Skip to main content

Cardiovascular Side Effects of Breast Cancer Therapy

Abstract

Each year, the world sees more than 1.6 million new breast cancer cases. While breast cancer therapy has greatly improved and is leading to increased cancer cure rates, side effects of breast cancer therapy are also common. This chapter serves as an introduction to cardiovascular sequelae of breast cancer treatment with anthracyclines, hormonal therapy, radiation therapy, and targeted anti-cancer therapies. While there is some knowledge of mechanisms by which cardiovascular side effects may occur, and a few potential intervention strategies have been identified, much is still unknown. This chapter provides a brief discussion of pre-clinical and clinical research into biological mechanisms and strategies for early detection and intervention. There are recent efforts to provide a more extensive cardiovascular follow-up of cancer patients in integrated cardio-oncology clinical teams. Improved methods of early detection and disease management will aid in these collaborative efforts to make breast cancer therapy more effective and safer.

Keywords

  • Breast cancer
  • Side effects
  • Cardiotoxicity
  • Anthracyclines
  • Radiation therapy
  • Targeted therapies
  • Trastuzumab
  • Cardio-oncology

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-71135-5_17
  • Chapter length: 14 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-71135-5
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   149.00
Price excludes VAT (USA)
Hardcover Book
USD   149.00
Price excludes VAT (USA)

References

  1. GLOBOCAN. Estimated cancer incidence, mortality and prevalence worldwide in 2012. World Health Organization; 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 25 Jun 2017.

  2. National Cancer Institute Surveillance, Epidemiology, and End Result Program. 2014. https://seer.cancer.gov/statfacts/html/breast.html. Accessed 28 Jun 2017.

  3. Becker S. A historic and scientific review of breast cancer: the next global healthcare challenge. Int J Gynaecol Obstet. 2015;131(Suppl 1):S36–9.

    PubMed  CrossRef  Google Scholar 

  4. Hallam S, Govindarajulu S, Huckett B, Bahl A. BRCA1/2 mutation-associated breast cancer, wide local excision and radiotherapy or unilateral mastectomy: a systematic review. Clin Oncol (R Coll Radiol). 2015;27(9):527–35.

    CrossRef  CAS  Google Scholar 

  5. Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304–20.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  6. Santa-Maria CA, Camp M, Cimino-Mathews A, Harvey S, Wright J, Stearns V. Neoadjuvant therapy for early-stage breast cancer: current practice, controversies, and future directions. Oncology (Williston Park). 2015;29(11):828–38.

    Google Scholar 

  7. Madeddu C, Deidda M, Piras A, Cadeddu C, Demurtas L, Puzzoni M, Piscopo G, Scartozzi M, Mercuro G. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection):e12–8.

    CrossRef  CAS  Google Scholar 

  8. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther. 2017;31(1):63–75.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  9. Mele D, Tocchetti CG, Pagliaro P, Madonna R, Novo G, Pepe A, Zito C, Maurea N, Spallarossa P. Pathophysiology of anthracycline cardiotoxicity. J Cardiovasc Med (Hagerstown). 2016c;17(Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection):e3–e11.

    CrossRef  CAS  Google Scholar 

  10. Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol. 2012;30(18):2232–9.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  11. Damiani RM, Moura DJ, Viau CM, Caceres RA, Henriques JA, Saffi J. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch Toxicol. 2016;90(9):2063–76.

    PubMed  CrossRef  CAS  Google Scholar 

  12. Mele D, Nardozza M, Spallarossa P, Frassoldati A, Tocchetti CG, Cadeddu C, Madonna R, Malagu M, Ferrari R, Mercuro G. Current views on anthracycline cardiotoxicity. Heart Fail Rev. 2016b;21(5):621–34.

    PubMed  CrossRef  CAS  Google Scholar 

  13. Spallarossa P, Maurea N, Cadeddu C, Madonna R, Mele D, Monte I, Novo G, Pagliaro P, Pepe A, Tocchetti CG, Zito C, Mercuro G. A recommended practical approach to the management of anthracycline-based chemotherapy cardiotoxicity: an opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian society of cardiology. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection):e84–92.

