Abstract
Anti-neoplastic chemotherapy can determine various side effects, including cardiotoxicity, and no real guidelines for its early detection and management have been developed. The aim of this study is to find some plasmatic markers able to identify breast cancer patients that are at greater risk of developing cardiovascular complications during chemotherapy, in particular heart failure. A prospective study on 100 breast cancer patients with mean age of 66 years in adjuvant treatment with anthracyclines, taxanes, and trastuzumab was performed. Patients underwent cardiological examination before starting treatment (T0) and at 3 months (T1), 6 months (T2), and 1 year (T3) after treatment. Evaluation of serum cardiac markers and N-terminal pro-brain natriuretic peptide (NT-proBNP) was performed at T0, T1, T2, and T3, simultaneously to electrocardiogram and echocardiogram, showing a significant increase in NT-proBNP concentration (p > 0.0001) at T1, T2, and T3, before left ventricular ejection fraction decrease became evident. Human epidermal growth factor receptor 2 (HER2)-negative patients were more susceptible to mild hematological cardiotoxicity, while HER2-positive patients were more susceptible to severe cardiotoxicity. A significant correlation between NT-proBNP increased values after chemotherapy and prediction of mortality at 1 year was evidenced. From our experience, serum biomarker detection was able to support an early diagnosis of cardiac damage, also in the absence of left ventricular ejection fraction decrease. Therefore, the evaluation of specific plasmatic markers for cardiac damage is more sensitive than echocardiography in the early diagnosis of chemotherapy-related cardiotoxicity; furthermore, it can also add a prognostic value on outcome.
Similar content being viewed by others
References
Guo S, Wong S. Cardiovascular toxicities from systemic breast cancer therapy. Front Oncol. 2014;4:346. doi:10.3389/fonc.2014.00346.
Fabian C. Prevention and treatment of cardiac dysfunction in breast cancer survivors. Adv Exp Med Biol. 2015;862:213–30. doi:10.1007/978-3-319-16366-6-14.
Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102:14–25. doi:10.1093/jnci/djp440.
Bowles EJ, Wellman R, Feigelson HS. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104:1293–305. doi:10.1093/jnci/djs317.
Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT, Hudis CA, et al. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat. 2015;149:489–95. doi:10.1007/s10549-014-3253-7.
Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y, et al. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci. 2015;36:326–48. doi:10.1016/j.tips.2015.03.005.
Vulsteke C, Pfeil AM, Maggen C, Schwenkglenks M, Pettengell R, Szucs TD, et al. Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Breast Cancer Res Treat. 2015;152:67–76. doi:10.1007/s10549-015-3437-9.
Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869–79.
Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13:699–709.
Wang L, Tan TC, Halpern EF, Neilan TG, Francis SA, Picard MH, et al. Major cardiac events and the value of echocardiographic evaluation in patients receiving anthracycline-based chemotherapy. Am J Cardiol. 2015. doi:10.1016/j.amjcard.2015.04.064.
Francis SA, Cheng S, Arteaga CL, Moslehi J. Heart failure and breast cancer therapies: moving towards personalized risk assessment. J Am Heart Assoc. 2014;3:e000780. doi:10.1161/JAHA.113.000780.
Villarraga HR, Herrmann J, Nkomo VT. Cardio-oncology: role of echocardiography. Prog Cardiovasc Dis. 2014;57:10–8. doi:10.1016/j.pcad.2014.05.002.
Sandoo A, Kitas GD, Carmichael AR. Breast cancer therapy and cardiovascular risk: focus on trastuzumab. Vasc Health Risk Manag. 2015;11:223–8. doi:10.2147/VHRM.S69641.
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 Imag. 2012;5:596–603.
Chavez-MacGregor M, Niu J, Zhang N, Elting LS, Smith BD, Banchs J, et al. Cardiac monitoring during adjuvant trastuzumab-based chemotherapy among older patients with breast cancer. J Clin Oncol. 2015;33:2176–83. doi:10.1200/JCO.2014.58.9465.
Appel JM, Zerahn B, Møller S, Christensen HM, Søgaard P, Ejlertsen B, et al. Long-term heart function after adjuvant epirubicin chemotherapy for breast cancer. Acta Oncol. 2012;51:1054–61. doi:10.3109/0284186X.2012.702920.
van Boxtel W, Bulten BF, Mavinkurve-Groothuis AM, Bellersen L, Mandigers CM, Joosten LA, et al. New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide. Biomarkers. 2015;20:143–8. doi:10.3109/1354750X.2015.1040839.
Lenihan DJ. Cardiac biomarkers, cardiotoxicity, and active collaboration: is this the final frontier or the wave we should catch? J Am Coll Cardiol. 2014;63:817–8. doi:10.1016/j.jacc.2013.10.060.
Morris PG, Chen C, Steingart R, Fleisher M, Lin N, Moy B, et al. Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res. 2011;17:3490–9. doi:10.1158/1078-0432.CCR-10-1359.
