Skip to main content

Advertisement

SpringerLink
Log in

Cardiotoxicity of Contemporary Breast Cancer Treatments

  • Cardio-oncology (MG Fradley, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Treatment-related cardiotoxicity remains a significant concern for breast cancer patients undergoing cancer treatment and extends into the survivorship period, with adverse cardiovascular (CV) outcomes further compounded by the presence of pre-existing CV disease or traditional CV risk factors. Awareness of the cardiotoxicity profiles of contemporary breast cancer treatments and optimization of CV risk factors are crucial in mitigating cardiotoxicity risk. Assessment of patient- and treatment-specific risk with appropriate CV surveillance is another key component of care. Mismatch between baseline cardiotoxicity risk and intensity of cardiotoxicity surveillance can lead to unnecessary downstream testing, increased healthcare expenditure, and interruption or discontinuation of potentially life-saving treatment. Efforts to identify early imaging and/or circulating biomarkers of cardiotoxicity and develop effective management strategies are needed to optimize the CV and cancer outcomes of breast cancer survivors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. • Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz-Flores S, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137(8):e30–66. https://doi.org/10.1161/CIR.0000000000000556 This is the first American Heart Association scientific statement providing a comprehensive evidence-based discussion on the association between breast cancer and CVD.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Abdel-Qadir H, Austin PC, Lee DS, Amir E, Tu JV, Thavendiranathan P, et al. A population-based study of cardiovascular mortality following early-stage breast cancer. JAMA Cardiol. 2017;2(1):88–93. https://doi.org/10.1001/jamacardio.2016.3841.

    Article  PubMed  Google Scholar 

  4. Hershman DL, Till C, Shen S, Wright JD, Ramsey SD, Barlow WE, et al. Association of cardiovascular risk factors with cardiac events and survival outcomes among patients with breast cancer enrolled in SWOG Clinical Trials. J Clin Oncol. 2018;36(26):2710–7. https://doi.org/10.1200/JCO,10.1200/JCO.2017.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, et al. Anthracyclines in early breast cancer: the ABC trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017;35(23):2647–55. https://doi.org/10.1200/JCO,10.1200/JCO.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18(11):1639–42. https://doi.org/10.1038/nm.2919.

    Article  CAS  PubMed  Google Scholar 

  7. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012;52(6):1213–25. https://doi.org/10.1016/j.yjmcc.2012.03.006.

    Article  CAS  PubMed  Google Scholar 

  8. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–79. https://doi.org/10.1002/cncr.11407.

    Article  CAS  PubMed  Google Scholar 

  9. • Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981–8. https://doi.org/10.1161/CIRCULATIONAHA.114.013777 This is a surveillance study among adult patients characterizing the incidence, timing, risk factors, and trend of anthracycline-induced cardiotoxicity over a median follow-up of 5.2 years. It also showed that partial or full LVEF recovery after prompt initiation of HF therapy occurred in the majority of those who developed cardiotoxicity.

    Article  CAS  PubMed  Google Scholar 

  10. •• Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, 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(8):893–911. https://doi.org/10.1200/JCO.2016.70.5400 This contains guideline recommendations based on available evidence and expert consensus describing the approach to adult cancer survivors before, during, and after cancer treatment. It also identified evidence gaps and future directions particularly relevant in the field of cardio-oncology.

    Article  PubMed  Google Scholar 

  11. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, 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(31):3792–9. https://doi.org/10.1200/JCO.2011.40.0010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Advani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA. Long-term cardiac safety analysis of NCCTG N9831 (Alliance) adjuvant trastuzumab trial. J Clin Oncol. 2016;34(6):581–7. https://doi.org/10.1200/JCO.2015.61.8413.

    Article  CAS  PubMed  Google Scholar 

  13. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.

    Article  CAS  PubMed  Google Scholar 

  14. Marty M, Espie M, Llombart A, Monnier A, Rapoport BL, Stahalova V, et al. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol. 2006;17(4):614–22. https://doi.org/10.1093/annonc/mdj134.

    Article  CAS  PubMed  Google Scholar 

  15. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, et al. Cardioprotection with dexrazoxane for doxorubicin- containing therapy in advanced breast cancer. J Clin Oncol. 1997;15:1318–32.