    CrossRef  CAS  Google Scholar 

  14. Zhang S, Liu X, Bawa-Khalfe T, LS L, Lyu YL, Liu LF, Yeh ET. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18(11):1639–42.

    PubMed  CrossRef  CAS  Google Scholar 

  15. Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol. 2014;64(9):938–45.

    PubMed  CrossRef  CAS  Google Scholar 

  16. Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016;29:90–106.

    PubMed  CrossRef  Google Scholar 

  17. Tahover E, Patil YP, Gabizon AA. Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index: focus on liposomes. Anti-Cancer Drugs. 2015;26(3):241–58.

    PubMed  CrossRef  CAS  Google Scholar 

  18. Xing M, Yan F, Yu S, Shen P. Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials. PLoS One. 2015;10(7):e0133569.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  19. Chen JJ, PT W, Middlekauff HR, Nguyen KL. Aerobic exercise in anthracycline-induced cardiotoxicity: a systematic review of current evidence and future directions. Am J Physiol Heart Circ Physiol. 2017;312(2):H213–22.

    PubMed  CrossRef  Google Scholar 

  20. Scott JM, Adams SC, Koelwyn GJ, Jones LW. Cardiovascular late effects and exercise treatment in breast cancer: current evidence and future directions. Can J Cardiol. 2016;32(7):881–90.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  21. Jones RL. Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity. Expert Rev Cardiovasc Ther. 2008;6(10):1311–7.

    PubMed  CrossRef  CAS  Google Scholar 

  22. Kim IH, Lee JE, Youn HJ, Song BJ, Chae BJ. Cardioprotective effect of dexrazoxane in patients with HER2-positive breast cancer who receive anthracycline based adjuvant chemotherapy followed by trastuzumab. J Breast Cancer. 2017a;20(1):82–90.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  23. Tahover E, Segal A, Isacson R, Rosengarten O, Grenader T, Gips M, Cherny N, Heching NI, Mesika L, Catane R, Gabizon A. Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival. Anti-Cancer Drugs. 2017;28(7):787–94.

    PubMed  CrossRef  CAS  Google Scholar 

  24. Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, von Knobelsdorff-Brenkenhoff F, Bratland A, Storas TH, Hagve TA, Rosjo H, Steine K, Geisler J, Omland T. 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.

    Google Scholar 

  25. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  26. Tashakori BA, Mostafavi TH, Hosseini G, Zarifian A, Homaei SF, Fazlinezhad A. Carvedilol administration can prevent doxorubicin-induced cardiotoxicity: a double-blind randomized trial. Cardiology. 2016;134(1):47–53.

    CrossRef  CAS  Google Scholar 

  27. Wittayanukorn S, Qian J, Westrick SC, Billor N, Johnson B, Hansen RA. Prevention of trastuzumab and anthracycline-induced cardiotoxicity using angiotensin-converting enzyme inhibitors or beta-blockers in older adults with breast cancer. Am J Clin Oncol. 2017.

    Google Scholar 

  28. Zagar TM, Cardinale DM, Marks LB. Breast cancer therapy-associated cardiovascular disease. Nat Rev Clin Oncol. 2016;13(3):172–84.

    PubMed  CrossRef  CAS  Google Scholar 

  29. Sahu BD, Kumar JM, Kuncha M, Borkar RM, Srinivas R, Sistla R. Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice. Life Sci. 2016;144:8–18.

    PubMed  CrossRef  CAS  Google Scholar 

  30. Singh P, Sharma R, McElhanon K, Allen CD, Megyesi JK, Benes H, Singh SP. Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radic Biol Med. 2015;86:90–101.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  31. Burnett JP, Lim G, Li Y, Shah RB, Lim R, Paholak HJ, McDermott SP, Sun L, Tsume Y, Bai S, Wicha MS, Sun D, Zhang T. Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells. Cancer Lett. 2017;394:52–64.

