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Mechanisms and potential interventions associated with the cardiotoxicity of ErbB2-targeted drugs: Insights from in vitro, in vivo, and clinical studies in breast cancer patients

Abstract

Breast cancer is the most frequently occurring cancer among women worldwide. Human epidermal growth factor receptor 2 (HER2 or ErbB2) is overexpressed in between 20 and 25% of invasive breast cancers and is associated with poor prognosis. Trastuzumab, an anti-ErbB2 monoclonal antibody, reduces cancer recurrence and mortality in HER2-positive breast cancer patients, but unexpectedly induces cardiac dysfunction, especially when used in combination with anthracycline-based chemotherapy. Novel approved ErbB2-targeting drugs, including lapatinib, pertuzumab, and trastuzumab-emtansine, also potentially cause cardiotoxicity, although early clinical studies demonstrate their cardiac safety profile. Unfortunately, the mechanism involved in causing the cardiotoxicity is still not completely understood. In addition, the use of preventive interventions against trastuzumab-induced cardiac dysfunction, including angiotensin-converting enzyme inhibitors and beta-blockers, remain controversial. Thus, this review aims to summarize and discuss the evidence currently available from in vitro, in vivo, and clinical studies regarding the mechanism and potential interventions associated with the cardiotoxicity of ErbB2-targeted drugs.

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References

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

    PubMed  Article  Google Scholar 

  2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    PubMed  CAS  Article  Google Scholar 

  3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    PubMed  CAS  Article  Google Scholar 

  4. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    PubMed  CAS  Article  Google Scholar 

  5. Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, Ageev FT, Hitre E, Groetz J, Iwata H, Knap M, Gnant M, Muehlbauer S, Spence A, Gelber RD, Piccart-Gebhart MJ (2007) Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25:3859–3865

    PubMed  CAS  Article  Google Scholar 

  6. Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT, Hudis CA, Dang CT, Steingart RM (2015) Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 149:489–495

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  7. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, Criscitiello C, Goldhirsch A, Cipolla C, Roila F (2012) Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 23(Suppl 7):155–166

    Article  Google Scholar 

  8. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM (2016) 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37:2768–2801

    PubMed  Article  Google Scholar 

  9. Cote GM, Sawyer DB, Chabner BA (2012) ERBB2 inhibition and heart failure. N Engl J Med 367:2150–2153

    PubMed  CAS  Article  Google Scholar 

  10. Linggi B, Carpenter G (2006) ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 16:649–656

    PubMed  CAS  Article  Google Scholar 

  11. Jones RB, Gordus A, Krall JA, MacBeath G (2006) A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439:168–174

    PubMed  CAS  Article  Google Scholar 

  12. Hu S, Sun Y, Meng Y, Wang X, Yang W, Fu W, Guo H, Qian W, Hou S, Li B, Rao Z, Lou Z, Guo Y (2015) Molecular architecture of the ErbB2 extracellular domain homodimer. Oncotarget 6:1695–1706

    PubMed  PubMed Central  Article  Google Scholar 

  13. Lemmens K, Doggen K, De Keulenaer GW (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960

    PubMed  CAS  Article  Google Scholar 

  14. Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, Chien KR, Birchmeier C, Garratt AN (2002) Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 99:8880–8885

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  15. Garcia-Rivello H, Taranda J, Said M, Cabeza-Meckert P, Vila-Petroff M, Scaglione J, Ghio S, Chen J, Lai C, Laguens RP, Lloyd KC, Hertig CM (2005) Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am J Physiol Heart Circ Physiol 289:H1153–H1160

    PubMed  CAS  Article  Google Scholar 

  16. Munk M, Memon AA, Goetze JP, Nielsen LB, Nexo E, Sorensen BS (2012) Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes. PLoS One 7:e40243

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  17. Camprecios G, Lorita J, Pardina E, Peinado-Onsurbe J, Soley M, Ramirez I (2011) Expression, localization, and regulation of the neuregulin receptor ErbB3 in mouse heart. J Cell Physiol 226:450–455

    PubMed  CAS  Article  Google Scholar 

  18. Eldridge S, Guo L, Mussio J, Furniss M, Hamre J 3rd, Davis M (2014) Examining the protective role of ErbB2 modulation in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci 141:547–559