    Article  CAS  PubMed  Google Scholar 

  16. Tocchetti CG, Ragone G, Coppola C, Rea D, Piscopo G, Scala S, et al. Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge. Eur J Heart Fail. 2012;14(2):130–7. https://doi.org/10.1093/eurjhf/hfr165.

    Article  CAS  PubMed  Google Scholar 

  17. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195–205. https://doi.org/10.1016/s0140-6736(16)32616-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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(14):1273–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol. 2012;60(24):2504–12. https://doi.org/10.1016/j.jacc.2012.07.068.

    Article  CAS  PubMed  Google Scholar 

  20. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104(17):1293–305. https://doi.org/10.1093/jnci/djs317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. • Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134–41. https://doi.org/10.1056/NEJMoa1406281 This is a trial demonstrating the efficacy and cardiac safety of a non-anthracycline adjuvant treatment with paclitaxel and trastuzumab in patients with stage 1 HER2-positive disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tan TC, Bouras S, Sawaya H, Sebag IA, Cohen V, Picard MH, et al. Time trends of left ventricular ejection fraction and myocardial deformation indices in a cohort of women with breast cancer treated with anthracyclines, taxanes, and trastuzumab. J Am Soc Echocardiogr. 2015;28(5):509–14. https://doi.org/10.1016/j.echo.2015.02.001.

    Article  PubMed  Google Scholar 

  23. Banke A, Fosbol EL, Ewertz M, Videbaek L, Dahl JS, Poulsen MK, et al. Long-term risk of heart failure in breast cancer patients after adjuvant chemotherapy with or without trastuzumab. JACC Heart Fail. 2019;7(3):217–24. https://doi.org/10.1016/j.jchf.2018.09.001.

    Article  PubMed  Google Scholar 

  24. 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(2):489–95. https://doi.org/10.1007/s10549-014-3253-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215–21.

    Article  CAS  PubMed  Google Scholar 

  26. de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol. 2014;32(20):2159–65. https://doi.org/10.1200/JCO.2013.53.9288.

    Article  CAS  PubMed  Google Scholar 

  27. Ezaz G, Long JB, Gross CP, Chen J. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc. 2014;3(1):e000472. https://doi.org/10.1161/JAHA.113.000472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122–31. https://doi.org/10.1056/NEJMoa1703643.

    Article  Google Scholar 

  29. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34. https://doi.org/10.1056/NEJMoa1413513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gianni L, Pienkowski T, Im Y-H, Tseng L-M, Liu M-C, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791–800. https://doi.org/10.1016/s1470-2045(16)00163-7.

    Article  CAS  PubMed  Google Scholar 

  31. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018;89:27–35. https://doi.org/10.1016/j.ejca.2017.10.021.

    Article  CAS  PubMed  Google Scholar 

  32. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91. https://doi.org/10.1056/NEJMoa1209124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2018;380:617–28. https://doi.org/10.1056/NEJMoa1814017.

    Article  Google Scholar 

  34. Tykerb (lapatinib) [package insert]. GlaxoSmithKline, Research Triangle Park, NC. 2007.

  35. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83(6):679–86. https://doi.org/10.4065/83.6.679.

    Article  PubMed  Google Scholar 

  36. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538–46. https://doi.org/10.1200/JCO.2009.23.3734.

    Article  CAS  PubMed  Google Scholar 

  37. de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. The Lancet Oncology. 2014;15(10):1137–46. https://doi.org/10.1016/s1470-2045(14)70320-1.

    Article  PubMed  Google Scholar 

  38. Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34(10):1034–42. https://doi.org/10.1200/JCO.2015.62.1797.

    Article  CAS  PubMed  Google Scholar 

  39. Geyer CE, Forster J, LIndquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–43.

    Article  CAS  PubMed  Google Scholar 

  40. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30(21):2585–92. https://doi.org/10.1200/JCO.2011.35.6725.

    Article  CAS  PubMed  Google Scholar 

  41. Buza V, Rajagopalan B, Curtis AB. Cancer treatment-induced arrhythmias: focus on chemotherapy and targeted therapies. Circ Arrhythm Electrophysiol. 2017;10(8). https://doi.org/10.1161/CIRCEP.117.005443.

  42. Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688–700. https://doi.org/10.1016/S1470-2045(17)30717-9.

    Article  CAS  PubMed  Google Scholar 

  43. Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301–7. https://doi.org/10.1200/JCO.2009.25.8707.

