|Year : 2016 | Volume
| Issue : 2 | Page : 107-110
Cardiac biomarker changes with neoadjuvant epirubicin-based chemotherapy
Modupe A Kuti1, Adeyemi Ogunleye1, Adeyinka F Ademola2
1 Department of Chemical Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria
2 Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria
|Date of Web Publication||4-Aug-2016|
Adeyinka F Ademola
Department of Surgery, College of Medicine, University of Ibadan, Ibadan
Source of Support: None, Conflict of Interest: None
Aim: A major concern with epirubicin-based neoadjuvant chemotherapy, a mainstay of neoadjuvant treatment for breast cancer in Nigeria, is their association with cardiotoxicity. We investigated for possible changes in the level of cardiac markers, troponin T, and N-terminal pro-brain natriuretic peptide (NT-ProBNP) detectable after least three cycles of epirubicin in the neoadjuvant setting.
Methods: Thirty consenting female patients who had received at least three cycles of epirubicin-based neoadjuvant chemotherapy were recruited from the Surgical Oncology Unit of the University College Hospital. Patients who were eligible for neoadjuvant chemotherapy for breast cancer but who had not commenced the same were recruited to serve as controls. Samples for troponin T and NT-ProBNP were collected on the day of commencement of the next cycle, before the administration of the dose.
Results: The mean troponin T and median NT-ProBNP values were significantly higher among the women on epirubicin-based chemotherapy (0.76 ng/ml vs. 0.68 ng/ml, P = 0.047 and 114.5 pg/ml vs. 103 pg/ml, P = 0.007), respectively. Values of NT-ProBNP exceeding 200 pg/ml were significantly more frequently observed in the same group (40% vs. 16.7%, P = 0.01). A significant relationship between the number of cycles received and level of NT-ProBNP was observed (P = 0.015). A similar relationship was not observed with troponin T.
Conclusion: Epirubicin-based chemotherapy may be associated with increased elaboration of the cardiac markers, NT-ProBNP, and troponin T early during neoadjuvant chemotherapy. The potential clinical utility of these markers in predicting cardiotoxicity needs to be further evaluated in prospective studies.
Keywords: Epirubicin, N-terminal pro-brain natriuretic peptide, troponin I
|How to cite this article:|
Kuti MA, Ogunleye A, Ademola AF. Cardiac biomarker changes with neoadjuvant epirubicin-based chemotherapy. Nig J Cardiol 2016;13:107-10
| Introduction|| |
The incidence of persons presenting with locally advanced breast cancer (LABC) and inoperable breast cancer has seen major reductions in developed countries.  In Nigeria, like most other resource-poor countries, these modes of presentation continue to significantly characterize the epidemiology of the disease. , In recognition of these, the Breast Health Global Initiative Systemic Therapy Focus Group published treatment guidelines with particular attention to low- and middle-income countries.  These guidelines recommend that primary systemic therapy should be a standard of care for LABC and inoperable breast cancer. Such therapy may involve the use of chemotherapy, biologic targeted therapy, hormone therapy, or a combination of these. 
Most reports from Nigeria on primary systemic (neoadjuvant) therapy are centered on the use of neoadjuvant chemotherapy. ,,, This typically involves the administration of six to eight courses of anthracycline-based chemotherapeutic agents.  An important concern with this regimen is anthracycline-induced cardiotoxicity (AIC). Recent evidence suggests that this is a product of the binding of anthracycline to topoisomerase 2b enzyme, which unlike topoisomerase 2a, is present only in normal cells and not tumor cells.  This binding results in DNA damage with changes that may lead to the generation of reactive oxygen species (ROS). When the rate of production of these ROS overwhelms antioxidant defense mechanisms, a series of events is triggered that is thought to involve mitochondrial dysfunction and terminates with cardiomyocyte necrosis.  In addition to this, it has been demonstrated that doxorubicin induces a rapid increase in the expression and activation of certain extracellular matrix (ECM) effectors such as the matrix metalloproteinases (MMPs). These processes in addition to fibroblast infiltration, and upregulation of tissue-based inhibitors of MMPs contribute to the extensive remodeling of the cardiac tissue ECM that results in the most common manifestation of this drug-induced disorder - heart failure with reduced left ventricular ejection fraction (LVEF). Essentially, cardiomyocyte cell death is followed by extensive abnormal remodeling which results in reduced systolic function and consequently heart failure.