    PubMed  CrossRef  CAS  Google Scholar 

  32. Kim SH, Park HJ, Moon DO. Sulforaphane sensitizes human breast cancer cells to paclitaxel-induced apoptosis by downregulating the NF-kappaB signaling pathway. Oncol Lett. 2017b;13(6):4427–32.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  33. Yang L, Palliyaguru DL, Kensler TW. Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. Semin Oncol. 2016;43(1):146–53.

    PubMed  CrossRef  CAS  Google Scholar 

  34. Fabian CJ. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer. Int J Clin Pract. 2007;61(12):2051–63.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  35. Colleoni M, Giobbie-Hurder A. Benefits and adverse effects of endocrine therapy. Ann Oncol. 2010;21(Suppl 7):vii107–11.

    PubMed  PubMed Central  Google Scholar 

  36. Foglietta J, Inno A, De Iuliis F, Sini V, Duranti S, Turazza M, Tarantini L, Gori S. Cardiotoxicity of aromatase inhibitors in breast cancer patients. Clin Breast Cancer. 2017;17(1):11–7.

    Google Scholar 

  37. Khosrow-Khavar F, Filion KB, Al-Qurashi S, Torabi N, Bouganim N, Suissa S, Azoulay L. 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.

    PubMed  CAS  Google Scholar 

  38. Beck RE, Kim L, Yue NJ, Haffty BG, Khan AJ, Goyal S. Treatment techniques to reduce cardiac irradiation for breast cancer patients treated with breast-conserving surgery and radiation therapy: a review. Front Oncol. 2014;4:327.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  39. Lemanski C, Thariat J, Ampil FL, Bose S, Vock J, Davis R, Chi A, Dutta S, Woods W, Desai A, Godinez J, Karlsson U, Mills M, Nguyen NP, Vinh-Hung V. Image-guided radiotherapy for cardiac sparing in patients with left-sided breast cancer. Front Oncol. 2014;4:257.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  40. Shah C, Badiyan S, Berry S, Khan AJ, Goyal S, Schulte K, Nanavati A, Lynch M, Vicini FA. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol. 2014;112(1):9–16.

    PubMed  CrossRef  Google Scholar 

  41. Verma V, Shah C, Mehta MP. Clinical outcomes and toxicity of proton radiotherapy for breast cancer. Clin Breast Cancer. 2016;16(3):145–54.

    PubMed  CrossRef  Google Scholar 

  42. Boda-Heggemann J, Knopf AC, Simeonova-Chergou A, Wertz H, Stieler F, Jahnke A, Jahnke L, Fleckenstein J, Vogel L, Arns A, Blessing M, Wenz F, Lohr F. Deep inspiration breath hold-based radiation therapy: a clinical review. Int J Radiat Oncol Biol Phys. 2016;94(3):478–92.

    PubMed  CrossRef  Google Scholar 

  43. Smyth LM, Knight KA, Aarons YK, Wasiak J. The cardiac dose-sparing benefits of deep inspiration breath-hold in left breast irradiation: a systematic review. J Med Radiat Sci. 2015;62(1):66–73.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  44. Taylor CW, McGale P, Povall JM, Thomas E, Kumar S, Dodwell D, Darby SC. Estimating cardiac exposure from breast cancer radiotherapy in clinical practice. Int J Radiat Oncol Biol Phys. 2009;73(4):1061–8.

    PubMed  CrossRef  CAS  Google Scholar 

  45. Taylor CW, Povall JM, McGale P, Nisbet A, Dodwell D, Smith JT, Darby SC. Cardiac dose from tangential breast cancer radiotherapy in the year 2006. Int J Radiat Oncol Biol Phys. 2008;72(2):501–7.

    PubMed  CrossRef  Google Scholar 

  46. Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F, Darby SC. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys. 2015;93(4):845–53.

    PubMed  CrossRef  Google Scholar 

  47. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98.

    PubMed  CrossRef  CAS  Google Scholar 

  48. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557–65.

    PubMed  CrossRef  Google Scholar 

  49. Fajardo LF, Eltringham JR, Steward JR. Combined cardiotoxicity of adriamycin and x-radiation. Lab Investig. 1976;34(1):86–96.