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  19. Cote GM, Miller TA, Lebrasseur NK, Kuramochi Y, Sawyer DB (2005) Neuregulin-1alpha and beta isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro. Exp Cell Res 311:135–146

    PubMed  CAS  Article  Google Scholar 

  20. Lemmens K, Segers VF, Demolder M, De Keulenaer GW (2006) Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. J Biol Chem 281:19469–19477

    PubMed  CAS  Article  Google Scholar 

  21. Okoshi K, Nakayama M, Yan X, Okoshi MP, Schuldt AJ, Marchionni MA, Lorell BH (2004) Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation 110:713–717

    PubMed  CAS  Article  Google Scholar 

  22. Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM (2002) Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105:1551–1554

    PubMed  CAS  Article  Google Scholar 

  23. Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW (2004) Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation 109:324–326

    PubMed  CAS  Article  Google Scholar 

  24. Timolati F, Ott D, Pentassuglia L, Giraud MN, Perriard JC, Suter TM, Zuppinger C (2006) Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 41:845–854

    PubMed  CAS  Article  Google Scholar 

  25. Rohrbach S, Muller-Werdan U, Werdan K, Koch S, Gellerich NF, Holtz J (2005) Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. J Mol Cell Cardiol 38:485–493

    PubMed  CAS  Article  Google Scholar 

  26. Kurokawa YK, Shang MR, Yin RT, George SC (2018) Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes. Toxicol Lett 285:74–80

    PubMed  CAS  Article  Google Scholar 

  27. Belmonte F, Das S, Sysa-Shah P, Sivakumaran V, Stanley B, Guo X, Paolocci N, Aon MA, Nagane M, Kuppusamy P, Steenbergen C, Gabrielson K (2015) ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol 309:H1271–H1280

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  28. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328

    PubMed  CAS  Article  Google Scholar 

  29. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  30. Grazette LP, Boecker W, Matsui T, Semigran M, Force TL, Hajjar RJ, Rosenzweig A (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231–2238

    PubMed  CAS  Article  Google Scholar 

  31. Hsu WT, Huang CY, Yen CYT, Cheng AL, Hsieh PCH (2018) The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling. Theranostics 8:3176–3188

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  32. Fedele C, Riccio G, Malara AE, D’Alessio G, De Lorenzo C (2012) Mechanisms of cardiotoxicity associated with ErbB2 inhibitors. Breast Cancer Res Treat 134:595–602

    PubMed  CAS  Article  Google Scholar 

  33. Gordon LI, Burke MA, Singh AT, Prachand S, Lieberman ED, Sun L, Naik TJ, Prasad SV, Ardehali H (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284:2080–2087

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. Pentassuglia L, Timolati F, Seifriz F, Abudukadier K, Suter TM, Zuppinger C (2007) Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp Cell Res 313:1588–1601

    PubMed  CAS  Article  Google Scholar 

  35. De Lorenzo C, Paciello R, Riccio G, Rea D, Barbieri A, Coppola C, Maurea N (2018) Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. Onco Targets Ther 11:2241–2250

    PubMed  PubMed Central  Article  Google Scholar 

  36. Seemann I, te Poele JA, Song JY, Hoving S, Russell NS, Stewart FA (2013) Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents. Breast Cancer Res Treat 141:385–395

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  37. ElZarrad MK, Mukhopadhyay P, Mohan N, Hao E, Dokmanovic M, Hirsch DS, Shen Y, Pacher P, Wu WJ (2013) Trastuzumab alters the expression of genes essential for cardiac function and induces ultrastructural changes of cardiomyocytes in mice. PLoS One 8:e79543

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  38. Kabel AM, Elkhoely AA (2017) Targeting proinflammatory cytokines, oxidative stress, TGF-beta1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. Biomed Pharmacother 93:17–26

    PubMed  CAS  Article  Google Scholar 

  39. Riccio G, Antonucci S, Coppola C, D’Avino C, Piscopo G, Fiore D, Maurea C, Russo M, Rea D, Arra C, Condorelli G, Di Lisa F, Tocchetti CG, De Lorenzo C, Maurea N (2018) Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ros production. Front Physiol 9:38

