Abstract
Purpose
Anthracyclines are an integral component of breast cancer chemotherapy. They exert many cardiotoxic effects, including heart failure. The onset of anthracycline-induced heart failure (AIHF) can occur years after completion of chemotherapy and incurs significant morbidity and mortality. Few studies have attempted to characterize risk factors for its development. Our purpose was to determine the incidence of early and late AIHF in breast cancer survivors and to identify factors that increase the risk for late-onset AIHF.
Methods
Patients with invasive breast cancer who received doxorubicin-containing chemotherapy at University Hospitals Case Medical Center from 1998 to 2006 were included. Medical history and tumor and treatment characteristics were abstracted from medical records. Patients who developed heart failure were compared to those who did not and were also stratified based on timing of heart failure.
Results
One thousand one hundred fifty-three patients received doxorubicin-based chemotherapy for invasive breast cancer with an average follow-up of 7.6 years (standard deviation (SD) = 3.4). The overall incidence of heart failure was 10.4, with a 2.9 and 7.6 % incidence of early- and late-onset heart failure, respectively. Human epidermal growth factor receptor 2 (HER2) status, hypertension, and coronary artery disease were significant predictors for both heart failure groups (p < 0.001). Type II diabetes was a risk factor for the late-onset AIHF group (p < 0.001).
Conclusions
HER2 status and cardiovascular risk factors increased the risk of heart failure among doxorubicin users. Patients with type II diabetes were at increased risk of late-onset AIHF.
Implications for cancer survivors
We identified at risk survivors who may benefit from prolonged monitoring and/or early intervention.
Similar content being viewed by others
References
Dang CT. Drug treatments for adjuvant chemotherapy in breast cancer: recent trials and future directions. Expert Rev Anticancer Ther. 2006;6:427–36.
Sachelarie I, Grossbard ML, Chadha M, Feldman S, Ghesani M, Blum RH. Primary systemic therapy of breast cancer. Oncologist. 2006;11:574–89.
Maughan KL, Lutterbie MA, Ham PS. Treatment of breast cancer. Am Fam Physician. 2010;81:1339–46.
Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007;8:1039–58.
Von Hoff DD, Layard MW, Basa P, Davis Jr HL, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710–7.
Chen MH, Colan SD, Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res. 2011;108:619–28.
Yeh ETH, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53:2231–47.
Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115:155–62.
Sabel MS, Levine EG, Hurd T, Schwartz GN, Zielinski R, Hohn D, et al. Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy? Multiple gated acquisition. Am J Clin Oncol. 2001;24:425–8.
Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol. 1998;25:72–85.
Trachtenberg BH, Landy DC, Franco VI, Henkel JM, Pearson EJ, Miller TL, et al. Anthracycline-associated cardiotoxicity in survivors of childhood cancer. Pediatr Cardiol. 2011;32:342–53.
Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol. 2007;25:3808–15.
Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL. Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. J Clin Oncol. 2005;23:8597–605.
Yood MU, Wells KE, Alford SH, Dakki H, Beiderbeck AB, Hurria A, et al. Cardiovascular outcomes in women with advanced breast cancer exposed to chemotherapy. Pharmacoepidemiol Drug Saf [Internet]. 2012 [cited 2012 May 22]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/22419528.
Brower V. Cardiotoxicity debated for anthracyclines and trastuzumab in breast cancer. J Natl Cancer Inst. 2013;105:835–6.
Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, et al. American society of clinical oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. 2007;25:3991–4008.
Barrett-Lee PJ, Dixon JM, Farrell C, Jones A, Leonard R, Murray N, et al. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann Oncol. 2009;20:816–27.
Ryberg M, Nielsen D, Cortese G, Nielsen G, Skovsgaard T, Andersen PK. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst. 2008;100:1058–67.
Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337.
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.
Feola M, Garrone O, Occelli M, Francini A, Biggi A, Visconti G, 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.
Garrone O, Crosetto N, Lo Nigro C, Catzeddu T, Vivenza D, Monteverde M, et al. Prediction of anthracycline cardiotoxicity after chemotherapy by biomarkers kinetic analysis. Cardiovasc Toxicol. 2012;12:135–42.
Romano S, Fratini S, Ricevuto E, Procaccini V, Stifano G, Mancini M, et al. Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer. 2011;105:1663–8.
Meinardi MT, Van Der Graaf WTA, Gietema JA, Van Den Berg MP, Sleijfer DT, De Vries EGE, et al. Evaluation of long term cardiotoxicity after epirubicin containing adjuvant chemotherapy and locoregional radiotherapy for breast cancer using various detection techniques. Heart. 2002;88:81–2.
Russell SD, Blackwell KL, Lawrence J, Pippen Jr JE, Roe MT, Wood F, et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. 2010;28:3416–21.
Verma S, Ewer MS. Is cardiotoxicity being adequately assessed in current trials of cytotoxic and targeted agents in breast cancer? Ann Oncol. 2011;22:1011–8.
Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother. 2008;42:99–104.
What are the key statistics about breast cancer? [Internet]. [cited 2011 Sep 13]. Available from: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-key-statistics.
Cancer of the Breast—SEER stat fact sheets [Internet]. [cited 2011 Sep 13]. Available from: http://seer.cancer.gov/statfacts/html/breast.html#survival.
Allen LA, Yood MU, Wagner EH, Aiello Bowles EJ, Pardee R, Wellman R, et al. Performance of claims-based algorithms for identifying heart failure and cardiomyopathy among patients diagnosed with breast cancer. Med Care. 2012.
Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, Dombernowsky P. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol. 1998;16:3502–8.
Romond EH, Jeong J-H, Rastogi P, Swain SM, Geyer CE, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:3792–9.
Shelburne N, Adhikari B, Brell J, Davis M, Desvigne-Nickens P, Freedman A, et al. Cancer treatment-related cardiotoxicity: current state of knowledge and future research priorities. J. Natl. Cancer Inst. 2014;106.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273–83.
Sysa-Shah P, Xu Y, Guo X, Belmonte F, Kang B, Bedja D, et al. Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. PLoS One. 2012;7:e42805.
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetol. 2014.
Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 2014.
Vinereanu D, Nicolaides E, Tweddel AC, Mädler CF, Holst B, Boden LE, et al. Subclinical left ventricular dysfunction in asymptomatic patients with type II diabetes mellitus, related to serum lipids and glycated haemoglobin. Clin Sci. 2003;105:591–9.
Ky B, Vejpongsa P, Yeh ETH, Force T, Moslehi JJ. Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res. 2013;113:754–64.
Poterucha JT, Kutty S, Lindquist RK, Li L, Eidem BW. Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction. J Am Soc Echocardiogr. 2012;25:733–40.
Stoodley PW, Richards DAB, Hui R, Boyd A, Harnett PR, Meikle SR, et al. Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy. Eur J Echocardiogr. 2011;12:945–52.
Conflict of interest
Authors Angel Qin, Cheryl Thompson, and Paula Silverman declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 13 kb)
Rights and permissions
About this article
Cite this article
Qin, A., Thompson, C.L. & Silverman, P. Predictors of late-onset heart failure in breast cancer patients treated with doxorubicin. J Cancer Surviv 9, 252–259 (2015). https://doi.org/10.1007/s11764-014-0408-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11764-014-0408-9