    PubMed  CAS  Google Scholar 

  50. Gillette EL, McChesney SL, Hoopes PJ. Isoeffect curves for radiation-induced cardiomyopathy in the dog. Int J Radiat Oncol Biol Phys. 1985;11(12):2091–7.

    PubMed  CrossRef  CAS  Google Scholar 

  51. McChesney SL, Gillette EL, Powers BE. Radiation-induced cardiomyopathy in the dog. Radiat Res. 1988;113(1):120–32.

    PubMed  CrossRef  CAS  Google Scholar 

  52. Boerma M, Sridharan V, Mao XW, Nelson GA, Cheema AK, Koturbash I, Singh SP, Tackett AJ, Hauer-Jensen M. Effects of ionizing radiation on the heart. Mutat Res. 2016;770(Pt B):319–27.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  53. Slezak J, Kura B, Ravingerova T, Tribulova N, Okruhlicova L, Barancik M. Mechanisms of cardiac radiation injury and potential preventive approaches. Can J Physiol Pharmacol. 2015;93(9):737–53.

    PubMed  CrossRef  CAS  Google Scholar 

  54. Stewart FA, Seemann I, Hoving S, Russell NS. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol (R Coll Radiol). 2013;25(10):617–24.

    CrossRef  CAS  Google Scholar 

  55. Tapio S. Pathology and biology of radiation-induced cardiac disease. J Radiat Res. 2016;57(5):439–48.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  56. Gabriels K, Hoving S, Seemann I, Visser NL, Gijbels MJ, Pol JF, Daemen MJ, Stewart FA, Heeneman S. Local heart irradiation of ApoE(−/−) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis. Radiother Oncol. 2012;105(3):358–64.

    PubMed  CrossRef  Google Scholar 

  57. Hoving S, Heeneman S, Gijbels MJ, te Poele JA, Russell NS, Daemen MJ, Stewart FA. Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE(−/−) mice. Int J Radiat Oncol Biol Phys. 2008;71(3):848–57.

    PubMed  CrossRef  CAS  Google Scholar 

  58. Hoving S, Heeneman S, Gijbels MJ, te Poele JA, Visser N, Cleutjens J, Russell NS, Daemen MJ, Stewart FA. Irradiation induces different inflammatory and thrombotic responses in carotid arteries of wildtype C57BL/6J and atherosclerosis-prone ApoE(−/−) mice. Radiother Oncol. 2012;105(3):365–70.

    PubMed  CrossRef  CAS  Google Scholar 

  59. Mancuso M, Pasquali E, Braga-Tanaka I III, Tanaka S, Pannicelli A, Giardullo P, Pazzaglia S, Tapio S, Atkinson MJ, Saran A. Acceleration of atherogenesis in ApoE−/− mice exposed to acute or low-dose-rate ionizing radiation. Oncotarget. 2015;6(31):31263–71.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  60. Stewart FA, Heeneman S, Te Poele J, Kruse J, Russell NS, Gijbels M, Daemen M. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE−/− mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol. 2006;168(2):649–58.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  61. Tiamson E, Fritz KE, Campana H, Anzola E, Zgoda A, Daoud AS. Studies in rabbits of cellular mechanisms accounting for enhancement of diet-induced atherosclerosis by x-irradiation. Exp Mol Pathol. 1970;12(2):175–84.

    PubMed  CrossRef  CAS  Google Scholar 

  62. Borghini A, Gianicolo EA, Picano E, Andreassi MG. Ionizing radiation and atherosclerosis: current knowledge and future challenges. Atherosclerosis. 2013;230(1):40–7.

    PubMed  CrossRef  CAS  Google Scholar 

  63. Boerma M, Singh P, Sridharan V, Tripathi P, Sharma S, Singh SP. Effects of local heart irradiation in a glutathione S-transferase alpha 4-null mouse model. Radiat Res. 2015;183(6):610–9.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  64. de Freitas RB, Boligon AA, Rovani BT, Piana M, de Brum TF, da Silva JR, Rother FC, Alves NM, Teixeira da Rocha JB, Athayde ML, Barrio JP, de Andrade ER, de Freitas BL. Effect of black grape juice against heart damage from acute gamma TBI in rats. Molecules. 2013;18(10):12154–67.

