Investigation of biomarker-based follow-up of anthracycline-induced cardiotoxicity in patients with breast cancer based on the latest protocol from the European Society of Cardiology guideline on cardio-oncology

doi:10.21203/rs.3.rs-2840873/v1

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Research Article

Investigation of biomarker-based follow-up of anthracycline-induced cardiotoxicity in patients with breast cancer based on the latest protocol from the European Society of Cardiology guideline on cardio-oncology

https://doi.org/10.21203/rs.3.rs-2840873/v1

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Background

Anthracyclines are commonly used for the treatment of solid tumors and hematological malignancies because of their inevitable dose-dependent cardiotoxic effects. The study aimed to assess the feasibility of applying a biomarker-based surveillance strategy according to European guidelines for the early prediction of anthracycline-induced cardiotoxicity in patients with breast cancer.

Methods

From April 2018 to December 2021, 45 women with breast cancer (53.9 ± 11.0 years) treated with anthracycline-based regimens were evaluated for 1 year. We measured and analyzed high-sensitivity cardiac troponin T (hsTnT), B-type natriuretic peptide (BNP), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) at baseline, and 3 and 6 months after the initiation of anthracycline-based chemotherapy. Cardiotoxicity was defined as a reduction in LVEF > 10% compared with baseline to LVEF < 53%, or a decline in GLS > 15% from baseline.

Results

After initiating anthracycline treatment, hsTnT levels peaked at 3 months, whereas BNP levels were the highest at 6 months. Cardiotoxicity was detected in 18 (20.0%) patients (one patient with LVEF decline), where GLS declined over time yet became significant only after 6 months. Elevated hsTnT at 3 months were significantly associated with a GLS decline at 6 months (P < 0.001, Youden index 0.009 g/mL increase from baseline; sensitivity and specificity were 100% and 80.5%, respectively). In contrast, changes in BNP were not associated with changes in LVEF or GLS. No symptomatic heart failure occurred within 1 year of chemotherapy.

Conclusions

Among patients with early-stage breast cancer, an increase in hsTnT at 3 months after initiation of the anthracycline-based regimen predicted a subsequent decline in GLS with high sensitivity and moderate specificity.

anthracycline-induced cardiotoxicity

breast cancer

biomarker

global longitudinal strain

left ventricular ejection fraction

Advances in cancer therapy, moving away from traditional cytotoxic chemotherapy to personalized treatments with targeted therapy and immunotherapy, have increased the number of long-term cancer survivors, but have also contributed to an exponential increase in the number of patients suffering from serious side effects related to cancer therapy, especially cardiovascular events.¹ In patients with breast cancer and hematologic malignancies, use of cardiotoxic agents increases the risk of heart failure by approximately 1.7 and 3.6 times, respectively.²

Anthracyclines, a class of cytotoxic agents, are still widely used in chemotherapy for solid tumors and hematologic malignancies and are known to exhibit dose-dependent cardiotoxicity, with doxorubicin showing a 5% incidence of heart failure at a cumulative dose of 400 mg/m² and 48% at 700 mg/m².³ In addition, the susceptibility to anthracycline-induced cardiotoxicity varies with genetic and cardiovascular risk factors,⁴ even in the low cumulative dose (e.g., doxorubicin < 250 mg/m²).⁵ Most patients remain asymptomatic during the early phase of heart failure⁶ and delayed initiation of cardioprotective agents reduces the likelihood of cardiac functional recovery.⁷ Therefore, early detection of subclinical cardiac impairment is crucial, and much effort has been made to establish a methodology for cardiac dysfunction surveillance.⁸

In recent decades, speckle-tracking strain echocardiography has emerged as a more efficient method for detecting subtle myocardial defects than conventional echocardiography. Two-dimensional global longitudinal strain (GLS) is being proven as a useful tool to detect asymptomatic LV dysfunction associated with future cardiovascular events.⁹ In a recent randomized controlled trial, the GLS-guided initiation of cardioprotective agents was associated with a less frequent reduction of left ventricular ejection fraction (LVEF) by > 10% from the normal compared with the LVEF-guided therapy.¹⁰ Nevertheless, GLS has disadvantages such as insufficient standardized measurements between echo models, high cost, and the need for frequent echocardiographic examinations, which are still preventing facilities from incorporating it into clinical use.¹¹