    PubMed  PubMed Central  Article  Google Scholar 

  40. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, Ganame J, Sebag IA, Agler DA, Badano LP, Banchs J, Cardinale D, Carver J, Cerqueira M, DeCara JM, Edvardsen T, Flamm SD, Force T, Griffin BP, Jerusalem G, Liu JE, Magalhaes A, Marwick T, Sanchez LY, Sicari R, Villarraga HR, Lancellotti P (2014) 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 27:911–939

    PubMed  Article  Google Scholar 

  41. Cornarotti M, Tinelli S, Willmore E, Zunino F, Fisher LM, Austin CA, Capranico G (1996) Drug sensitivity and sequence specificity of human recombinant DNA topoisomerases IIalpha (p170) and IIbeta (p180). Mol Pharmacol 50:1463–1471

    PubMed  CAS  Google Scholar 

  42. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, Mutharasan RK, Naik TJ, Ardehali H (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124:617–630

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  43. Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E, Hasegawa K, Kita T, Kimura T (2010) Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res 87:656–664

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. Gabrielson K, Bedja D, Pin S, Tsao A, Gama L, Yuan B, Muratore N (2007) Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury. Cancer Res 67:1436–1441

    PubMed  CAS  Article  Google Scholar 

  45. Ozturk M, Ozler M, Kurt YG, Ozturk B, Uysal B, Ersoz N, Yasar M, Demirbas S, Kurt B, Acikel C, Oztas Y, Arpaci F, Topal T, Ozet A, Ataergin S, Kuzhan O, Oter S, Korkmaz A (2011) Efficacy of melatonin, mercaptoethylguanidine and 1400 W in doxorubicin- and trastuzumab-induced cardiotoxicity. J Pineal Res 50:89–96

    PubMed  CAS  Article  Google Scholar 

  46. Kertmen N, Aksoy S, Uner A, Sargon M, Ozkayar O, Keskin O, Babacan T, Sarici F, Sendur MA, Arik Z, Akin S, Altundag K (2015) Which sequence best protects the heart against trastuzumab and anthracycline toxicity? An electron microscopy study in rats. Anticancer Res 35:857–864

    PubMed  CAS  Google Scholar 

  47. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (neosphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32

    PubMed  CAS  Article  Google Scholar 

  48. Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811–7819

    PubMed  CAS  Article  Google Scholar 

  49. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375:377–384

    PubMed  CAS  Article  Google Scholar 

  50. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273–1283

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  51. Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461–471

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  52. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538–5546

    PubMed  CAS  Article  Google Scholar 

  53. Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, Lorvidhaya V, Jiang Z, Yang J, Makhson A, Leung WL, Russo MW, Newstat B, Wang L, Chen G, Oliva C, Gomez H (2013) Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J Clin Oncol 31:1947–1953

    PubMed  CAS  Article  Google Scholar 

  54. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF (2008) Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544–5552

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA, Gersh BJ, Jaffe AS, Rodeheffer RJ (2008) Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26:1231–1238

    PubMed  CAS  Article  Google Scholar 

  56. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortes J (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278–2284

    PubMed  CAS  Article  Google Scholar 

  57. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122–131

    Article  Google Scholar 

  58. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379:633–640

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  59. Pizzuti L, Barba M, Giannarelli D, Sergi D, Botti C, Marchetti P, Anza M, Maugeri-Sacca M, Natoli C, Di Filippo S, Catenaro T, Tomao F, Amodio A, Carpano S, Perracchio L, Mottolese M, Di Lauro L, Sanguineti G, Di Benedetto A, Giordano A, Vici P (2016) Neoadjuvant sequential docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab, the DECT trial. J Cell Physiol 231:2541–2547

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  60. Quartino AL, Hillenbach C, Li J, Li H, Wada RD, Visich J, Li C, Heinzmann D, Jin JY, Lum BL (2016) Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol 77:77–88

    PubMed  CAS  Article  Google Scholar 

  61. Pivot X, Suter T, Nabholtz JM, Pierga JY, Espie M, Lortholary A, Khayat D, Pauporte I, Romieu G, Kramar A, Fumoleau P (2015) Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study. Eur J Cancer 51:1660–1666