    PubMed  CrossRef  CAS  Google Scholar 

  65. Kruse JJ, Strootman EG, Wondergem J. Effects of amifostine on radiation-induced cardiac damage. Acta Oncol. 2003;42(1):4–9.

    PubMed  CrossRef  CAS  Google Scholar 

  66. Sridharan V, Seawright JW, Antonawich FJ, Garnett M, Cao M, Singh P, Boerma M. Late administration of a palladium lipoic acid complex (POLY-MVA) modifies cardiac mitochondria but not functional or structural manifestations of radiation-induced heart disease in a rat model. Radiat Res. 2017;187(3):361–6.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  67. Sridharan V, Tripathi P, Aykin-Burns N, Krager KJ, Sharma SK, Moros EG, Melnyk SB, Pavliv O, Hauer-Jensen M, Boerma M. A tocotrienol-enriched formulation protects against radiation-induced changes in cardiac mitochondria without modifying late cardiac function or structure. Radiat Res. 2015;183(3):357–66.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  68. Monceau V, Pasinetti N, Schupp C, Pouzoulet F, Opolon P, Vozenin MC. Modulation of the rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity. Curr Drug Targets. 2010;11(11):1395–404.

    PubMed  CrossRef  CAS  Google Scholar 

  69. Zhang K, He X, Zhou Y, Gao L, Qi Z, Chen J, Gao X. Atorvastatin ameliorates radiation-induced cardiac fibrosis in rats. Radiat Res. 2015;184(6):611–20.

    PubMed  CrossRef  CAS  Google Scholar 

  70. Hoving S, Heeneman S, Gijbels MJ, te Poele JA, Pol JF, Gabriels K, Russell NS, Daemen MJ, Stewart FA. Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice. Radiother Oncol. 2011;101(1):100–8.

    PubMed  CrossRef  CAS  Google Scholar 

  71. van der Veen SJ, Ghobadi G, de Boer RA, Faber H, Cannon MV, Nagle PW, Brandenburg S, Langendijk JA, van Luijk P, Coppes RP. ACE inhibition attenuates radiation-induced cardiopulmonary damage. Radiother Oncol. 2015;114(1):96–103.

    PubMed  CrossRef  CAS  Google Scholar 

  72. Yarom R, Harper IS, Wynchank S, van Schalkwyk D, Madhoo J, Williams K, Salie R, Genade S, Lochner A. Effect of captopril on changes in rats’ hearts induced by long-term irradiation. Radiat Res. 1993;133(2):187–97.

    PubMed  CrossRef  CAS  Google Scholar 

  73. Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 2009;48(7):964–70.

    PubMed  CrossRef  CAS  Google Scholar 

  74. 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.

    PubMed  CrossRef  Google Scholar 

  75. Ponde NF, Lambertini M, de Azambuja E. Twenty years of anti-HER2 therapy-associated cardiotoxicity. ESMO Open. 2016;1(4):e000073.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  76. Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf. 2013;36(5):295–316.

    PubMed  CrossRef  CAS  Google Scholar 

  77. Denegri A, Moccetti T, Moccetti M, Spallarossa P, Brunelli C, Ameri P. Cardiac toxicity of trastuzumab in elderly patients with breast cancer. J Geriatr Cardiol. 2016;13(4):355–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  78. de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, Untch M, Smith IE, Gianni L, Baselga J, Jackisch C, Cameron DA, Bell R, Leyland-Jones B, Dowsett M, Gelber RD, Piccart-Gebhart MJ, Suter TM. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  79. Mele D, Malagutti P, Indelli M, Ferrari L, Casadei F, Da Ros L, Pollina A, Fiorencis A, Frassoldati A, Ferrari R. Reversibility of left ventricle longitudinal strain alterations induced by adjuvant therapy in early breast cancer patients. Ultrasound Med Biol. 2016a;42(1):125–32.

