foi proposta como marcador de disfunção cardíaca relacionada ao trastuzumabe que pode ser detectada antes do aumento hemodinâmico dos volumes cardíacos ou redução da FEVE.13,20 No nosso estudo, não conseguimos demonstrar o significado estatístico de qualquer parâmetro diastólico basal (principalmente área do AE, onda Em e relação E/A) como fator preditivo de cardiotoxicidade relacionada ao trastuzumabe. Sabe-se que a disfunção diastólica precede a disfunção sistólica, mas pode estar presente isoladamente.34 Estudos prévios tiveram resultados diversos e inconclusivos quanto ao possível papel da disfunção diastólica como preditor de cardiotoxicidade relacionada à antraciclina.13,36 Consequentemente, os índices diastólicos derivados do Doppler não são úteis para a detecção precoce de insuficiência cardíaca relacionada à antraciclina.18 Com trastuzumabe, Cochet et al.16 relataram que a disfunção diastólica (avaliada por tempo de enchimento ventricular esquerdo máximo em ventriculografia radioisotópica prediz cardiotoxicidade mediada por trastuzumabe de modo independente. Ao contrário, em um pequeno estudo com 42 pacientes em tratamento com trastuzumabe adjuvante, a redução precoce dos índices diastólicos obtidos com Doppler tecidual não conseguiram predizer disfunção cardíaca relacionada ao trastuzumabe.13 Disfunção diastólica, na verdade, representa um estágio precoce no processo de lesão cardíaca; permanece, entretanto, presente nos estágios tardios (sistólica). Com base nos parâmetros basais de função diastólica, o nosso estudo não conseguiu identificar pacientes com redução de pelo menos 10% na FEVE basal durante um ano de tratamento com trastuzumabe adjuvante. Isso pode ser explicado pelo fato de que todos os valores basais achavam-se na faixa 'alto-normal'. Devido à enorme capacidade da reserva cardíaca, que não foi exaurida após uma dose cumulativa relativamente baixa de antraciclinas (as pacientes no nosso estudo receberam entre 300 e 400 mg/m2 de epidoxorrubicina ou 240 mg/m2 de doxorrubicina), a resposta adaptativa foi capaz de compensar por completo as toxicidades e, consequentemente, sobrepujou a capacidade preditiva dos outros índices sensíveis de disfunção diastólica. Embora não tenhamos conseguido identificar valor preditivo para as medidas obtidas com o Doppler tecidual de disfunção sistólica ou diastólica, acredita-se que medidas seriadas dos parâmetros ecocardiográficos com Doppler tecidual (especialmente, onda Sm) possam representar uma ferramenta adicional utilizável e confiável para a detecção precoce de redução ameaçadora da FEVE em pacientes em terapia oncológica cardiotóxica.18

