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Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies

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Abstract

Purpose

Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies.

Findings

Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval.

Conclusions

Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.

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References

  1. Slamon DJCG, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER2-2/neu oncogene. Science 235:177–182

    Article  CAS  PubMed  Google Scholar 

  2. Katzorke NRB, Haeberle L et al (2013) Prognostic value of HER2 on breast cancer survival. J Clin Onc 31(15):600–640

    Google Scholar 

  3. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr et al (2014) Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32(33):3744–3752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Slamon DJL-JB, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over-expresses HER2. N Eng J Med 344(344):783–792

    Article  CAS  Google Scholar 

  5. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP (2012) Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 60(24):2504–2512

    Article  CAS  PubMed  Google Scholar 

  6. Doroshow JH (1991) Doxorubicin-induced cardiac toxicity. N Engl J Med 324(12):843–845

    Article  CAS  PubMed  Google Scholar 

  7. Tewey KMRT, Yang L et al (1984) Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226(4673):466–468

    Article  CAS  PubMed  Google Scholar 

  8. De Keulenaer GW, Doggen K, Lemmens K (2010) The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res 106(1):35–46

    Article  PubMed  Google Scholar 

  9. Cote GM, Sawyer DB, Chabner BA (2012) ERBB2 inhibition and heart failure. N Engl J Med 367(22):2150–2153

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. Jain S, Wei J, Mitrani LR, Bishopric NH (2012) Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival. Breast Cancer Res Treat 135(1):103–114

    Article  CAS  PubMed  Google Scholar 

  12. Matsui T, Rosenzweig A (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 38(1):63–71

    Article  CAS  PubMed  Google Scholar 

  13. Grazette LP, Boecker W, Matsui T, Semigran M, Force TL, Hajjar RJ et al (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44(11):2231–2238

    Article  CAS  PubMed  Google Scholar 

  14. Sandoo AKG, Carmichael AR (2015) Breast cancer therapy and cardiovascular risk: focus on trastuzumab. Vasc Health Risk Manag 11:223–228

    Article  PubMed  PubMed Central  Google Scholar 

  15. Leung HW (2015) Trastuzumab-induced cardiotoxicity in elderly women with HER2-positive breast cancer: a meta-analysis of real-world data. Exp Opin Drug Safe. 14(11):1661–1671

    Article  CAS  Google Scholar 

  16. Jawa ZPR, Garlie L et al (2016) Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: a meta-analysis. Medicine 95(44):e5195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Naumann DRV, Margiotta C et al (2013) Factors predicting trastuzumab-related cardiotoxicity in a real-world population of women with HER2+ breast cancer. Anticancer Res 33(4):1717–1720

    CAS  PubMed  Google Scholar 

  18. Farolfi AME, Aquilina M et al (2013) Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart 99:634–639

    Article  CAS  PubMed  Google Scholar 

  19. Chavez-MacGregor MZN, Buchholz TA et al (2013) Trastuzumab-related cardiotoxicity among older patients with breast cancer. J Clin Onc 31:4222–4228

    Article  CAS  Google Scholar 

  20. Ezaz G, Long JB, Gross CP, Chen J (2014) Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 3(1):e000472

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gunaldi MDB, Afsar C et al (2015) Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: an observational single-centre study. J Onc Pharm Pract 22(2):242–247

    Article  Google Scholar 

  22. LA Guenancia C, Cardinale D et al (2016) Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis. J Clin Oncol 34(26):3157–3165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tang GHAS, Sevick L, Yan AT, Brezden-Masley C (2017) Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single “real-world” setting. Med Oncol 34(9):154

    Article  PubMed  Google Scholar 

  24. Baron KB, Brown JR, Heiss BL, Marshall J, Tait N, Tkaczuk KH et al (2014) Trastuzumab-induced cardiomyopathy: incidence and associated risk factors in an inner-city population. J Card Fail 20(8):555–559

    Article  CAS  PubMed  Google Scholar 

  25. Serrano CCJ, De Mattos-Arruda L et al (2012) Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Annals Onc 23(4):897–902

    Article  CAS  Google Scholar 

  26. Romond EHJJ, Rastogi P et al (2012) 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. Gr J Clin Oncol 30(31):3792–3799

    Article  CAS  Google Scholar 

  27. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO et al (2018) Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19(12):1630–1640

    Article  PubMed  Google Scholar 

  29. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R et al (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(9):2278–2284

