Role of Troponin and BNP in the Management of Patients With Cancer
Cardiotoxicity, or the adverse cardiovascular effects of cancer therapy, can mitigate the benefits of cancer treatments, limit therapeutic options, and impact long-term outcomes.1 Identifying patients at risk is challenging because manifestations and pathophysiologic mechanisms vary across therapeutic agents.2 However, accurate risk stratification would allow tailoring regimens to minimize risk, guide preventive therapies, and determine frequency of monitoring.3 Current strategies for cardiovascular risk stratification in patients with cancer have had limited success, mostly relying on imaging to identify cardiac dysfunction.4 Blood-based biomarkers have been explored as measures of subclinical injury for risk stratification and early identification of cardiotoxicity.5 Here we summarize the literature about the use of troponin (Tn) and B-type natriuretic peptide (BNP) in the management of cardiotoxicity in patients with cancer.
The emergence of high-sensitivity Tn assays (hs-Tn) has redefined the role of Tn from diagnosing acute coronary syndrome to potentially serving as a biomarker of risk and subclinical disease. Both conventional Tn and hs-Tn have been examined for this role in the setting of chemotherapy. Pre-chemotherapy Tn levels are predictive of cardiotoxicity in patients receiving trastuzumab who had a history of anthracycline use. The largest study examining this was a sub-analysis of the Herceptin Adjuvant (HERA) trial, in which 533 patients with breast cancer who were receiving trastuzumab had serial measurements of hs-TnI and hs-TnT.6,7 Abnormal serum levels were defined as >40 ng/L and >14 ng/L for hs-TnI and hs-TnT. The primary endpoints were symptomatic New York Heart Association Class III or IV heart failure and a significant drop in left ventricular ejection fraction (LVEF) (by >10% to <50%). Elevated pre-treatment Tn was associated with a fourfold increase in developing cardiotoxicity.7 These findings were similar to a study by Cardinale et al. that followed 251 patients with breast cancer who were receiving trastuzumab. Pre-therapy Tn was elevated in 7 of 42 patients who developed cardiomyopathy, and levels were undetectable in the 209 patients without cardiotoxicity at follow-up.8 Conversely, in patients without prior history of anthracyclines use, studies have found no association between pre-treatment Tn levels and incident cardiotoxicity.8-10
Tn may also have a role in monitoring cardiac function during cancer therapy. Numerous observational studies have demonstrated that abnormal levels of TnI, hs-TnI, TnT, and hs-TnT are associated with a decrease in LVEF after anthracycline or trastuzumab treatment.8 For instance, in a sub-analysis of the HERA trial, patients with persistent elevation in TnI were more likely to develop cardiotoxicity (84%) compared with patients who had only an initial rise in TnI (37%).9 Cardinale et al. confirmed these findings, demonstrating an association between an increase in TnI and cardiotoxicity after trastuzumab in the setting of prior anthracycline use.8
In patients who received radiation therapy, Tn was not associated with radiation dose or subsequent left ventricular dysfunction.11-14
B-Type Natriuretic Peptide
Results of studies examining an association between pre-treatment BNP level and cardiac toxicity have been mixed. Feola et al. followed 53 patients with breast cancer who were receiving anthracycline treatment and found that patients with a decrease in LVEF of >10% at follow-up had pre-treatment BNP of 55.5 ± 72.3 pg/mL, and those who did not had a baseline of 26.1 ± 21.4 pg/mL.10 Other studies examining the association between BNP and cardiotoxicity did not show similar findings.7,15,16
BNP and N-terminal pro BNP (NT-proBNP) measured during treatment may be more sensitive for predicting cardiotoxicity compared with echocardiography, at least with certain cancer therapies. Lenihan et al. found that patients who experienced cardiotoxicity (defined as reduction in LVEF >15% or >10% and below 50%, symptomatic heart failure or arrhythmia or sudden cardiac death at 1 year) had BNP levels significantly higher after every cycle of anthracycline therapy, with at least 1 measurement >100 pg/mL. By comparison, only 30% of those same subjects had a significant ejection fraction reduction detected beforehand.4 Sandri et al. also found an association between persistent BNP elevation (defined as 153 and 88 ng/L for women and men <50 years of age and 334 and 227 ng/L for those >50 years of age) at 72 hours after chemotherapy, and decreased left ventricular diastolic function 1 year later.11
For cardiotoxicity screening in patients receiving tyrosine kinase inhibitors, several studies have demonstrated elevations in NT-proBNP after treatment without an associated increased risk of cardiovascular outcomes.12-13
Several studies by D'Errico et al. of patients with breast cancer who were receiving radiation therapy found that NT-proBNP was elevated 22 months after radiation therapy and was highest in those who received both anthracyclines and radiation (median of 90 pg/ml in the treatment group compared with 63.2 pg/ml in control group; p = 0.03).11 The BNP increase correlated with cumulative cardiac radiation dose.16,17 The association of BNP with long-term outcomes post-radiation was not examined.