As part of efforts to minimize the occurrence of the above, the European Society of Medical Oncology  published recommendations for cardiotoxicity monitoring and management during chemotherapy. For persons on anthracycline therapy, evaluations of LVEF are recommended at baseline, after the administration of half the planned dose of anthracycline, or after the administration of a cumulative dose of epirubicin of 360 mg/m 2 and before every next administration of the anthracycline. However, given the suboptimal sensitivity of LVEF in the detection of early alterations in myocardial function, the authors note the possible utility of the biochemical markers, specifically the cardiac troponins and natriuretic peptides. They requested studies to assess the clinical utility of these biomarkers in monitoring cardiac dysfunction associated with oncological therapy. As part of and providing a basis for further such studies, we here describe the changes in the markers, troponin I, and -terminal pro-brain natriuretic peptide (NT-ProBNP) among breast cancer patients on neoadjuvant treatment with epirubicin.
| Methods|| |
Participants were recruited from Surgical Oncology Clinic of the University College Hospital, Ibadan, during a 6-month period. Inclusion in the study required that consenting female patients must have histologically diagnosed breast cancer and have received at least three cycles of epirubicin-based neoadjuvant chemotherapy. Patients who were eligible for neoadjuvant chemotherapy for breast cancer but who had not commenced the same were recruited to serve as controls. All patients receiving epirubicin are required to have echocardiographic evidence of normal systolic function before the commencement of the anthracycline-based chemotherapy. The dose of epirubicin was calculated at 100 mg/m 2 . Staging of disease before the commencement of chemotherapy was recorded.
Ethical clearance was obtained from the University of Ibadan/University College Hospital, Ibadan, Ethical Review Committee.
Sample collection/laboratory studies
Venous blood samples were collected into plain bottles. This was done on the day of commencement of the next cycle, before the administration of the dose. Serum obtained was stored frozen at −20°C until analysis. The analysis of both troponin T and NT-ProBNP was done by enzyme-linked immunosorbent assay.
Continuous variables are presented as mean (standard deviation) and categorical variables as number (%). Comparisons of means were performed using the Student's t-test, whereas proportions were compared using the Chi-squared test. Pearson's or Spearman's correlations were done with parametric and nonparametric variables, respectively.
| Results|| |
Sixty women with histological diagnosis of breast cancer were recruited during the period of the study. Thirty of these women had completed at least three cycles of epirubicin-based neoadjuvant chemotherapy. The others were yet to commence any form of treatment. General characteristics of these subjects are as shown in [Table 1]. The age range for those on treatment was 32-67 years, whereas for those yet to commence chemotherapy, it ranged from 32 to 70 years. Over 80% of the women presented with Stage 3 disease and above, in both groups.
The median NT-ProBNP value of the women on chemotherapy was significantly higher than for those who had yet to commence therapy [Table 1]. One of the women who had completed four cycles of epirubicin had a markedly elevated NT-ProBNP value (>2000 pg/ml). When her data were excluded from the analysis, the difference in the median NT-ProBNP value was still significantly higher for those on epirubicin (113.0 (420.0) pg/ml vs. 103.0 (317) pg/ml, P = 0.01). Values exceeding 200 pg/ml were observed in 5 (16.7%) of those not on epirubicin and 12 (40.0%) among those on epirubicin. This difference was statistically significant (P = 0.045). Furthermore, there was a significant relationship between the number of cycles received and the level of NT-ProBNP (Spearman's rho = 0.312, P = 0.015) [Table 2]. This was also true for the relationship between cumulative epirubicin dose received and level of NT-ProBNP (Spearman's rho = 0.301, P = 0.019). The mean troponin T values of the women on epirubicin were significantly higher than for those yet to commence the drug [Table 1]. None of the participants, however, had a value above 0.01 ng/ml, the 99 th percentile that would have been consistent with acute myocardial infarction. Troponin T levels did not have any significant relationship with a number of cycles of chemotherapy received or cumulative epirubicin dosage.
