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Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy

Abstract

Background:

Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied.

Objective:

To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy.

Methods:

Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time.

Results:

Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity.

Conclusion:

In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Keywords:
Ventricular Dysfunction, Left; Drug Therapy; Cardiotoxicity; Breast Neoplasms; Anthracyclines; Trastuzumab

Resumo

Fundamento:

Os agentes quimioterápicos da classe das antraciclinas e dos anticorpos monoclonais humanizados são tratamentos eficazes para o câncer de mama, entretanto, apresentam alto risco de cardiotoxicidade. Diversos parâmetros têm sido reconhecidos como preditores no desenvolvimento de toxicidade cardíaca, sendo que a avaliação da alteração contrátil segmentar ventricular esquerda (ACSVE) ainda não foi estudada.

Objetivo:

Analisar a associação entre o surgimento de ACSVE e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia.

Métodos:

Coorte prospectiva de pacientes diagnosticados com câncer de mama e em tratamento quimioterápico com doxorrubicina e/ou trastuzumab. Foram realizados ecocardiogramas transtorácicos antes, durante e depois do tratamento para avaliar a presença ou não de cardiotoxicidade. A cardiotoxicidade foi definida por um decréscimo de 10% na fração de ejeção do ventrículo esquerdo, em pelo menos um ecocardiograma. Modelos de regressão logística multivariada foram utilizados para verificar os fatores preditores na ocorrência de cardiotoxicidade ao longo do tempo.

Resultados:

Dos 112 pacientes selecionados (idade média = 51,3 ± 12,9 anos), 18 (16,1%) apresentaram cardiotoxicidade. Na análise multivariada os pacientes com ACSVE (OR = 6,25 [IC 95%: 1,03; 37,95], p < 0,05), diâmetro sistólico do VE (OR = 1,34 [IC 95%:1,01; 1,79], p < 0,05) e strain longitudinal global pela técnica de speckle tracking (OR = 1,48 [IC 95%: 1,02; 2,12], p < 0,05) foram preditores significativos e independentes na predição de cardiotoxidade.

Conclusão:

Mostramos que ACSVE, bem como a redução do strain longitudinal global foram preditores independentes para cardiotoxicidade, podendo ser úteis na estratificação de risco destes pacientes.

Palavras-chave:
Disfunção Ventricular Esquerda; Tratamento Farmacológico; Cardiotoxicidade; Neoplasias da Mama; Antraciclinas; Trastuzumab

Introduction

The introduction of new chemotherapeutic agents, and the use of advanced and precise radiotherapy techniques in the last decades have dramatically improved breast cancer survival.11 DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439-48. Chemotherapeutic drugs of the anthracycline class, and the humanized monoclonal antibodies, such as trastuzumab, are widely used and highly effective agents for breast cancer treatment.22 Hari KN, Benjamin F, Abigail MK, Theodore P, David H, Akinyemi B, et al. Noninvasive measures of ventricular-arterial coupling and circumferential strain predict cancer therapeutics-related cardiac dysfunction. JACC Cardiovasc Imaging. 2016;9(10):1131-41. Unfortunately, anthracyclines can induce cardiotoxic effects, and the severity of these adverse effects is compounded by concomitant use of trastuzumab.33 Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231-47.

Chemotherapy may induce numerous cardiovascular complications, including hypertension, congestive heart failure, thromboembolic diseases, ischemic heart disease, QT prolongation, and bradycardia.33 Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231-47. When used in combination, anthracyclines and trastuzumab may result in heart failure in up to 27% of patients.44 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-92. Among cancer survivors, a third will die of cardiovascular disease. Thus, the need for optimal cardiac care in the cancer population has become evident. Early detection of cardiac dysfunction may allow implementation of cardioprotective strategies before potentially irreversible myocardial damage has occured.55 Yeh ET, Chang H. Oncocardiology - past, present, and future. A review. JAMA Cardiol. 2016;1(9):1066-72.