On the other hand, regarding biomarkers reflecting preclinical cardiac dysfunction, cardiac troponin and natriuretic peptide have been shown to be among the few biomarkers associated with future cardiac events in cancer patients.^12–14 A pilot study showed the feasibility of serial measurement of cardiac troponin and early treatment with angiotensin-converting enzyme inhibitors in preventing cancer therapy-related cardiac dysfunction.¹¹ In this context, the latest European Society of Cardiology (ESC) guidelines on cardio-oncology recommends the use of these biomarkers for baseline risk stratification and diagnosis of early cardiotoxicity in the field of cardio-oncology.¹⁵ However, more data are still needed on biomarkers and advanced echocardiography for the detection of early cardiotoxicity, including cutoffs (i.e., absolute values or changes from baseline) in cardiac biomarkers to detect clinically meaningful myocardial injuries.

This study aimed to assess the relationship between biomarkers, especially cardiac troponin T and B-type natriuretic peptide (BNP), and their values and changes in anthracycline-induced cardiotoxicity among patients with breast cancer whose biomarkers and echocardiography were serially measured during chemotherapy according to the latest ESC guidelines.

Participants

Female patients diagnosed with early breast cancer who started chemotherapy at the Keio University Hospital between April 2018 and December 2021 were considered eligible. We prospectively obtained all data including information on medication use, smoking history, and medical and surgical histories. Patients who underwent chemotherapy but did not receive anthracyclines were excluded from the study. All patients received anthracyclines with cyclophosphamide four times every 3 weeks for four times in the first 3 months, and if patients were eligible, subsequent taxane agents were administered. The patients were followed up for 1 year after the initiation of chemotherapy. Before the launch of this study, information on the objectives and social significance of the study, as well as an abstract, was provided for clinical trial registration to the University Hospital Medical Information Network of Japan (UMIN000033773). The Institutional Review Board of the Keio University Hospital approved the study protocol (permission number: 20170413), and the study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient before participation in the study.

Study protocol

As shown in Fig. 1, three echocardiography tests and three blood tests were performed during the 6 months study period. Echocardiography and blood tests were conducted on the same day. The first test was performed before the first initiation of anthracycline agents with cyclophosphamide; the second test was performed before the first administration of taxane agents (after completing four cycles of anthracycline agent administration); and the third test was performed 3 weeks after the last taxane agent administration.

Echocardiography

Each transthoracic echocardiography (TTE) was performed by experienced technicians using a GE ultrasound system (Vivid 7, E9, E95; GE Healthcare, Milwaukee, WI, USA). For the measurement of two-dimensional GLS, four-, three-, and 2-chamber apical images of the left ventricle were obtained for four cardiac cycles. The GLS was measured using automated myocardial contours generated by placing seven seed points on each of the three long-axis views using EchoPAC (v202, AFI, GE Healthcare, Milwaukee, WI, USA). The contours were adjusted as necessary. After three attempts, poorly tracked segments were excluded, and the GLS was recorded as the average of the remaining segments. As for other echocardiographic parameters, we included LVEF (calculated by the modified Simpson method), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), E/e', estimated pulmonary artery end-systolic pressure (PASP; calculated as the sum of tricuspid regurgitation peak gradient and estimated right atrial pressure (3 mmHg if inferior vena cava diameter [IVC] is < 20 mm with ≥ 50% respiratory change [RC]; 10 mmHg if either IVC is ≥ 20 mm or RC is < 50%; 15 mmHg if IVC is ≥ 20 mm and RC is < 50) and right ventricle S' (RVS’).

Blood test

High-sensitivity cardiac troponin T (hsTnT) was measured using the Elecsys Troponin T hs assay (Roche), with a lower detection limit of 0.003 ng/ml, and > 0.014 ng/ml (99th percentile) was considered elevated. BNP was measured by AIA-Pack CL BNP (Tosoh) whose lower detection limit was 2.0 pg/ml, and > 18.4 pg/ml was considered elevated.