    Article  CAS  PubMed  Google Scholar 

  30. Hurvitz SA, Caswell-Jin JL, McNamara KL, Zoeller JJ, Bean GR, Dichmann R et al (2020) Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07). Nat Commun 11(1):5824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang C-S, Thompson AM et al (2018) Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19(1):115–126

    Article  CAS  PubMed  Google Scholar 

  32. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK et al (2015) Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372(2):134–141

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tolaney SMT, Barrey L et al (2019) A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). San Antonio Breast Cancer Symposium (SABCS), San Antonio, Texas

    Google Scholar 

  34. Rushton MJC, Dent S (2017) Trastuzumab-induced cardiotoxicity: testing a clinical risk score in a real-world cardio-oncology population. Curr Onc 24(3):176–180

    Article  CAS  Google Scholar 

  35. Abdel-Qadir H, Thavendiranathan P, Austin PC, Lee DS, Amir E, Tu JV et al (2019) Development and validation of a multivariable prediction model for major adverse cardiovascular events after early stage breast cancer: a population-based cohort study. Eur Heart J 40(48):3913–3920

    Article  PubMed  Google Scholar 

  36. Jordan JHTR, Vasu S, Hundley WG (2018) Cardiovascular magnetic resonance in the oncology patient. JACC Cardiovasc Imag 11(8):1150–1172

    Article  Google Scholar 

  37. Plana JCGM, Barac A et al (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. Euro Heart J Cardioasc Imag 15(10):1063–1093

    Article  Google Scholar 

  38. Wehner GJ, Jing L, Haggerty CM, Suever JD, Leader JB, Hartzel DN et al (2020) Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? Eur Heart J 41(12):1249–1257

    Article  PubMed  Google Scholar 

  39. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28(1):1-39.e14

    Article  PubMed  Google Scholar 

  40. Huang H, Nijjar PS, Misialek JR, Blaes A, Derrico NP, Kazmirczak F et al (2017) Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: comparison with cardiovascular magnetic resonance. J Cardiovasc Magn Reson 19(1):34

    Article  PubMed  PubMed Central  Google Scholar 

  41. Manrique CR, Tiwari N, Plana JC, Garcia MJ (2017) diagnostic strategies for early recognition of cancer therapeutics–related cardiac dysfunction. Clin Med Insights Cardiol 11: eCollection

  42. Negishi KNT, Hare JL et al (2013) Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echo 26(5):493–498

    Article  Google Scholar 

  43. Thavendiranathan P, Negishi T, Somerset E, Negishi K, Penicka M, Lemieux J et al (2021) Strain-guided management of potentially cardiotoxic cancer therapy. J Am Coll Cardiol 77(4):392–401

    Article  CAS  PubMed  Google Scholar 

  44. Bloom MWHC, Cardinale D et al (2016) Cancer therapy-related cardiac dysfunction and heart failure: part 1: definitions, pathophysiology, risk factors, and imaging. Circ Heart Fail 9(1):002661

    Article  Google Scholar 

  45. Thavendiranthan PWB, Flamm SD et al (2013) Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imag 6(6):1080–1091

    Article  Google Scholar 

  46. Smith GKP, Carpenter JP et al (2009) Cardiovascular magnetic resonance imaging in early anthracycline cardiotoxicity. J Cardiovasc Magn Reson 11(S1):18

    Article  Google Scholar 

  47. Jordan JH, Castellino SM, Meléndez GC, Klepin HD, Ellis LR, Lamar Z et al (2018) Left ventricular mass change after anthracycline chemotherapy. Circ Heart Fail 11(7):e004560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal DS (2008) Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson 10(1):5

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zardavas DST, Van Veldhuisen DJ et al (2017) Role of troponins I and T and N-terminal prohormone of brain natriuretic peptide in monitoring cardiac safey of patients with early-stage human epidermal growth factor receptor 2-positive breast cancer receiving trastuzumab: a herceptin adjuvant study car. J Clin Oncol 35(8):878–884

    Article  CAS  PubMed  Google Scholar 

  50. Cardinale DCA, Torrisi R et al (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 28(25):3910–3916

    Article  CAS  PubMed  Google Scholar 

  51. Sawaya HSI, Plana JC et al (2011) Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 107(9):1375–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sendur MAAS, Ozdemir N et al (2015) Comparison of long-term cardiac effects of 9-and 52-week trastuzumab in HER2-positive early breast cancer. Curr Med Res Opin 3:547–556