The definition of cancer therapy-related cardiac dysfunction (CTRCD) is based on a serial decline in left ventricular (LV) ejection fraction (EF). Two-dimensional echocardiography (2DE) is increasingly used for monitoring cardiac function during cancer treatment due to its widespread availability and safety. Echocardiography allows assessment of systolic and diastolic function, pulmonary pressures, valvular function, right ventricular function, and the pericardium.66 López-Fernández T, Thavendiranathan P. Emerging cardiac imaging modalities for the early detection of cardiotoxicity due to anticancer therapies. Rev Esp Cardiol. 2017;70(6):487-95.

Reduction in LV EF likely occurs late in the natural history of CTRCD patients as reduction in LV EF may not be overt until a substantial amount of myocardial reserve has been exhausted, therefore more sensitive screening modalities for LV dysfunction are needed. Despite the recognition of several echocardiographic parameters associated with CTRCD, including novel echocardiography-derived parameters of myocardial mechanics, such as strain and strain rate, currently there is no consensus in the medical practice to fully predict which patients are prone to develop cardiotoxicity.66 López-Fernández T, Thavendiranathan P. Emerging cardiac imaging modalities for the early detection of cardiotoxicity due to anticancer therapies. Rev Esp Cardiol. 2017;70(6):487-95.

7 Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, et al. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without Trastuzumab. Med Oncol. 2017;34(5):75.
-88 Reinbolt RE, Patel R, Pan X, Timmers CD, Pilarski R, Shapiro CL. et al. Risk factors for anthracycline-associated cardiotoxicity. Support Care Cancer. 2016;24(5):2173- 80. Previous studies have demonstrated the presence of regional myocardial dysfunction in patients with CTRCD,99 Piotrowski G, Gawor R, Stasiak A, Gawor Z, Potemski P, Banach M. Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 - a prospective study. Arch Med Sci. 2012;8(2):227-35

10 Kapusta L, Thijssen J, Groot-Loonen J, Antonius T, Mulder J, Daniëls O. Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines. Ultrasound Med Biol. 2000;26(7):1099-108.
-1111 Kapusta L, Groot-Loonen J, Thijssen J, de Graaf R, Daniëls O. Regional cardiac wall motion abnormalities during and shortly after anthracyclines therapy. Med Pediatr Oncol. 2003;41(5):426-35. however its role as a risk predictor has not been established. The purpose of this study is to verify the association between the occurrence of LV segmental wall motion abnormality and the development of cardiotoxicity in patients with breast cancer undergoing chemotherapy.

Methods

Study population

This study is part of a prospective cohort study of patients with breast cancer recruited from the Mater Dei Hospital in the city of Belo Horizonte - MG from January 2010 through December 2016. Inclusion criteria were, age above 18 years, histologically confirmed breast cancer diagnosis, treatment with doxorubicin and/or trastuzumab, and who underwent echocardiography, according to the rules of the hospital protocol. Exclusion criteria were patients with previous diagnosis of ventricular dysfunction including regional wall motion abnormality, significant valve disease, congenital heart disease, arrhythmias, chronic coronary artery disease and left bundle branch block by electrocardiography. Treatment regimens were at the discretion of the oncologist and consisted of the use of the following drugs alone or in combination: 1) doxorubicin and cyclophosphamide; 2) paclitaxel; 3) trastuzumab. The dosages of the medications were prescribed according to guidelines.1212 Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associate with adjuvant Trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5(4):154-66.

Clinical (e.g., hypertension, dyslipidemia, diabetes) laboratorial (e.g., sodium, potassium, calcium, magnesium, hemoglobin, creatinine and BNP) and transthoracic echocardiograms were collected at baseline and standardized time intervals for each treatment regimen, 6 months after treatment completion and annually thereafter.