    PubMed  CrossRef  Google Scholar 

  80. Pivot X, Suter T, Nabholtz JM, Pierga JY, Espie M, Lortholary A, Khayat D, Pauporte I, Romieu G, Kramar A, Fumoleau P. Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study. Eur J Cancer. 2015;51(13):1660–6.

    PubMed  CrossRef  CAS  Google Scholar 

  81. Maurea N, Coppola C, Piscopo G, Galletta F, Riccio G, Esposito E, De Lorenzo C, De Laurentiis M, Spallarossa P, Mercuro G. Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection):e19–26.

    CrossRef  CAS  Google Scholar 

  82. Yousif NG, Al-Amran FG. Novel toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC Cardiovasc Disord. 2011;11:62.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  83. Abdel-Rahman O, Alorabi M. Use of angiotensin-converting enzyme inhibitors in the prophylaxis of anthracycline or trastuzumab-related cardiac dysfunction: preclinical and clinical considerations. Expert Rev Anticancer Ther. 2015;15(7):829–37.

    PubMed  CrossRef  CAS  Google Scholar 

  84. Boekhout AH, Gietema JA, Milojkovic KB, van Werkhoven ED, Altena R, Honkoop A, Los M, Smit WM, Nieboer P, Smorenburg CH, Mandigers CM, van der Wouw AJ, Kessels L, van der Velden AW, Ottevanger PB, Smilde T, de Boer J, van Veldhuisen DJ, Kema IP, de Vries EG, Schellens JH. 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.

    PubMed  CrossRef  Google Scholar 

  85. Guglin M, Munster P, Fink A, Krischer J. Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: a rationale and design of a randomized clinical trial. Am Heart J. 2017;188:87–92.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  86. Magne N, Chargari C, MacDermed D, Conforti R, Vedrine L, Spano JP, Khayat D. Tomorrow’s targeted therapies in breast cancer patients: what is the risk for increased radiation-induced cardiac toxicity? Crit Rev Oncol Hematol. 2010;76(3):186–95.

    PubMed  CrossRef  Google Scholar 

  87. Seemann I, te Poele JA, Song JY, Hoving S, Russell NS, Stewart FA. Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents. Breast Cancer Res Treat. 2013;141(3):385–95.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  88. Sridharan V, Thomas CJ, Cao M, Melnyk SB, Pavliv O, Joseph J, Singh SP, Sharma S, Moros EG, Boerma M. Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart. Radiother Oncol. 2016;119(2):259–64.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  89. Yavas C, Yavas G, Toy H, Ata O. The use of concurrent hormonotherapy and radiotherapy does not deteriorate radiation-induced cardiac toxicity. Hum Exp Toxicol. 2016;36(8):795–801.

    PubMed  CrossRef  CAS  Google Scholar 

  90. Rahmani H, Shahriary A, Sheikhi MA, Ebadi A, Davoodzadeh H. Applications of cardiotoxicity in breast cancer: a meta-analysis. Panminerva Med. 2017;59(1):90–6.

    PubMed  Google Scholar 

  91. Yu AF, Manrique C, Pun S, Liu JE, Mara E, Fleisher M, Patil S, Jones LW, Steingart RM, Hudis CA, Dang CT. Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer. Oncologist. 2016;21(4):418–24.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  92. Lange SA, Jung J, Jaeck A, Hitschold T, Ebner B. Subclinical myocardial impairment occurred in septal and anterior LV wall segments after anthracycline-embedded chemotherapy and did not worsen during adjuvant trastuzumab treatment in breast cancer patients. Cardiovasc Toxicol. 2016;16(2):193–206.

    PubMed  CrossRef  CAS  Google Scholar 

  93. van Ramshorst MS, van Werkhoven E, Honkoop AH, Dezentje VO, Oving IM, Mandjes IA, Kemper I, Smorenburg CH, Stouthard JM, Linn SC, Sonke GS. Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: the TRAIN-2 study. Breast. 2016;29:153–9.