    Article  Google Scholar 

  53. Putt MHV, Januzzi JL et al (2015) Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem 61(9):1164–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ponde NBI, Lambertini M et al (2018) Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1–06). Breast Cancer Res Treat 168(3):631–638

    Article  CAS  PubMed  Google Scholar 

  55. Morris PG, Steingart R et al (2011) Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res 17(10):3490–3499

    Article  CAS  PubMed  Google Scholar 

  56. Matos EJB, Blagus R et al (2016) A prospective cohort study on cardiotoxicity of adjuvant trastuzumab in breast cancer patients. Arq Bras Cardiol 107(1):40–47

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Fallah-Rad NWJ, Wassef A et al (2011) Utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuv. J Am Coll Cardiol 57(22):2263–2270

    Article  CAS  PubMed  Google Scholar 

  58. de Vries Schultink AHM, Boekhout AH, Gietema JA, Burylo AM, Dorlo TPC, van Hasselt JGC et al (2018) Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens. J Pharmacokinet Pharmacodyn 45(3):431–442

    Article  PubMed  PubMed Central  Google Scholar 

  59. Cardinale DSM, Martinoni A et al (2000) Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 36(2):517–522

    Article  CAS  PubMed  Google Scholar 

  60. Cardinale DSM, Colombo A et al (2004) Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulat 109(22):2749–2754

    Article  CAS  Google Scholar 

  61. Demissei BG, Hubbard RA, Zhang L, Smith AM, Sheline K, McDonald C et al (2020) Changes in cardiovascular biomarkers with breast cancer therapy and associations with cardiac dysfunction. J Am Heart Assoc 9(2):e014708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kittiwarawut AVY, Tanasanvimon S et al (2013) Serum NT-proBNP in the early detection of doxorubicin-induced cardiac dysfunction. Asia Pac J Clin Oncol 9(2):155–161

    Article  PubMed  Google Scholar 

  63. Lenihan DJ, Massey M et al (2016) The utility of point of care biomarkers to detect cardiotoxicity during anthracycline chemotherapy: a feasibility study. J Card Fail 22(6):433–438

    Article  CAS  PubMed  Google Scholar 

  64. Romano SFS, Ricevuto E et al (2011) Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer 105(11):1663–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sandri MT, Cardinale D et al (2005) N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction. Clin Chem 51(8):1405–1410

    Article  CAS  PubMed  Google Scholar 

  66. Gujral DM, Bhattacharyya S (2018) Effect of prophylactic betablocker or ACE inhibitor on cardiac dysfunction and heart failure during anthracycline chemotherapy trastuzumab. Breast 37:64–71

    Article  PubMed  Google Scholar 

  67. Pituskin EMJ, Koshman S et al (2016) 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(8):870–877

    Article  PubMed  Google Scholar 

  68. Guglin MKJ, Tamura R et al (2019) Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer. J Am Coll Cardiol 73(22):2859–2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gulati GHS, Ree AH et al (2016) Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 37(21):1671–1680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Calvillo-Arguelles O, Michalowaska M et al (2019) Cardioprotective effect of statins in patients with her2-positive breast cancer receiving trastuzumab therapy. Can J Cardiol 35(2):153–159

    Article  PubMed  Google Scholar 

  71. Boekhout AH, Kerklaan BM et al (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(8):1030–1037

    Article  PubMed  Google Scholar 

  72. Ewer MSVM, Durand JB et al (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820–7826

    Article  CAS  PubMed  Google Scholar 

  73. Lynce F, Barac A, Geng X, Dang C, Yu AF, Smith KL et al (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(3):595–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Leong DP, Cosman T, Alhussein MM, Tyagi NK, Karampatos S, Barron CC et al (2019) Safety of continuing trastuzumab despite mild cardiotoxicity. JACC Cardio Oncol 1(1):1–10

    Article  Google Scholar 

  75. Yancy CWJM, Bozkurt B et al (2017) 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the american college of cardiology/american heart association task force on clinical practice guidelines and the heart failure society of amer. J Am Coll Cardiol 70(6):776–803

    Article  PubMed  Google Scholar 

  76. Von Minckwitz GPM, de Azambuja E et al (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Eng J Med 377(2):122–131