Echocardiography

All patients were referred to a transthoracic echocardiogram, including longitudinal strain assessment with two-dimensional speckle-tracking echocardiography (2D STE). The echocardiographic studies and analyses were performed by an experienced cardiologist (M.V.L.B.). The following echocardiographic parameters were assessed: LV end-systolic and end-diastolic diameters and left atrial diameter. LV ejection fraction was assessed using Simpson's biplane method. Visual assessment of regional myocardial function was assessed on the basis of the observed wall thickening and endocardial motion of the myocardial segment, as described previously.1313 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39.e14. Abnormal septal motion was characterized as a atypical movement of the interventricular septum during cardiac cycle with a two-dimensional echocardiography-guided M-mode approach. Diastolic function was assessed and classified using published criteria.1414 Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the american society of echocardiography and the european association of cardiovascular imaging. J Am Soc Echocardiogr. 2016;29(4):277- 314 LV diastolic dysfunction was stratified into four grades as normal, impaired relaxation, pseudo normal filling or restrictive.

Longitudinal strain by 2D STE was obtained from apical four-chamber, two- chamber, and long-axis views. Three cardiac cycles from each view were recorded for offline analyses with a frame rate > 50 frames/sec. Peak negative longitudinal strain was assessed in 16 LV segments, defined as the peak negative value during the entire cardiac cycle, hence including post systolic shortening, and was averaged to global longitudinal strain (GLS). CTRCD was defined as a decrease in LVEF of > 10 percentage points, to a value < 53% at repeated cardiac imaging studies during follow-up after chemotherapy.1515 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.

The echocardiographic studies were performed at standardized intervals according to the treatment regimen. 1) Patients treated with anthracyclines without trastuzumab underwent an echocardiographic study at baseline, at completion of chemotherapy, and every six months after completed treatment. 2) Patients treated with anthracyclines and trastuzumab underwent an echocardiographic study at baseline, after completion of the anthracycline treatment regimen, every 3 months during trastuzumab therapy, and every six months after completed treatment. 3) Patients treated with trastuzumab without anthracyclines underwent an echocardiographic study at baseline, every 3 months during trastuzumab therapy, and every six months after completed treatment.

Echocardiographic assessment was completed in patients with at least three echocardiographic studies performed during the research period.

Statistical Analysis

To describe the qualitative variables, the absolute and relative frequencies were used, while to describe the quantitative variables, measures of central tendency, dispersion and position were used.

In order to identify the factors that influenced the occurrence of cardiotoxicity over time, the Generalized Estimation Equations (GEE) approach was used. An exchangeable correlation structure was assumed for the repeated observations of the same individual. Univariable and multivariable models with a logit link function were considered. There was no occurrence of cardiotoxicity at the first measurement occasion and therefore we also included the baseline values of the time-dependent predictors. Missing values were excluded from the analyses. Variables that were statistically significant at the 0.20 level were included in the multivariable model. For this final model, a level of significance of 0.05 was adopted. Reproducibility of visual assessment of abnormal regional myocardial function was evaluated by the kappa statistics.

ROC curves were built and the discrimination ability of the model was assessed by the area under the ROC curve. All statistical analysis was performed using R Statistical Software 3.4.1 and the R packages gee, pROC and PredictABEL.

Ethical considerations

The study complies with the Declaration of Helsinki and was approved by the Research and Ethical Council of the Mater Dei Hospital.

Results

Studied population

A total of 112 patients were included. Mean follow-up time was 491 days. The characteristics of the population studied are summarized in Table 1. Most of the patients in the cohort were female (98.2%). Mean age was 51.3 ± 12.9 years.

Table 1
Clinical and laboratorial characteristics of 112 patients undergoing chemotherapy

Of the 112 patients followed up, 18 (16.1%) presented CTRCD.

The characteristics of the patients with abnormal LV segmental wall motion are summarized in table 2. LV segmental wall motion abnormality was found in 16 (14%) patients, most commonly at the time of the second echocardiographic study (43%). LV segmental wall motion analyses by visual assessment showed abnormalities most frequently in the interventricular septum (78.5% - Figure 1), the inferior (14.3%), and the inferolateral (7.1%) walls. During the follow-up, no patient presented left bundle branch block by electrocardiography study.