    Article  CAS  PubMed  Google Scholar 

  44. Nerlynx (neratinib) [package insert]. Puma Biotechnology, Los Angeles, CA. 2017.

  45. Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016;22(23):5696–705. https://doi.org/10.1158/1078-0432.CCR-16-1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Thein KZ, Ball S, Zaw MH, Tun AM, Quirch M, Hardwicke F, et al. Updated meta-analysis of randomized controlled trials (RCTs) to determine the CDK 4/6 inhibitors associated venous thromboembolism (VTE) risk in hormone receptor-positive breast cancer (BC) patients. Ann Oncol. 2018;29(suppl_8):viii603-viii40. https://doi.org/10.1093/annonc/mdy300.

    Article  Google Scholar 

  47. Kisqali (ribociclib) [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 2017.

  48. Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KA, et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2018;37(5):423–38. https://doi.org/10.1200/JCO.18.01160.

    Article  PubMed  Google Scholar 

  49. Khosrow-Khavar F, Filion KB, Al-Qurashi S, Torabi N, Bouganim N, Suissa S, et al. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol. 2017;28(3):487–96. https://doi.org/10.1093/annonc/mdw673.

    Article  CAS  PubMed  Google Scholar 

  50. Esteva FJ, Hortobagyi GN. Comparative assessment of lipid effects of endocrine therapy for breast cancer: implications for cardiovascular disease prevention in postmenopausal women. Breast. 2006;15:301–12. https://doi.org/10.1016/j.breast.2005.08.033.

    Article  CAS  PubMed  Google Scholar 

  51. Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103(17):1299–309. https://doi.org/10.1093/jnci/djr242.

    Article  CAS  PubMed  Google Scholar 

  52. Arimidex T, Alone or in Combination Trialists’ Group, Buzdar A, Howell A, Cuzick J, Wale C, et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7(8):633–43.

    Article  Google Scholar 

  53. Blaes A, Beckwith H, Florea N, Hebbel R, Solovey A, Potter D, et al. Vascular function in breast cancer survivors on aromatase inhibitors: a pilot study. Breast Cancer Res Treat. 2017;166(2):541–7. https://doi.org/10.1007/s10549-017-4447-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. van de Velde CJH, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011;377(9762):321–31.

    Article  PubMed  Google Scholar 

  55. Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol. 2015;5:39. https://doi.org/10.3389/fonc.2015.00039.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2013;14(8):721–40. https://doi.org/10.1093/ehjci/jet123.

    Article  PubMed  Google Scholar 

  57. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98. https://doi.org/10.1056/NEJMoa1209825.

    Article  CAS  PubMed  Google Scholar 

  58. Cheng YJ, Nie XY, Ji CC, Lin XX, Liu LJ, Chen XM, et al. Long-term cardiovascular risk after radiotherapy in women with breast cancer. J Am Heart Assoc. 2017;6(5). https://doi.org/10.1161/JAHA.117.005633.

  59. Nilsson G, Holmberg L, Garmo H, Duvernoy O, Sjogren I, Lagerqvist B, et al. Distribution of coronary artery stenosis after radiation for breast cancer. J Clin Oncol. 2012;30(4):380–6. https://doi.org/10.1200/JCO.2011.34.5900.

    Article  PubMed  Google Scholar 

  60. Lo Q, Hee L, Batumalai V, Allman C, MacDonald P, Lonergan D, et al. Strain imaging detects dose-dependent segmental cardiac dysfunction in the acute phase after breast irradiation. Int J Radiat Oncol Biol Phys. 2017;99(1):182–90. https://doi.org/10.1016/j.ijrobp.2017.05.030.

    Article  PubMed  Google Scholar 

  61. Jacob S, Broggio D, Derreumaux S, Camilleri J, Lapeyre M, Bruguiere E, et al. Cardiac radiation exposure due to breast cancer radiotherapy: why mean heart dose is a limited parameter for cardiotoxicity studies? (BACCARAT study). Eur Heart J. 2018;39(suppl_1). https://doi.org/10.1093/eurheartj/ehy563.P3505.