Outcome definitions

Both LVEF- and GLS-based cancer therapy-related cardiac dysfunction (CTRCD) were defined by the criteria suggested by the American Society of Echocardiography and European Association of Cardiovascular Imaging.¹⁶ LVEF-based CTRCD was defined as a 10% or greater change to less than 53%. When the baseline LVEF was below the lower LVEF threshold, a further reduction of 10% constituted CTRCD. GLS-based CTRCD is defined as a relative reduction greater than 15% in GLS compared to baseline. We performed the analysis according to the definition described above and then performed the same analysis later with the ESC definition, whose GLS-based CTRCD was defined as the same and LVEF-based CTRCD was defined as a 10% or greater change to less than 50%.¹⁵

Statistical analysis

Categorical variables were analyzed using the chi-squared test and expressed as percentages. Continuous variables were analyzed using the Mann-Whitney U test after evaluating the normalcy of data (using the Shapiro-Wilk test) and were expressed as means and interquartile ranges. For predictive variables in the univariate model (P < 0.05), the receiver operating characteristic (ROC) curve was computed, and the cutoff that produced maximum sensitivity and specificity was considered by calculating the Youden index. Statistical analyses were performed using R software (version 4.2.1) and GraphPad Prism 9 (GraphPad Software, San Diego, California, USA).

Participants

The patient flow is described in Fig. 2. Of the 107 females, there were 38 without anthracycline agents in their chemotherapy regimens; hence, they were excluded from the study. Among the remaining 69 patients, 15 were excluded due to a lack of baseline echocardiographic or laboratory test results, five were excluded for low-quality strain echocardiographic images, and four were lost or died within 6 months of follow-up. In total, data from 45 women were analyzed.

The demographic and clinical characteristics of the participants are shown in Table 1. Among 45 patients (mean age 53.9 ± 11.0 years) who received anthracyclines (epirubicin, n = 43 [95.6%]) combined with cyclophosphamide, 44 patients (97.8%) also received taxane. None of the patients developed CTRCD within 3 months, and nine patients (20%) who were asymptomatic developed CTRCD within 6 months. All CTRCDs met the GLS-based criteria, whereas only one met the LVEF-based criteria. These results were similar to those defined in the ESC of Cardiology guidelines. The development of CTRCD in our study was irrespective of smoking, history of diabetes mellitus, ischemic heart disease, or radiotherapy, since all of which are considered risk factors for CTRCD.¹⁵ There were also no significant differences in age, BMI, and other risk factors such as hypertension, medication status, oncologic status, dose of anthracycline and taxane, baseline hsTnT, and BNP. Among the nine patients who developed CTRCD, one patient had prior use of anthracycline, and one patient with a higher age (73 years) had atrial flutter. The remaining seven patients had no attributable risk factors for CTRCD. Of note, our study included two patients who had received prior HER2-targeted therapy, and five patients who started three months after the initiation of anthracycline, and all of them neither developed CTRCD nor had an elevation of hsTnT.