Table 2
Characteristics in patients with segmental wall motion abnormality during chemotherapy

Figure 1
Two-dimensional echocardiography-guided M-mode showing abnormal motion of interventricular septum (arrow) during chemotherapy treatment. LV: left ventricle; RV: right ventricle.

Among the variables studied, it was observed at multivariable analysis that GLS measurements as well as LV systolic dimensions and the presence of LV regional wall motion abnormalities at the baseline study could predict development of cardiotoxicity (Tables 3 and 4). The analysis of ROC curve of the final model (Figure 2) showed an area under the curve (AUC) of 0.93 (0.88 - 0.98). When we exclude the presence of wall motion abnormality in the model, the AUC was 0.84 (0.72-0.96) showing additive predictive power of this variable (p = 0.047). Intraobserver variability and interobserver variability for wall motion assessment were 0.89 and 0.81, respectively.

Table 3
Univariate analyses of predictors related of cardiotoxicity
Table 4
Multivariate analysis of predictors related of cardiotoxicity

Figure 2
Roc curve of the multivariate model with and without evaluation of segmental abnormal contractility.

Discussion

In this prospective, longitudinal cohort study, we showed that the presence of regional wall motion disturbance and decreased GLS are strong predictors of CTRCD.

Earlier histopathological studies performed from endomyocardial biopsies have demonstrated an initially focal and dispersed involvement of myocytes, surrounded by normal cells in patients treated with anthracyclines.1616 Singal P, Deally C, Weinberg L. Subcellular effects of adriamycin in the heart: A concise review. J Mol Cell Cardiol. 1987;19(8):817-28. As the toxicity evolves, the frequency of these alterations increases, leading to significant myocardial damage and later on to diffuse myocardial fibrosis. Thus, segmental contractile dysfunction may precede the intense and diffuse involvement of the heart seen in CTRCD. In this context, interventricular septum dyssynchrony, as well as segmental hypokinesia may be present due to tissue edema and/or focal cellular damage.1717 De Beer E, Bottone A, Voest E. Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. Eur J Pharmacol. 2001;415(1):1-11.

Indeed, Piotrowsk et al.99 Piotrowski G, Gawor R, Stasiak A, Gawor Z, Potemski P, Banach M. Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 - a prospective study. Arch Med Sci. 2012;8(2):227-35 demonstrated that in 60.9% of patients with LV systolic dysfunction regional wall motion abnormalities were observed in the first echocardiography that revealed a significant drop of LVEF. In the majority of these cases (64%), regional hypokinesis involved the interventricular septum.99 Piotrowski G, Gawor R, Stasiak A, Gawor Z, Potemski P, Banach M. Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 - a prospective study. Arch Med Sci. 2012;8(2):227-35 Previous studies using tissue Doppler and 2D strain have also shown regional contractile alterations in patients treated with chemotherapy.1010 Kapusta L, Thijssen J, Groot-Loonen J, Antonius T, Mulder J, Daniëls O. Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines. Ultrasound Med Biol. 2000;26(7):1099-108.,1111 Kapusta L, Groot-Loonen J, Thijssen J, de Graaf R, Daniëls O. Regional cardiac wall motion abnormalities during and shortly after anthracyclines therapy. Med Pediatr Oncol. 2003;41(5):426-35. Boyd et al.1818 Boyd A, Stoodley P, Richards D, Hui R, Harnett P, Vo K, et al. Anthracyclines induce early changes in left ventricular systolic and diastolic function: A single centre study. PLoS ONE. 2017;12(4):e0175544. demonstrated that in the group with subclinical LV dysfunction (> 11% reduction in GLS compared to before therapy) 58% of regional segments had a reduction in strain by > 11%, compared to 29% of regional segments in the group without subclinical LV dysfunction (p < 0.001).1818 Boyd A, Stoodley P, Richards D, Hui R, Harnett P, Vo K, et al. Anthracyclines induce early changes in left ventricular systolic and diastolic function: A single centre study. PLoS ONE. 2017;12(4):e0175544.