  62. van den Bogaard VA, Ta BD, van der Schaaf A, Bouma AB, Middag AM, Bantema-Joppe EJ, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35(11):1171–8. https://doi.org/10.1200/JCO.2016.69.8480.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yu AF, Ho AY, Braunstein LZ, Thor ME, Lee Chuy K, Eaton A et al. Assessment of early radiation-induced changes in LV function by myocardial strain imaging after breast radiation therapy. J Am Soc Echocardiogr. 2019;32(4)521–28. https://doi.org/10.1016/j.echo.2018.12.009.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671–80. https://doi.org/10.1093/eurheartj/ehw022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, das Dores Cruz F, Goncalves Brandao SM, Rigaud VOC, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial. J Am Coll Cardiol. 2018;71(20):2281–90. https://doi.org/10.1016/j.jacc.2018.02.049.

    Article  CAS  PubMed  Google Scholar 

  66. Boekhout AH, Gietema JA, Milojkovic Kerklaan B, van Werkhoven ED, Altena R, Honkoop A, 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(8):1030–7. https://doi.org/10.1001/jamaoncol.2016.1726.

    Article  PubMed  Google Scholar 

  67. Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol. 2017;35(8):870–7. https://doi.org/10.1200/JCO.2016.68.7830.

    Article  CAS  PubMed  Google Scholar 

  68. Guglin ME. Lisinopril or carvedilol for prevention of trastuzumab induced cardiotoxicity - lisinopril or carvedilol for cardiotoxicity. Presented at American College of Cardiology Annual Scientific Session (ACC 2018); March 11, 2018; Orlando, FL2018. This is a randomized, placebo-controlled primary prevention study assessing the value of lisinopril or carvedilol in preventing cardiomyopathy among patients treated with trastuzumab therapy, stratified according to anthracycline exposure. Results showed that lisinopril or carvedilol can mitigate LVEF decline in a subset of patients who received prior anthracycline.

  69. Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18(11):1519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis. 2004;15(5):251–8.

    Article  PubMed  Google Scholar 

  71. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol. 2012;60(23):2384–90. https://doi.org/10.1016/j.jacc.2012.07.067.

    Article  CAS  PubMed  Google Scholar 

  72. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911–39. https://doi.org/10.1016/j.echo.2014.07.012.

    Article  PubMed  Google Scholar 

  73. Florido R, Smith KL, Cuomo KK, Russell SD. Cardiotoxicity From human epidermal growth factor receptor-2 (HER2) targeted therapies. J Am Heart Assoc. 2017;6(9). https://doi.org/10.1161/jaha.117.006915.

  74. 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(19):2176–83. https://doi.org/10.1200/JCO.2014.58.9465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. • Henry ML, Niu J, Zhang N, Giordano SH, Chavez-MacGregor M. Cardiotoxicity and cardiac monitoring among chemotherapy-treated breast cancer patients. JACC Cardiovasc Imaging. 2018;11(8):1084–93. https://doi.org/10.1016/j.jcmg.2018.06.005 This study assessed adherence to recommended cardiac monitoring during breast cancer treatment among > 16,000 adult patients. Guideline-adherent monitoring during trastuzumab therapy was suboptimal, regardless of age or comorbidities. This highlights the importance of considering patient-specific CV risk factors in the cardiotoxicity surveillance of breast cancer patients.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dang CT, Yu AF, Jones LW, Liu J, Steingart RM, Argolo DF, et al. Cardiac surveillance guidelines for trastuzumab-containing therapy in early-stage breast cancer: getting to the heart of the matter. J Clin Oncol. 2016;34(10):1030–3.

    Article  PubMed  PubMed Central  Google Scholar 

  77. • Lynce F, Barac A, Geng X, Dang CT, Yu AF, Smith KL, et al. SAFE-HEaRt: a pilot study assessing the cardiac safety of HER2 targeted therapy in patients with HER2 positive breast cancer and reduced left ventricular function. J Clin Oncol. 2018;36(15_suppl):1038 This is the first prospective trial to evaluate the safety of anti-HER2 therapies among 30 breast cancer patients with asymptomatic mildly decreased LV function (40–49%), while receiving appropriate HF medications (beta blockers and ACEis) and regular cardiac surveillance.

    Article  Google Scholar 

  78. Hussain Y, Drill E, Dang CT, Liu JE, Steingart RM, Yu AF. Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction. Breast Cancer Res Treat. 2019. https://doi.org/10.1007/s10549-019-05139-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. 2014;63(25 Pt A):2751–68. https://doi.org/10.1016/j.jacc.2014.01.073.