Table 1

Baseline patient characteristics
	Total (n = 45)	No cardiotoxicity (n = 36)	Cardiotoxicity (n = 9)	P value (No cardiotoxicity vs. Cardiotoxicity)
Age (years) [range]	53.9 ± 11.0 [28–73]	53.6 ± 11.0 [28–72]	55.2 ± 11.7 [40–73]	0.717
BMI	22.21 ± 3.3	22.49 ± 3.4	21.09 ± 2.7	0.2077
Cardiovascular risk factors
Hypertension	10 (22.2)	8 (22.2)	2 (22.2)	> 0.9999
Diabetes mellitus	1 (2.2)	1 (2.8)	0 (0)	> 0.9999
Dyslipidemia	4 (8.9)	2 (5.6)	2 (22.2)	0.1734
Prior use of ACEi, Beta blockers	4 (8.9)	4 (11.1)	0 (0)	0.5687
Ischemic heart disease	1 (2.2)	1 (2.8)	0 (0)	> 0.9999
Atrial fibrillation/flutter	2 (4.4)	1 (2.8)	1 (11.1)	0.3636
Smoking	3 (6.7)	3 (8.3)	0 (0)	> 0.9999
Oncologic status
Left-sided breast cancer	27 (60)	21 (58.3)	6 (66.7)	0.4781
Bilateral breast cancer	2 (4.4)	2 (5.6)	0 (0)	> 0.9999
Neoadjuvant chemotherapy	22 (48.9)	19 (52.8)	3 (33.3)	0.4591
Adjuvant chemotherapy	19 (42.2)	14 (38.9)	5 (55.6)	0.4605
Chemotherapy for recurrent/metastatic	4 (8.9)	3 (8.3)	1 (11.1)	> 0.9999
Radiotherapy	27 (60)	21 (58.3)	6 (66.7)	0.7212
Anthracycline administration
Epirubicin	43 (95.6)	34 (94.4)	9 (100)	> 0.9999
Cumulative dose (mg/m²)	356.1 ± 40.2	356.9 ± 36.7	352.9 ± 54.2	0.8386
Doxorubicin	2 (4.4)	2 (5.6)	0 (0)	> 0.9999
Cumulative dose (mg/m²)	280 ± 99.0	280 ± 99.0
Taxane administration
No taxane administration	1 (2.2)	1 (2.8)	0 (0)	> 0.9999
Docetaxel	38 (84.4)	30 (83.3)	8 (88.9)	> 0.9999
Cumulative dose (mg/m²)	291.6 ± 44.6	290.8 ± 49.7	294.4 ± 15.9	0.7247
Paclitaxel	6 (13.3)	5 (13.9)	1 (11.1)	> 0.9999
Cumulative dose (mg/m²)	677.2 ± 355.5	794.6 ± 233.5	90 ± 0.0
Categorical variables were analyzed using the chi-squared test and expressed as percentages. Continuous variables were analyzed using the Mann-Whitney U test after evaluating the normalcy of data (using the Shapiro-Wilk test) and were expressed as means and interquartile ranges.

Changes in echocardiographic parameters and biomarkers

The time courses of echocardiographic parameters and serum biomarkers are depicted in Figs. 3 and S1. The GLS significantly decreased by 3 months (mean difference, -1.1%; mean relative difference, 5.0%) and continued to decrease further to 6 months (mean difference − 1.6%, mean relative difference, 8.0%). In contrast, an LVEF decrease in the CTRCD group at 3 months (mean difference − 4.2%) was observed but was not statistically significant. All other echocardiographic parameters remained unchanged throughout the study period (Figure S2).

As for serum biomarkers, the absolute value of hsTnT peaked at 3 months, whose elevations were all significant in both groups, and a significant between-group difference was observed only at 3 months. Although we observed increased BNP levels at 6 months, they remained insignificant.

Association between echocardiographic parameters and biomarkers

Figure 4 shows that both the absolute value and difference in hsTnT levels at 3 months were significantly associated with a decline in GLS at 6 months (r² = 0.213, P = 0.0014 for absolute value; r² = 0.211, P = 0.0015 for the difference between baseline and 3 months), whereas no association was observed with the decline in LVEF. Notably, no significant association was observed between the BNP levels and GLS (Figure S3).

We then analyzed the predictive value of hsTnT levels in GLS-defined CTRCD. Figure 5 shows that both the absolute value and the elevated difference in hsTnT levels at 3 months successfully predicted the decline in GLS at 6 months (absolute value, P < 0.001; Youden index, 0.018 ng/ml; ROC-AUC, 0.853; sensitivity and specificity, 88.9% and 80.5%, respectively). The differences from baseline (P < 0.001), Youden index (0.009 ng/ml), ROC-AUC (0.875), with sensitivity and specificity at 100% and 80.6%, respectively. These results were further supported by an analysis that excluded patients with a cardiologic history, previous use of anthracyclines, and use of ACE inhibitors, ARBs, or beta-blockers (Figure S4).

The latest ESC guidelines on cardio-oncology propose biomarker- and echocardiography-based screening strategies for the early diagnosis of CTRCD. This single-center prospective cohort study, which followed the ESC guidelines for patients with breast cancer receiving anthracycline-based chemotherapy, offers several insights. First, hsTnT levels peaked 3 months after the first initiation of anthracycline agents (i.e., completing 4-cycle of anthracyclines). Second, LV systolic function deteriorated over time, but it only became prominent enough to be diagnosed with CTRCD within 6 months. Finally, the increase in hsTnT, but not BNP, was significantly associated with the subsequent development of CTRCD, particularly when the absolute value exceeded 0.018 ng/ml or the increase from baseline exceeded 0.009 ng/ml.