It is well known that reduction of longitudinal strain is an early predictive factor of cardiotoxicity induced by treatment with anthracyclines and trastuzumab, as confirmed by our results. Negishi et al. showed that GLS was an independent predictor of subsequent reductions in EF, with a discrimination improvement by adding GLS of -18.6% to traditional parameters by echocardiography in patients at risk for trastuzumab-induced cardiotoxicity.1919 Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr. 2013;26(5):493-8. In another study, Sawaya el al.2020 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. showed that in patients with breast cancer treated with chemotherapy, GLS measured at the completion of anthracycline therapy was useful in the prediction of subsequent cardiotoxicity.2020 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.

It was shown in a systematic review that an early reduction of 10% to 15% in GLS was a useful parameter for the prediction of cardiotoxicity.2121 Thavendiranathan P, Poulin F, Lim K, Plana J, Woo A, Marwick T. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy. J Am Coll Cardiol. 2014;63 (25 Pt A):2751-68. A small cohort study was associated with subclinical LV dysfunction as early as 1 week after treatment, showing a significant decrease in GLS and annular systolic velocity of the lateral LV wall 7 days after by trastuzumab treatment.2222 Emren SV, Tuluce SY, Levent F, Tuluce K, Kalkan T, Alacacioglu A, et al. Evaluation of Trastuzumab-induced early cardiac dysfunction using two dimensional Strain Echocardiography. Med Ultrason. 2015;17(4):496-502. Fei et al.2323 Fei HW, Ali MT, Tan TC, Cheng KH, Salama L, Hua L, et al. Left ventricular global longitudinal strain in HER-2 + breast cancer patients treated with anthracyclines and trastuzumab who develop cardiotoxicity is associated with subsequent recovery of left ventricular ejection fraction. Echocardiography. 2016;33(4):519-26. found, in a cohort of 95 patients treated with anthracycline and trastuzumab, and followed for a mean time of 17 months, 20% with cardiotoxicity, demonstrating a significant association between GLS reduction and LVEF decline.2323 Fei HW, Ali MT, Tan TC, Cheng KH, Salama L, Hua L, et al. Left ventricular global longitudinal strain in HER-2 + breast cancer patients treated with anthracyclines and trastuzumab who develop cardiotoxicity is associated with subsequent recovery of left ventricular ejection fraction. Echocardiography. 2016;33(4):519-26.