    Article  PubMed  Google Scholar 

  80. Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr. 2013;26(5):493–8. https://doi.org/10.1016/j.echo.2013.02.008.

    Article  PubMed  Google Scholar 

  81. 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 Imaging. 2012;5(5):596–603. https://doi.org/10.1161/CIRCIMAGING.112.973321.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Fei HW, Ali MT, Tan TC, Cheng KH, Salama L, Hua L, et al. Left ventricular global longitudinal strain in HER-2 + breast cancer patients treated with anthracyclines and trastuzumab who develop cardiotoxicity is associated with subsequent recovery of left ventricular ejection fraction. Echocardiography. 2016;33(4):519–26. https://doi.org/10.1111/echo.13168.

    Article  PubMed  Google Scholar 

  83. Jacob S, Walker V, Fondard O, Chevelle C, Jimenez G, Bernier MO, et al. Use of myocardial strain imaging by echocardiography for the early detection of radiotherapy-induced cardiotoxicity in breast cancer patients (BACCARAT study). Arch Cardiovasc Dis Suppl. 2019;11(1):49–50. https://doi.org/10.1016/j.acvdsp.2018.10.107.

    Article  Google Scholar 

  84. Cardinale D, Ciceri F, Latini R, Franzosi MG, Sandri MT, Civelli M, et al. Anthracycline-induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: the International CardioOncology Society-one trial. Eur J Cancer. 2018;94:126–37. https://doi.org/10.1016/j.ejca.2018.02.005.

    Article  CAS  PubMed  Google Scholar 

  85. •• Negishi T, Thavendiranathan P, Negishi K, Marwick TH, investigators S. Rationale and design of the strain surveillance of chemotherapy for improving cardiovascular outcomes: the SUCCOUR trial. JACC Cardiovasc Imaging. 2018;11(8):1098–105. https://doi.org/10.1016/j.jcmg.2018.03.019 This ongoing international multicenter randomized controlled trial is the first to compare conventional LVEF- versus GLS-guided surveillance and initiation of cardioprotective therapy among high-risk patients undergoing cardiotoxic chemotherapy over a 3-year follow-up period.

    Article  PubMed  Google Scholar 

  86. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging. 2013;6(6):1080–91. https://doi.org/10.1161/CIRCIMAGING.113.000899.

    Article  PubMed  Google Scholar 

  87. Galan-Arriola C, Lobo M, Vilchez-Tschischke JP, Lopez GJ, de Molina-Iracheta A, Perez-Martinez C, et al. Serial magnetic resonance imaging to identify early stages of anthracycline-induced cardiotoxicity. J Am Coll Cardiol. 2019;73(7):779–91. https://doi.org/10.1016/j.jacc.2018.11.046.

    Article  PubMed  Google Scholar 

  88. Yu AF, Chan AT, Steingart RM. Cardiac magnetic resonance and cardio-oncology: does T2 signal the end of anthracycline cardiotoxicity? J Am Coll Cardiol. 2019;73(7):792–4. https://doi.org/10.1016/j.jacc.2018.11.045.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Melendez GC, Sukpraphrute B, D’Agostino RB Jr, Jordan JH, Klepin HD, Ellis L, et al. Frequency of left ventricular end-diastolic volume-mediated declines in ejection fraction in patients receiving potentially cardiotoxic cancer treatment. Am J Cardiol. 2017;119(10):1637–42. https://doi.org/10.1016/j.amjcard.2017.02.008.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, 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(8):809–16. https://doi.org/10.1016/j.jacc.2013.10.061.

    Article  CAS  PubMed  Google Scholar 

  91. 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(25):3910–6. https://doi.org/10.1200/JCO.2009.27.3615.