|Table 2: Association of NT-ProBNP and troponin with certain clinical characteristics |
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| Discussion|| |
The present study demonstrates statistically significant higher levels of the cardiac biomarker NT-ProBNP among female patients who have received at least three cycles (300 mg/m 2 ) of anthracycline-based chemotherapy for breast cancer in the neoadjuvant setting compared with similar women yet to receive the drug. Furthermore, the women on treatment were also more likely to have values that exceeded 200 pg/ml. The value of 200 mg/dL is higher than would be associated with health in females in the age group studied. Increased production of NT-ProBNP or its sister molecule BNP, from cardiac myocytes, is thought to be associated with ventricular stress induced by myocardial stretching.  The findings in this study may thus suggest epirubicin therapy induces ventricular stretching which may be detectable by increased NT-ProBNP after just 3 months of neoadjuvant chemotherapy. Meinardi et al. have previously demonstrated significantly higher concentrations of BNP after only 4 weeks of epirubicin-containing therapy for breast cancer. Their study was however carried out in the adjuvant setting among patients who had also received locoregional radiotherapy.  A study conducted by Chow et al. to evaluate the safety profile of an epirubicin-containing regimen in the neoadjuvant setting reported a significant decrease in the level of NT-ProBNP compared to baseline values among 34 women with LABC. They however used a smaller dose of epirubicin (75 mg/m 2 ) compared with the dose given to our patients (100 mg/m 2 ). Furthermore, all their measurements were taken after three cycles.  The seeming difference in the latter report and the current study is really an underscoring that cumulative dose is a major risk factor for AIC, , as the cumulative dose for our patients are higher.
The demonstration of a higher concentration of troponin T among our epirubicin-treated cohort is consistent with the proposed pathogenesis of nature of the injury induced as including myocyte necrosis. The study by Chow et al.  reported an insignificant increase in troponin I among their cohort of patients although as noted earlier, they used a smaller dose of epirubicin. Similarly, Mercuro et al.  found no significant increase in the level of troponin I among their set of 16 patients with histologically confirmed tumors at different locations (including breast cancer). The diversity of the diagnoses in the latter study meant different regimen of chemotherapy with some combinations using as low as 40 mg/m 2 of epirubicin. The association of dose received with troponin release is also supported by the report that among women treated with high-dose chemotherapy for poor prognosis breast cancer, over 50% of women on a regimen containing epirubicin at 200 mg/m 2 experienced a rise in troponin I concentration exceeding 0.5 ng/ml.  Similar to our findings, none of the troponin I concentrations observed was outside of the reference interval. However, unlike the latter group, we did not demonstrate a relationship between the number of cycles received and higher troponin T concentrations. This may be explained by the difference in the sampling time employed by our group. While Cardinale et al. measured troponin I in the hours (up to 72 h) after administration of the chemotherapeutic agent, our sampling was done 4 weeks after the last dose. This sampling frame may have allowed us to identify, among our women, those with significant and more lasting myocardial injury/necrosis.
As we have demonstrated that neoadjuvant chemotherapy with epirubicin causes significant changes in the levels of the biomarkers, NT-ProBNP and troponin T among women with breast cancer, the degree of change or the persistence of the change may be useful in identifying those women at risk of the long-term development of cardiotoxicity. Pichon et al. conducted prospective protocol of anthracycline-treated breast cancer patients that compared BNP concentrations and LVEF, both determined during and after treatment. They reported that BNP concentration was negatively correlated with LVEF and suggested, following receiver operating curve analysis, that a BNP concentration of 100 ng/ml or greater, at any time during therapy, may be a warning for the potential development of anthracycline cardiac toxicity. Similarly, a report of 71 patients undergoing anthracycline therapy for breast cancer observed that those with persistently elevated NT-ProBNP concentrations during therapy had significantly worse LVEF compared with those with normal or only transient elevation of the molecule. 
The early identification of women at risk of anthracycline-induced cardiac injury made possible by the use of these markers may allow them to complement or even replace the demanding echocardiography schedule recommended for persons on anthracycline therapy.  In resource-poor economies, the serial measurement of these biochemical markers may also be more easily affordable in comparison with periodic echocardiography studies. Early identification may also allow for proactive therapy alteration of therapy or the use of cardioprotective strategies such as the use of dexrazoxane or angiotensin-converting enzyme inhibitor therapy. 
| Conclusion|| |
We have demonstrated that anthracycline therapy in the neoadjuvant setting results in the increased elaboration of the cardiac markers NT-ProBNP and troponin T. The potential clinical utility of these markers in predicting cardiotoxicity in this setting needs to be further evaluated in prospective studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]