    PubMed  CrossRef  Google Scholar 

  94. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, Allen LA, Nekhlyudov L, Goddard KA, Davis RL, Habel LA, Yood MU, McCarty C, Magid DJ, Wagner EH, Pharmacovigilance Study Team. 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.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  95. Du F, Yuan P, Zhu W, Wang J, Ma F, Fan Y, Xu B. Is it safe to give anthracyclines concurrently with trastuzumab in neo-adjuvant or metastatic settings for HER2-positive breast cancer? A meta-analysis of randomized controlled trials. Med Oncol. 2014;31(12):340.

    PubMed  CrossRef  CAS  Google Scholar 

  96. Hamirani Y, Fanous I, Kramer CM, Wong A, Salerno M, Dillon P. Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study. Med Oncol. 2016;33(7):82.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  97. Bian SX, Korah MP, Whitaker TR, Ji L, Groshen S, Chung E. No acute changes in LVEF observed with concurrent trastuzumab and breast radiation with low heart doses. Clin Breast Cancer. 2017;17(7):510–5.

    PubMed  CrossRef  CAS  Google Scholar 

  98. Halyard MY, Pisansky TM, Dueck AC, Suman V, Pierce L, Solin L, Marks L, Davidson N, Martino S, Kaufman P, Kutteh L, Dakhil SR, Perez EA. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol. 2009;27(16):2638–44.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  99. Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, Amoroso D, Barni S, Bengala C, Guarneri V, Marchetti P, Martella F, Piovano P, Vannini A, Desideri I, Tarquini R, Galanti G, Barletta G, Livi L. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab. Med Oncol. 2017;34(5):75.

    PubMed  CrossRef  CAS  Google Scholar 

  100. Boyd A, Stoodley P, Richards D, Hui R, Harnett P, Vo K, Marwick T, Thomas L. Anthracyclines induce early changes in left ventricular systolic and diastolic function: a single centre study. PLoS One. 2017;12(4):e0175544.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  101. Fei HW, Ali MT, Tan TC, Cheng KH, Salama L, Hua L, Zeng X, Halpern EF, Taghian A, Macdonald SM, Scherrer-Crosbie M. 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.

    PubMed  CrossRef  Google Scholar 

  102. Narayan HK, Finkelman B, French B, Plappert T, Hyman D, Smith AM, Margulies KB, Ky B. Detailed echocardiographic phenotyping in breast cancer patients: associations with ejection fraction decline, recovery, and heart failure symptoms over 3 years of follow-up. Circulation. 2017;135(15):1397–412.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  103. Santoro C, Arpino G, Esposito R, Lembo M, Paciolla I, Cardalesi C, de Simone G, Trimarco B, De Placido S, Galderisi M. 2D and 3D strain for detection of subclinical anthracycline cardiotoxicity in breast cancer patients: a balance with feasibility. Eur Heart J Cardiovasc Imaging. 2017;18(8):930–6.

    PubMed  CrossRef  Google Scholar 

  104. Jassal DS, Han SY, Hans C, Sharma A, Fang T, Ahmadie R, Lytwyn M, Walker JR, Bhalla RS, Czarnecki A, Moussa T, Singal PK. Utility of tissue Doppler and strain rate imaging in the early detection of trastuzumab and anthracycline mediated cardiomyopathy. J Am Soc Echocardiogr. 2009;22(4):418–24.

    PubMed  CrossRef  Google Scholar 

  105. Jeong D, Patel A, Francois CJ, Gage KL, Fradley MG. Cardiac magnetic resonance imaging in oncology. Cancer Control. 2017;24(2):147–60.

    PubMed  CrossRef  Google Scholar 

  106. Bottinor WJ, Migliore CK, Lenneman CA, Stoddard MF. Echocardiographic assessment of cardiotoxic effects of cancer therapy. Curr Cardiol Rep. 2016;18(10):99.

    PubMed  CrossRef  Google Scholar 

  107. Carver JR, Szalda D, Ky B. Asymptomatic cardiac toxicity in long-term cancer survivors: defining the population and recommendations for surveillance. Semin Oncol. 2013;40(2):229–38.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  108. Villarraga HR, Herrmann J, Nkomo VT. Cardio-oncology: role of echocardiography. Prog Cardiovasc Dis. 2014;57(1):10–8.