Biomarker-Guided Treatment for Cardiotoxicity
Biomarker-guided prophylaxis to prevent cardiac toxicity in patients with cancer is an area of active research, with several studies showing that serum levels of TnI are modified by medical therapy for heart failure. Cardinale et al. randomized 114 patients undergoing high-dose chemotherapy with post-treatment TnI greater than 0.08 without evidence of heart failure to receive enalapril versus standard care. The primary endpoint was a decrease in ejection fraction >10% to an absolute value below 50%. At 1 year, the treatment group had a significantly higher ejection fraction (62.43% vs. 48.39%; p < 0.001), lower incidence of arrhythmias requiring treatment (2% vs. 17%; p = 0.01), and an incidence of cardiotoxicity of zero (0% vs. 43% risk; p < 0.001).18 Tn-guided treatment may benefit patients on anti-vascular endothelial growth factor antibodies and tyrosine kinase inhibitors.19 The Cardiac CARE trial is an ongoing trial examining TnT-guided initiation of angiotensin-converting-enzyme inhibitors and beta-blocker therapy.20
Data supporting BNP-guided treatment are lacking. In 1 study, 206 patients with breast cancer and a history of anthracycline treatment were randomized to candesartan or placebo with serial biomarker levels and echocardiography. The treatment group had a non-significant trend toward less-frequent symptomatic heart failure (7.8% vs. 12.6%; p = 0.36). There was no change in ejection fraction or biomarker levels.21
Blood-based biomarkers have proved to be useful in various aspects of cardiovascular care. The current evidence for the use of biomarkers in cardio-oncology, however, has major limitations: studies are small in sample size, with significant heterogeneity in patient characteristics and variable assay sensitivity. Although there may be evidence of an association between certain biomarkers and cardiotoxicity, data showing a clinical benefit from routine monitoring are lacking. As a consequence, current clinical recommendations for cardiac biomarker use are largely based on expert opinion.4,23,24 Until high-quality evidence is produced, the use of Tn and BNP measurements should be considered adjunctive to a comprehensive cardiovascular evaluation including a detailed history, physical exam, cardiac imaging, and traditional risk factor assessment. Cardiac biomarkers may not be the ideal markers of risk in this patient population because they reflect myocardial stress and injury, which are often absent in patients undergoing treatment for cancer. The advent of high-throughput precision-medicine tools such as metabolomics and proteomics may lead to the identification of novel biomarkers of risk, but it requires careful study and validation in large and well-defined cohorts.
- Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215-21.
- Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Hear Fail 2013;1:72-8.
- Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. J Am Coll Cardiol 2017;70:2536-51.
- Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768-801.
- Hoeger CW, Hayek SS. Role of Cardiovascular Biomarkers in the Risk Stratification, Monitoring, and Management of Patients with Cancer. Cardiol Clin 2019;37:505-23.
- Cardinale D, Biasillo G, Salvatici M, Sandri MT, Cipolla CM. Using biomarkers to predict and to prevent cardiotoxicity of cancer therapy. Expert Rev Mol Diagn 2017;17:245-56.
- Zardavas D, Suter TM, Van Veldhuisen DJ, et al. Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy. J Clin Oncol 2017;35:878-84.
- Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910-6.
- Lenihan DJ, Stevens PL, Massey M, et al. The Utility of Point-of-Care Biomarkers to Detect Cardiotoxicity During Anthracycline Chemotherapy: A Feasibility Study. J Card Fail 2016;22:433-8.
- Feola M, Garrone O, Occelli M, et al. Cardiotoxicity after anthracycline chemotherapy in breast carcinoma: effects on left ventricular ejection fraction, troponin I and brain natriuretic peptide. Int J Cardiol 2011;148:194-8.
- D'Errico MP, Grimaldi L, Petruzzelli MF, et al. N-terminal pro-B-type natriuretic peptide plasma levels as a potential biomarker for cardiac damage after radiotherapy in patients with left-sided breast cancer. Int J Radiat Oncol Biol Phys 2012;82:e239-46.
- Narayan V, Keefe S, Haas N, et al. Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res 2017;23:3601-9.
- Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26:5204-12.
- Zidan A, Sherief LM, El-sheikh A, et al. NT-proBNP as early marker of subclinical late cardiotoxicity after doxorubicin therapy and mediastinal irradiation in childhood cancer survivors. Dis Markers 2015;2015:513219. doi:10.1155/2015/513219
- Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol 2008;97:318-26.
- Sawaya H, Sebag IA, Plana JC, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 2011;107:1375-80.
- D'Errico MP, Petruzzelli MF, Gianicolo EA, et al. Kinetics of B-type natriuretic peptide plasma levels in patients with left-sided breast cancer treated with radiation therapy: Results after one-year follow-up. Int J Radiat Biol 2015;91:804-9.
- Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474-81.
- Ederhy S, Massard C, Dufaitre G, et al. Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials. Invest New Drugs 2012;30:611-5.
- The Cardiac CARE Trial Can we prevent heart muscle injury related to chemotherapy? (The University of Edinburgh website). January 16, 2019. Available at https://www.ed.ac.uk/usher/edinburgh-clinical-trials/our-studies/ukcrc-studies/cardiac-care/cardiac-care-trial. Accessed December 10, 2019.
- Boekhout AH, Gietema JA, Milojkovic Kerklaan B, et al. Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 2016;2:1030-7.
- Armenian SH, Lacchetti C, Barac A, et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:893-911.
- Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23:vii155-66.
- Virani SA, Dent S, Brezden-Masley C, et al. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy. Can J Cardiol 2016;32:831-41.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound
Keywords: Cardio-oncology, Cardiotoxicity, Cardiotoxins, Natriuretic Peptide, Brain, Anthracyclines, Enalapril, Stroke Volume, Vascular Endothelial Growth Factor A, Angiotensin-Converting Enzyme Inhibitors, Troponin, Metabolomics, Incidence, Proteomics, Acute Coronary Syndrome, Expert Testimony, Follow-Up Studies, Risk Factors, Benzimidazoles, Ventricular Dysfunction, Left, Ventricular Function, Left, Peptide Fragments, Heart Failure, Cardiomyopathies, Echocardiography, Death, Sudden, Cardiac, Arrhythmias, Cardiac, Breast Neoplasms, Protein-Tyrosine Kinases, Radiation Dosage
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