The presence of diastolic dysfunction was not an independent predictor of CTRCD in our study. The use of diastolic dysfunction as a surrogate marker for predicting trastuzmab-induced cardiotoxicity is controversial. Earlier studies have shown that diastolic impairment of the LV occurs before deterioration in LV EF in anthracycline2424 Lee BH, Goodenday LS, Muswick GJ, Yasnoff WA, Leighton RF, Skeel RT. Alterations in left ventricular diastolic function with doxorubicin therapy. J Am Coll Cardiol. 1987;9(1):184-8.,2525 Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, et al. Early detection of doxorubicin cardiotoxicity: Interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989;118(1):92-8. and transtuzumab2626 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.,2727 Cao L, Cai G, Chang C, Miao AY, Yu XL, Yang ZZ, et al. Diastolic dysfunction occurs early in her2-positive breast cancer patients treated concurrently with radiation therapy and trastuzumab. Oncologist. 2015;20(6):605-14. induced cardiotoxicity. Development of diastolic dysfunction has been reported in up to 57% of patients after treatment with anthracyclines or anthracyclines plus trastuzumab.2828 Cochet A, Quilichini G, Dygai-Cochet I, Touzery C, Toubeau M, Berriolo- Riedinger A, et al. Baseline diastolic dysfunction as a predictive factor of trastuzumab- mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat. 2011;130(3):845-54. Cochet et al.2828 Cochet A, Quilichini G, Dygai-Cochet I, Touzery C, Toubeau M, Berriolo- Riedinger A, et al. Baseline diastolic dysfunction as a predictive factor of trastuzumab- mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat. 2011;130(3):845-54. Serrano et al.2929 Serrano JM, Gonzalez I, Del Castillo S, Muniz J, Morales LJ, Moreno F, et al. Diastolic dysfunction following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors. Oncologist. 2015;20(8): 864-72. evaluated MUGA-derived diastolic parameters and found that impaired LV diastolic function before treatment was an independent predictor of trastuzumab-mediated cardiotoxicity. Boyd at al.1818 Boyd A, Stoodley P, Richards D, Hui R, Harnett P, Vo K, et al. Anthracyclines induce early changes in left ventricular systolic and diastolic function: A single centre study. PLoS ONE. 2017;12(4):e0175544. showed in a cohort involving 140 patients followed for seven days that LV diastolic dysfunction grade significantly increased from 46% to 57% (p < 0.001) after treatment with anthracyclines. Importantly, diastolic dysfunction was more prevalent in the subgroup with a significant reduction in GLS, demonstrating the close association between systolic and diastolic dysfunction.1818 Boyd A, Stoodley P, Richards D, Hui R, Harnett P, Vo K, et al. Anthracyclines induce early changes in left ventricular systolic and diastolic function: A single centre study. PLoS ONE. 2017;12(4):e0175544. A study using MUGA-derived diastolic function parameters investigated whether impairment of systolic function was preceded by diastolic dysfunction in a group of 77 female breast cancer patients undergoing trastuzumab therapy. The results of this study showed a nearly even number of patients with diastolic dysfunction preceding systolic dysfunction (54%), as compared to the number of patients with the opposite order (42%).3030 Reuvekamp EJ, Bulten BF, Nieuwenhuis AA, Meekes MRA, de Haan AFJ, Tol J, et al. Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA). J Nucl Cardiol. 2016;23(4):824-32. Discrepancy among those studies is probably related to the different designs and interpretation of the results.

Limitations

All patients were recruited from one center and the study consisted of a limited number of patients. The study was limited by a short duration of patient follow-up, and therefore any possible long term impact of the early echocardiography abnormalities are uncertain. Long term follow up is therefore necessary to determine the significance of these early observations. The proposed treatment was individually defined, including the use of cardio-protective drugs, which may have influenced our results.

Conclusion

In this prospective cohort of 112 patients undergoing treatment with chemotherapy for breast cancer, we found segmental wall motion abnormality to be a strong predictor of cardiotoxicity. Therefore, assessment of segmental wall motion might be a useful tool in the evaluation of patients at risk of developing CTRCT, resulting in early detection of myocardial dysfunction and potential reduction in morbidity and mortality in these patients.

  • 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.
  • Ethics approval and consent to participate
    This study was approved by the Ethics Committee of the Faculdade de Saúde e Ecologia Humana (FASEH) under the protocol number CAAE 55029916.6.0000.5101. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

References

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    Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231-47.
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    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-92.
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    Yeh ET, Chang H. Oncocardiology - past, present, and future. A review. JAMA Cardiol. 2016;1(9):1066-72.
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    López-Fernández T, Thavendiranathan P. Emerging cardiac imaging modalities for the early detection of cardiotoxicity due to anticancer therapies. Rev Esp Cardiol. 2017;70(6):487-95.
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    Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, et al. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without Trastuzumab. Med Oncol. 2017;34(5):75.
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    Reinbolt RE, Patel R, Pan X, Timmers CD, Pilarski R, Shapiro CL. et al. Risk factors for anthracycline-associated cardiotoxicity. Support Care Cancer. 2016;24(5):2173- 80.
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    Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associate with adjuvant Trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5(4):154-66.
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    Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the american society of echocardiography and the european association of cardiovascular imaging. J Am Soc Echocardiogr. 2016;29(4):277- 314
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Publication Dates

  • Publication in this collection
    13 Dec 2018
  • Date of issue
    Jan 2019

History

  • Received
    30 Mar 2018
  • Reviewed
    05 July 2018
  • Accepted
    23 July 2018
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