    Article  Google Scholar 

  77. Gianni LPT, Im YH et al (2016) 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 17(6):791–800

    Article  CAS  PubMed  Google Scholar 

  78. Baselga JCJ, Kim SB et al (2012) CLEOPATRA study group: pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119

    Article  CAS  PubMed  Google Scholar 

  79. Krop IEKS, Gonzalez-Martin A et al (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(7):689–699

    Article  CAS  PubMed  Google Scholar 

  80. Verma SMD, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Eng J Med 367(19):1783–1791

    Article  CAS  Google Scholar 

  81. Hurvitz SAMM, Symmans WF et al (2018) Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19(1):115–126

    Article  CAS  PubMed  Google Scholar 

  82. Perez EABC, Eiermann W et al (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(2):141–148

    Article  CAS  PubMed  Google Scholar 

  83. Von Minckwitz GHC, Mano MS et al (2019) Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Eng J Med 380(7):617–628

    Article  Google Scholar 

  84. Perez EAKM, Byrne J et al (2008) Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 83(6):679–686

    Article  PubMed  Google Scholar 

  85. Geyer CEFJ, Lindquist D et al (2008) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Eng J Med 355(26):2733–2743

    Article  Google Scholar 

  86. Awada ACR, Inoue K et al (2016) Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial. JAMA Oncol 2(12):1557–1564

    Article  PubMed  Google Scholar 

  87. Chan ADS, Holmes FA et al (2016) Neratinib after trastuzumab- based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17(3):367–377

    Article  CAS  PubMed  Google Scholar 

  88. Murthy RBV, Conlin A et al (2018) Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol 19(7):880–888

    Article  CAS  PubMed  Google Scholar 

  89. Murthy RLS, Okines A et al (2020) Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Eng J Med 382:597–609

    Article  CAS  Google Scholar 

  90. Bang YJGG, Im S (2017) First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Annals Onc 28(4):855–861

    Article  CAS  Google Scholar 

  91. Rugo HWG, Seock-Ah I et al (2019) SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Onc 37(15):1000

    Article  Google Scholar 

  92. Modi SSC, Yamashita T et al (2020) Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Eng J Med 382:610–621

    Article  CAS  Google Scholar 

  93. Barok MJH, Isola J (2014) Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 16(2):209

    Article  PubMed  PubMed Central  Google Scholar 

  94. Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J et al (2017) Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 18(6):732–742

    Article  PubMed  PubMed Central  Google Scholar 

  95. Eiger D, Pondé NF, Agbor-Tarh D, Moreno-Aspitia A, Piccart M, Hilbers FS et al (2020) Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab treatment optimization trial. Br J Cancer 122(10):1453–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H et al (2017) 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 18(12):1688–1700

    Article  CAS  PubMed  Google Scholar 

  97. Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N et al (2017) Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: american society of clinical oncology clinical practice guideline. J Clin Oncol 35(8):893–911

    Article  PubMed  Google Scholar 

  98. Wittayanukorn S, Qian J, Westrick SC, Billor N, Johnson B, Hansen RA (2018) Prevention of trastuzumab and anthracycline-induced cardiotoxicity using angiotensin-converting enzyme inhibitors or β-blockers in older adults with breast cancer. Am J Clin Oncol 41(9):909–918

    Article  CAS  PubMed  Google Scholar 

  99. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A et al (2020) Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. ESMO Annals Oncol 31(2):171

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Divisions of Medical Oncology, Department of Medicine, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA

    Naomi Dempsey, Amanda Rosenthal, Yana Kropotova & Marc Lippman

  2. Divisions of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA

    Nitika Dabas

  3. Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd NW, Washington, DC, 20007, USA

    Marc Lippman & Nanette H. Bishopric

  4. MedStar Heart Research Institute, MedStar Washington Hospital Center, 110 Irving St NW, Washington, DC, 20010, USA

    Nanette H. Bishopric

  5. Department of Medicine, Kaiser Permanente Los Angeles Medical Center, 4867 Sunset Blvd, Los Angeles, CA, 90027, USA

    Amanda Rosenthal

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  1. Naomi Dempsey
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  2. Amanda Rosenthal
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  3. Nitika Dabas
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  4. Yana Kropotova
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  5. Marc Lippman
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  6. Nanette H. Bishopric
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Correspondence to Naomi Dempsey.

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Marc Lippman as a possible COI as a director of Seattle Genetics, the manufacturer of Tucatinib.

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Dempsey, N., Rosenthal, A., Dabas, N. et al. Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies. Breast Cancer Res Treat 188, 21–36 (2021). https://doi.org/10.1007/s10549-021-06280-x

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