    PubMed  CrossRef  Google Scholar 

  109. Yu AF, Ky B. Roadmap for biomarkers of cancer therapy cardiotoxicity. Heart. 2016;102(6):425–30.

    PubMed  CrossRef  CAS  Google Scholar 

  110. Ades F, Zardavas D, Pinto AC, Criscitiello C, Aftimos P, de Azambuja E. Cardiotoxicity of systemic agents used in breast cancer. Breast. 2014;23(4):317–28.

    PubMed  CrossRef  Google Scholar 

  111. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, Plana JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  112. Mokuyasu S, Suzuki Y, Kawahara E, Seto T, Tokuda Y. High-sensitivity cardiac troponin I detection for 2 types of drug-induced cardiotoxicity in patients with breast cancer. Breast Cancer. 2015;22(6):563–9.

    PubMed  CrossRef  Google Scholar 

  113. Leger KJ, Leonard D, Nielson D, de Lemos JA, Mammen PP, Winick NJ. Circulating microRNAs: potential markers of cardiotoxicity in children and young adults treated with anthracycline chemotherapy. J Am Heart Assoc. 2017;6(4).

    Google Scholar 

  114. Rigaud VO, Ferreira LR, Ayub-Ferreira SM, Avila MS, Brandao SM, Cruz FD, Santos MH, Cruz CB, Alves MS, Issa VS, Guimaraes GV, Cunha-Neto E, Bocchi EA. Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. Oncotarget. 2017;8(4):6994–7002.

    PubMed  CrossRef  Google Scholar 

  115. Todorova VK, Makhoul I, Wei J, Klimberg VS. Circulating miRNA profiles of doxorubicin-induced cardiotoxicity in breast cancer patients. Ann Clin Lab Sci. 2017;47(2):115–9.

    PubMed  CAS  Google Scholar 

  116. Ahmed SH, Moussa Sherif DE, Fouad Y, Kelany M, Abdel-Rahman O. Principles of a risk evaluation and mitigation strategy (REMS) for breast cancer patients receiving potentially cardiotoxic adjuvant treatments. Expert Opin Drug Saf. 2016;15(7):911–23.

    PubMed  CrossRef  CAS  Google Scholar 

  117. Giordano G, Spagnuolo A, Olivieri N, Corbo C, Campagna A, Spagnoletti I, Pennacchio RM, Campidoglio S, Pancione M, Palladino L, Villari B, Febbraro A. Cancer drug related cardiotoxicity during breast cancer treatment. Expert Opin Drug Saf. 2016;15(8):1063–74.

    PubMed  CrossRef  CAS  Google Scholar 

  118. 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.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  119. Snipelisky D, Park JY, Lerman A, Mulvagh S, Lin G, Pereira N, Rodriguez-Porcel M, Villarraga HR, Herrmann J. How to develop a cardio-oncology clinic. Heart Fail Clin. 2017;13(2):347–59.

    PubMed  CrossRef  Google Scholar 

  120. Sisler J, Chaput G, Sussman J, Ozokwelu E. Follow-up after treatment for breast cancer: practical guide to survivorship care for family physicians. Can Fam Physician. 2016;62(10):805–11.

    PubMed  PubMed Central  Google Scholar 

  121. Maas AH, Ottevanger N, Atsma F, Cramer MJ, Leiner T, Poortmans P. Cardiovascular surveillance in breast cancer treatment: a more individualized approach is needed. Maturitas. 2016;89:58–62.

    PubMed  CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marjan Boerma .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Boerma, M. (2018). Cardiovascular Side Effects of Breast Cancer Therapy. In: Mehta, J., McSweeney, J. (eds) Gender Differences in the Pathogenesis and Management of Heart Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-71135-5_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-71135-5_17

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-71134-8

  • Online ISBN: 978-3-319-71135-5

  • eBook Packages: MedicineMedicine (R0)