Recently, the Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes (SUCCOUR) trial reported the efficacy of treating early detected cardiotoxicity with cardioprotective agents, and the use of TTE with strain analysis has gained widespread acceptance as a convenient, less invasive, and sensitive modality for detecting CTRCD.¹⁰ Cardinale et al. previously demonstrated that the most significant deterioration of LVEF occurs within 6 months,¹⁴ while most studies have shown that the onset of GLS decline occurs mostly 3 months after the first initiation of anthracyclines.^17–21 A similar trend was observed in our study for both LVEF and GLS. The incidence of CTRCD was found to be 20% by the GLS-based definition and 2.2% by the LVEF-based definition, which is also consistent with previous studies.^{17,22, 23} However, our study reached different conclusions from past similar studies involving patients with relatively preserved EF, insignificant baseline hsTnT values, and a significant increase in hsTnT.^18,24

Few studies have addressed both biomarkers and echocardiographic parameters simultaneously for a longer period.¹⁸ However, the results are conflicting with regard to the timing of the decline in cardiac function and the association between the decline in cardiac function and the increase in cardiac troponins. Elevated cardiac troponin is a matter of debate in predicting the deterioration of LV function, as findings have been inconsistent across studies, including multiple foci on malignancies.^25,26 Data on the difference in cardiac troponin levels between patients with or without CTRCD are limited, but several studies reporting an increase in cardiac troponin after initiating anthracyclines were usually detected after three or four cycles of administration, regardless of the type of malignancy, dose, regimen, and protocol.^{17– 21}

Currently, the benefit of early detection of the rise in cardiac troponins remains inconclusive, as demonstrated by the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial,²⁷ which showed that cardioprotective agents can treat the rise in troponins but failed to demonstrate an association with cardiac function parameters. In contrast, a small-scale study suggested the feasibility of repeated measurement of cardiac troponin and early drug treatment in preventing CTRCD.⁸ The lack of consistency between the results of these trials may be due, in part, to the unclear cutoff for cardiac troponin, which is used to define myocardial damage that is strongly associated with future cardiac dysfunction and clinical outcomes. The cutoffs for hsTnT presented in our study indicate good discrimination but require further validation in larger studies. The current Cardiac CARE study²⁸ addressed this point and clarified the future role of measuring cardiac troponins.

The ability of cardiac troponin levels to predict CTRCD may also be influenced by ethnicity. Some studies have reported a higher susceptibility to CTRCD in patients of African ancestry,²⁹ but to our knowledge, no previous studies have examined the difference in the increase in cardiac troponins among different ethnicities. In the present study, both the absolute value and/or the change in hsTnT values and the incidence of CTRCD were similar to those of a previous study with different ethnicities.²⁴ Even though certain genetic variants have been identified as high or low risk,¹⁵ our study suggests that hsTnT levels and the incidence of CTRCD after initiating anthracyclines in patients with breast cancer are not significantly different in the monoracial Japanese population compared with Western populations.

The differences in chemotherapy protocols may explain the variation in conclusions related to the increase in hsTnT levels. Taxane and cyclophosphamide are also known to cause myocardial dysfunction, with varying incidences depending on the agent and dose. For instance, docetaxel has been reported to affect 2.3–13% of the population, whereas the incidence of paclitaxel is less than 1%.³⁰ For cyclophosphamide, the incidence varies from 7–28% depending on its dose.^30,31 However, few studies have addressed the difference in protocols with the same chemotherapeutic agents. In addition, no comparative studies have evaluated the cardiotoxicity of different agents in the same class. Previous studies have implied that epirubicin may be less likely than doxorubicin to cause myocardial dysfunction.⁹ In our study, most patients received epirubicin, but the cumulative dose exceeded 250 mg/m² doxorubicin equivalent, which is considered as a large amount; thus, recommended to follow up hsTnT as Class IIa in the ESC guidelines.¹⁵ Our result may well support the recommendation to measure the hsTnT of patients who are to receive the amount of anthracycline, and they may be considered to start monthly follow-ups of echocardiography for the subsequent 3 months in order to start cardioprotective agents and even SGLT2 inhibitor, which is suggested to be effective in preventing the decline of LV function by emerging results.³²