    PubMed  CAS  Article  Google Scholar 

  62. Earl HM, Vallier AL, Dunn J, Loi S, Ogburn E, McAdam K, Hughes-Davies L, Harnett A, Abraham J, Wardley A, Cameron DA, Miles D, Gounaris I, Plummer C, Hiller L (2016) Trastuzumab-associated cardiac events in the Persephone trial. Br J Cancer 115:1462–1470

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  63. Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Kiermaier A, Eng-Wong J, Dang C (2018) Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 29:646–653

    PubMed  CAS  Article  Google Scholar 

  64. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE (2010) Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist 15:924–934

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  65. Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS (2008) Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7:1769–1775

    PubMed  CAS  Article  Google Scholar 

  66. Krop IE, Kim SB, Gonzalez-Martin A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H (2014) Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15:689–699

    PubMed  CAS  Article  Google Scholar 

  67. Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P (2017) Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III Marianne study. J Clin Oncol 35:141–148

    PubMed  CAS  Article  Google Scholar 

  68. Lynce F, Barac A, Geng X, Dang C, Yu AF, Smith KL, Gallagher C, Pohlmann PR, Nunes R, Herbolsheimer P, Warren R, Srichai MB, Hofmeyer M, Cunningham A, Timothee P, Asch FM, Shajahan-Haq A, Tan MT, Isaacs C, Swain SM (2019) Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEART study. Breast Cancer Res Treat 175:595–603

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  69. Haykowsky MJ, Mackey JR, Thompson RB, Jones LW, Paterson DI (2009) Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin Cancer Res 15:4963–4967

    PubMed  CAS  Article  Google Scholar 

  70. Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH (2013) Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 6:420–426

    PubMed  CAS  Article  Google Scholar 

  71. Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, Pagano JJ, Chow K, Thompson RB, Vos LJ, Ghosh S, Oudit GY, Ezekowitz JA, Paterson DI (2017) 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 35:870–877

    PubMed  CAS  Article  Google Scholar 

  72. Boekhout AH, Gietema JA, Kerklaan BM, 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 (2016) Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer: a randomized clinical trial. JAMA Oncol 2:1030–1037

    PubMed  Article  Google Scholar 

  73. Guglin M, Krischer J, Tamura R, Fink A, Bello-Matricaria L, McCaskill-Stevens W, Munster PN (2019) Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer. J Am Coll Cardiol 73:2859–2868

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  74. Dong WG, Mei Q, Yu JP, Xu JM, Xiang L, Xu Y (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol 9:1307–1311

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  75. Fotino AD, Thompson-Paul AM, Bazzano LA (2013) Effect of coenzyme Q(1)(0) supplementation on heart failure: a meta-analysis. Am J Clin Nutr 97:268–275

    PubMed  CAS  Article  Google Scholar 

  76. Moon GJ, Kim SJ, Cho YH, Ryoo S, Bang OY (2014) Antioxidant effects of statins in patients with atherosclerotic cerebrovascular disease. J Clin Neurol 10:140–147

    PubMed  PubMed Central  Article  Google Scholar 

  77. Aldakkak M, Camara AK, Heisner JS, Yang M, Stowe DF (2011) Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts. Pharmacol Res 64:381–392

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  78. Tocchetti CG, Carpi A, Coppola C, Quintavalle C, Rea D, Campesan M, Arcari A, Piscopo G, Cipresso C, Monti MG, De Lorenzo C, Arra C, Condorelli G, Di Lisa F, Maurea N (2014) Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction. Eur J Heart Fail 16:358–366

    PubMed  CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by the Research Chair Grant from the National Science and Technology Development Agency Thailand (NC), the Thailand Research Fund RTA6080003 (SCC) and the Chiang Mai University Center of Excellence Award (NC).

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Correspondence to Nipon Chattipakorn.

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Leemasawat, K., Phrommintikul, A., Chattipakorn, S.C. et al. Mechanisms and potential interventions associated with the cardiotoxicity of ErbB2-targeted drugs: Insights from in vitro, in vivo, and clinical studies in breast cancer patients. Cell. Mol. Life Sci. 77, 1571–1589 (2020). https://doi.org/10.1007/s00018-019-03340-w

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  • DOI: https://doi.org/10.1007/s00018-019-03340-w

Keywords

  • Cardiotoxicity
  • Trastuzumab
  • Lapatinib
  • Pertuzumab
  • Trastuzumab-emtansine