No nosso estudo, apenas função sistólica basal emergiu como o único preditor independente estatisticamente significativo de disfunção cardíaca relacionada ao trastuzumabe. Entretanto, de forma inesperada e contrária aos resultados de alguns estudos usando diferentes definições para cardiotoxicidade,2,4,5 observamos que o risco foi 'proporcional' e não 'inversamente proporcional' à FEVE basal das pacientes, i.e., a chance de uma redução da FEVE ≥ 10% foi significativamente maior naquelas com maior FEVE basal, sendo o achado, portanto, clinicamente não importante. A média da FEVE basal das pacientes do nosso estudo foi alta, sendo 70,7% para aquelas com uma redução de pelo menos 10%, e 64,8% para aquelas sem tal redução. Em ensaios clínicos randomizados de tratamento adjuvante utilizando diferentes definições para cardiotoxicidade, uma redução de 10% ou 15% da FEVE basal para menos de 50% ou 55% foi considerada um evento cardíaco em pacientes assintomáticos. Nos estudos HERA37,38 e dois norte-americanos,2,5 a FEVE basal foi um importante preditor inversamente proporcional de cardiotoxicidade relacionada ao trastuzumabe. Em estudo norte-americano, pacientes com FEVE basal entre 50% e 54% apresentaram um risco 12 vezes maior do que aqueles com FEVE de pelo menos 65%.29 No entanto, nem todos os estudos mostraram ser importante o valor da FEVE basal. Em um dos primeiros e maiores estudos realizados pelo Cardiac Review and Evaluation Committee, incluindo mais de 100 pacientes com comprovada disfunção cardíaca relacionada ao trastuzumabe, a FEVE basal não foi identificada como importante preditor.39 Exceto pela HA, nossas pacientes não eram portadoras de doença cardiovascular, apresentavam função cardíaca normal e foram expostas a baixas doses de antraciclinas cardiotóxicas, tendo, portanto, FEVE alta-normal preservada. Uma possível explicação para a inesperada significativamente maior chance de redução de FEVE em pacientes com FEVE basal mais alta seria o recrutamento de mecanismos compensatórios. Sabe-se que cardiomiócitos têm grande capacidade de preservar débito cardíaco suficiente. Em pacientes com uma FEVE basal realmente alta, é possível que a redução da FEVE de 10% do débito cardíaco não esteja comprometida e que a resposta adaptativa seja ativada com atraso. Ao contrário, em pacientes com menor FEVE basal, mas ainda dentro da variação normal, a resposta adaptativa é ativada mais precocemente, com consequente redução adicional. Outra possível explicação é que 10 pontos percentuais representam valor relativamente maior em pacientes com FEVE basal mais baixa do que alta. No entanto, de acordo com os nossos resultados, uma redução da FEVE ≥ 10% em pacientes com nível basal alto-normal, embora estatisticamente significativa, não é clinicamente relevante nem prediz disfunção cardíaca.

Nosso estudo apresenta algumas limitações. Empregamos avaliação ecocardiográfica transtorácica bidimensional padrão. Conforme as recomendações da ASE e da EAE,18 ecocardiografia é adequada para avaliação seriada de estrutura e função ventricular esquerda em adultos durante e após tratamento de câncer. Entretanto, a utilização de métodos ecocardiográficos avançados, como strain e strain-rate ou ecocardiografia tridimensional, fortaleceria a acurácia científica de nossos resultados. No entanto, ecocardiografia padrão acompanhada de ecocardiografia com Doppler tecidual usada no nosso estudo acha-se prontamente disponível no contexto clínico. Logo, nossos resultados oferecem maior aplicabilidade na atual prática clínica de vigilância cardio-oncológica de pacientes com câncer de mama em terapia adjuvante com trastuzumabe. Além disso, nosso estudo foi reforçado para detectar significativa redução na FEVE, mas não para um novo evento de insuficiência cardíaca, cuja incidência é quase cinco vezes menor do que a de disfunção cardíaca assintomática.1 Não detectamos nenhum caso de novo evento de insuficiência cardíaca; logo, devemos enfatizar que isso possa dever-se simplesmente ao pequeno tamanho amostral.

 Conclusões

A identificação de mulheres com risco de desenvolver disfunção cardíaca relacionada ao trastuzumabe, quando usado como adjuvante, continua a ser um desafio. Neste estudo prospectivo de coorte, descobrimos que idade, HA, IMC, FEVE basal, VVESF, ondas Sm e Em, AE, E/A e NT-proBNP não são preditores de disfunção cardíaca relacionada ao trastuzumabe em pacientes com câncer de mama positivo para HER-2 submetidas a terapia adjuvante com trastuzumabe após baixas doses de antraciclina. Nessas pacientes, identificamos na ecocardiografia uma FEVE basal alta-normal. Uma redução na FEVE ≥ 10% em pacientes com FEVE basal alta-normal, ainda que estatisticamente significativa, não é clinicamente relevante e nem preditora de disfunção cardíaca.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.