    Article  CAS  PubMed  Google Scholar 

  92. Todorova VK, Makhoul I, Siegel ER, Wei J, Stone A, Carter W, et al. Biomarkers for presymptomatic doxorubicin-induced cardiotoxicity in breast cancer patients. PLoS One. 2016;11(8):e0160224. https://doi.org/10.1371/journal.pone.0160224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Leong SL, Chaiyakunapruk N, Lee SW. Candidate gene association studies of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis. Sci Rep. 2017;7(1):39. https://doi.org/10.1038/s41598-017-00075-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hertz DL, Caram MV, Kidwell KM, Thibert JN, Gersch C, Seewald NJ, et al. Evidence for association of SNPs in ABCB1 and CBR3, but not RAC2, NCF4, SLC28A3 or TOP2B, with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines. Pharmacogenomics. 2016;17(3):231–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Serie DJ, Crook JE, Necela BM, Dockter TJ, Wang X, Asmann YW, et al. Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial. Pharmacogenet Genomics. 2017;27(10):378–85. https://doi.org/10.1097/FPC.0000000000000302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gomez Pena C, Davila-Fajardo CL, Martinez-Gonzalez LJ, Carmona-Saez P, Soto Pino MJ, Sanchez Ramos J, et al. Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients: a meta-analysis. Pharmacogenet Genomics. 2015;25(8):388–93. https://doi.org/10.1097/FPC.0000000000000149.

    Article  CAS  PubMed  Google Scholar 

  97. Stanton SE, Ward MM, Christos P, Sanford R, Lam C, Cobham MV, et al. Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity. BMC Cancer. 2015;15(1). https://doi.org/10.1186/s12885-015-1298-6.

  98. Yu AF, Jones LW. Breast cancer treatment-associated cardiovascular toxicity and effects of exercise countermeasures. Cardiooncology. 2016;2. https://doi.org/10.1186/s40959-016-0011-5.

  99. Jones LW, Courneya KS, Mackey JR, Muss HB, Pituskin EN, Scott JM, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol. 2012;30(20):2530–7. https://doi.org/10.1200/JCO.2011.39.9014.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Jones LW, Habel LA, Weltzien E, Castillo A, Gupta D, Kroenke CH, et al. Exercise and risk of cardiovascular events in women with nonmetastatic breast cancer. J Clin Oncol. 2016;34(23):2743–9. https://doi.org/10.1200/JCO.2015.65.6603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007;50(15):1435–41. https://doi.org/10.1016/j.jacc.2007.06.037.

    Article  PubMed  Google Scholar 

  102. Scott JM, Iyengar NM, Nilsen TS, Michalski M, Thomas SM, Herndon J 2nd, et al. Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: a randomized controlled trial. Cancer. 2018;124(12):2552–60. https://doi.org/10.1002/cncr.31368.

    Article  CAS  PubMed  Google Scholar 

  103. Hornsby WE, Douglas PS, West MJ, Kenjale AA, Lane AR, Schwitzer ER, et al. Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: a phase II randomized trial. Acta Oncol. 2014;53(1):65–74. https://doi.org/10.3109/0284186X.2013.781673.

    Article  PubMed  Google Scholar 

  104. Mijwel S, Backman M, Bolam KA, Olofsson E, Norrbom J, Bergh J, et al. Highly favorable physiological responses to concurrent resistance and high-intensity interval training during chemotherapy: the OptiTrain breast cancer trial. Breast Cancer Res Treat. 2018;169(1):93–103. https://doi.org/10.1007/s10549-018-4663-8.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Pituskin E, Haykowsky M, McNeely M, Mackey J, Chua N, Paterson I. Rationale and design of the multidisciplinary team IntervenTion in cArdio-oNcology study (TITAN). BMC Cancer. 2016;16(1):733. https://doi.org/10.1186/s12885-016-2761-8.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Courneya KS, McNeely ML, Culos-Reed SN, Vallance JK, Bell GJ, Mackey JR, et al. The Alberta moving beyond breast cancer (AMBER) cohort study: recruitment, baseline assessment, and description of the first 500 participants. BMC Cancer. 2016;16:481. https://doi.org/10.1186/s12885-016-2534-4.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Cardiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Katherine Lee Chuy MD & Anthony F. Yu MD

  2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Anthony F. Yu MD

Authors
  1. Katherine Lee Chuy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony F. Yu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony F. Yu MD.

Ethics declarations

Conflict of Interest

Katherine Lee Chuy declares that she has no conflict of interest.

Anthony F. Yu has received compensation from Glenmark Pharmaceuticals, Takeda Oncology, Bristol-Myers Squibb, and Bayer for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cardio-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee Chuy, K., Yu, A.F. Cardiotoxicity of Contemporary Breast Cancer Treatments. Curr. Treat. Options in Oncol. 20, 51 (2019). https://doi.org/10.1007/s11864-019-0646-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-019-0646-1

Keywords

Search

Navigation