Mokuyasu S, Suzuki Y, Kawahara E, Seto T, Tokuda Y (2014) High-sensitivity cardiac troponin I detection for 2 types of drug-induced cardiotoxicity in patients with breast cancer. Breast Cancer 2014 Feb 23
Katsurada K, Ichida M, Sakuragi M, Takehara M, Hozumi Y, Kario K. High-sensitivity troponin T as a marker to predict cardiotoxicity in breast cancer patients with adjuvant trastuzumab therapy. Springerplus. 2014;3:620. doi:10.1186/2193-1801-3-620.
Ky B, French B, Levy WC, Sweitzer NK, Fang JC, Wu AH, et al. Multiple biomarkers for risk prediction in chronic heart failure. Circ Heart Fail. 2012;5:183–90. doi:10.1161/CIRCHEARTFAILURE.111.965020.
Ky B, Putt M, Sawaya H, French B, Januzzi Jr JL, 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. 2012;63:809–16. doi:10.1016/j.jacc.2013.10.061.
Tian S, Hirshfield KM, Jabbour SK, Toppmeyer D, Haffty BG, Khan AJ, et al. Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol. 2014;4:277. doi:10.3389/fonc.2014.00277.
Komiya K, Ishii H, Murakami J, Yamamoto H, Okada F, Satoh K, et al. Relationship between CT findings and the plasma levels of brain natriuretic peptide in 29 patients with acute cardiogenic pulmonary edema. Acad Radiol. 2012;19:851–6. doi:10.1016/j.acra.2012.03.014.
Ürun Y, Utkan G, Yalcin B, Akbulut H, Onur H, Oztuna DG, et al. The role of cardiac biomarkers as predictors of trastuzumab cardiotoxicity in patients with breast cancer. Exp Oncol. 2015;37:53–7.
Motiwala SR, Szymonifka J, Belcher A, Weiner RB, Baggish AL, Gaggin HK, et al. Measurement of novel biomarkers to predict chronic heart failure outcomes and left ventricular remodeling. J Cardiovasc Transl Res. 2014;7:250–61. doi:10.1007/s12265-013-9522-8.
Fiúza M. Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer. Adv Ther. 2009;26:9–17. doi:10.1007/s12325-009-0048-z.
Vasile VC, Saenger AK, Kroning JM, Klee GG, Jaffe AS. Biologic variation of a novel cardiac troponin I assay. Clin Chem. 2011;57:1080–1. doi:10.1373/clinchem.2011.162545.
Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–6. doi:10.1200/JCO.2009.27.3615.
Cil T, Kaplan AM, Altintas A, Akin AM, Alan S, Isikdogan A. Use of N-terminal pro-brain natriuretic peptide to assess left ventricular function after adjuvant doxorubicin therapy in early breast cancer patients: a prospective series. Clin Drug Investig. 2009;29:131–7. doi:10.2165/0044011-200929020-00007.
Kittiwarawut A, Vorasettakarnkij Y, Tanasanvimon S, Manasnayakorn S, Sriuranpong V. Serum NT-proBNP in the early detection of doxorubicin-induced cardiac dysfunction. Asia Pac J Clin Oncol. 2013;9:155–61. doi:10.1111/j.1743-7563.2012.01588.x.
Ky B, Putt M, Sawaya H, French B, Januzzi Jr JL, 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;63:809–16. doi:10.1016/j.jacc.2013.10.061.
Meacham LR, Chow EJ, Ness KK, Kamdar KY, Chen Y, Yasui Y, et al. Cardiovascular risk factors in adult survivors of pediatric cancer—a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2010;19:170–81. doi:10.1158/1055-9965.EPI-09-0555.
Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015. doi:10.1038/nrcardio.2015.65.
Shelburne N, Adhikari B, Brell J, Davis M, Desvigne-Nickens P, Freedman A, Minasian L, Force T, Remick SC (2014) Cancer treatment-related cardiotoxicity: current state of knowledge and future research priorities. J Natl Cancer Inst 106. doi: 10.1093/jnci/dju232
Stevens PL, Lenihan DJ. Cardiotoxicity due to chemotherapy: the role of biomarkers. Curr Cardiol Rep. 2015;17:603. doi:10.1007/s11886-015-0603-y.
Singh D, Thakur A, Tang WH. Utilizing cardiac biomarkers to detect and prevent chemotherapy-induced cardiomyopathy. Curr Heart Fail Rep. 2015;12:255–62. doi:10.1007/s11897-015-0258-4.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None
Rights and permissions
About this article
Cite this article
De Iuliis, F., Salerno, G., Taglieri, L. et al. Serum biomarkers evaluation to predict chemotherapy-induced cardiotoxicity in breast cancer patients. Tumor Biol. 37, 3379–3387 (2016). https://doi.org/10.1007/s13277-015-4183-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-4183-7