In facilities, acquiring reliable GLS is difficult; hence, hsTnT is undoubtedly a reliable biomarker to detect patients, especially those categorized as low-risk, who need to be referred for close cardiac surveillance. Highly-sensitive cardiac troponin can also contribute to populations for whom obtaining echocardiographic images of sufficient quality for analysis is challenging. A prospective study reported that approximately 10% of cases failed to measure the GLS due to insufficient image quality (e.g., left mastectomy and left breast prosthesis),³³ which is comparable to the results of our study. As long as the quality of echocardiographic images is reported to influence the evaluation of CTRCD,³³ further efforts should be made to identify the true cutoffs of hsTnT and to identify the ideal use for early detection of CTRCD to address the weakness of echocardiographic evaluation.

Our study has several limitations. First, the results were derived from a single university hospital with a single ethnic group. Second, most of our study population had a low to moderate risk of a cardiovascular event; hence, the results should be interpreted accordingly. Third, our study population incorporated a minor variance in chemotherapeutic agents, such as a small number of patients receiving doxorubicin and/or paclitaxel, whereas most patients received epirubicin and docetaxel, which might have affected the results. Fourth, a certain number of patients (10%) were excluded from the present analysis because of the low quality of echocardiographic images due to left-sided surgery or radiotherapy.

Although the role of cardio-oncology is being increasingly recognized, there are still obstacles to implementing all potentially beneficial practices in every facility. Indeed, routine GLS measurement is still not widely available in facilities administering chemotherapy for solid tumors and hematologic malignancies because of cost and technical limitations, whereas cardiac troponin is readily available in clinical practice. When following up breast cancer patients receiving anthracyclines according to the guideline-recommended algorithm, we found that our cutoff values of cardiac troponin for the early diagnosis of CTRCD have high sensitivity and moderate specificity. Further large-scale and cohort studies are needed to validate biomarker-based screening and treatment of CTRCD.

BNP - B-type natriuretic peptide

CTRCD - cancer therapy-related cardiac dysfunction

ESC - European Society of Cardiology

GLS - global longitudinal strain

hsTnT - high-sensitivity cardiac troponin T

IVC - inferior vena cava diameter

LVEDV - left ventricular end-diastolic volume

LVEF - left ventricular ejection fraction

LVESV - left ventricular end-systolic volume

PASP - pulmonary artery end-systolic pressure

PRADA - Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy

RC - respiratory change

ROC - receiver operating characteristic

TTE - transthoracic echocardiography

Ethics approval and consent to participate

The Institutional Review Board of the Keio University Hospital approved the study protocol (permission number: 20170413), and the study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient before participation in the study.

Consent for publication

Our manuscript did not contain any individual person’s data in any form, including individual details, images, or videos.

Availability of data and materials

All datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

S. Ko received Grant-in-Aid for JSPS (Japan Society for the Promotion of Science) Fellows, which had no role in this study’s design, conduct, analysis, and manuscript.

Authors’ contributions

Conceptualization was done by T. Hayashida and MK. Data collection and analysis were performed by SK. TH and YI took responsibility for the echocardiographic data’s integrity and analysis’s accuracy. Drafting was done by SK and YS. Reviewing was done by all authors. Supervision was done by T Hayashida and MK. All authors read and approved by the final manuscript.

Acknowledgments

We thank Ms. Hiromi Momota for creating the database with considerable work on submitting and extracting data for the current study.

Authors’ information

a. Department of Cardiology, Keio University School of Medicine, Tokyo, Japan

b. Institute for Integrated Sports Medicine, Keio University School of Medicine, Tokyo, Japan

c. Department of Surgery, Keio University School of Medicine, Tokyo, Japan

d. Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan

e. Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.

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Investigation of biomarker-based follow-up of anthracycline-induced cardiotoxicity in patients with breast cancer based on the latest protocol from the European Society of Cardiology guideline on cardio-oncology

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Abstract

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Background

Methods

Participants

Study protocol

Echocardiography

Blood test

Outcome definitions

Statistical analysis

Results

Participants

Changes in echocardiographic parameters and biomarkers

Association between echocardiographic parameters and biomarkers

Discussion

Conclusions

Abbreviations

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References

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