曲妥珠单抗致HER2阳性乳腺癌患者心脏毒性的研究进展

doi:10.6040/j.issn.1671-7554.0.2025.0035

摘要/Abstract

摘要： 曲妥珠单抗是一种靶向人表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)的人源化单克隆抗体,在HER2阳性乳腺癌的临床治疗中表现出显著效果,但其临床应用可能引发左室射血分数降低、充血性心力衰竭及心律失常等心脏毒性问题。本文旨在综述当前关于曲妥珠单抗治疗HER2阳性乳腺癌诱导心脏毒性发生的相关研究进展,以及如何监测和预防相关心脏毒性的发生,以期为未来基础研究方向选择及临床优化曲妥珠单抗用药管理策略提供依据。

关键词: 乳腺癌, 人表皮生长因子受体2, 曲妥珠单抗, 心脏毒性, 危险因素

Abstract: Trastuzumab is a humanised monoclonal antibody that targets the human epidermal growth factor receptor 2(HER2)and has shown significant efficacy in the clinical treatment of HER2-positive breast cancer. However, its clinical use may lead to cardiotoxicity issues such as reduction in left ventricular ejection fraction(LVEF), congestive heart failure(CHF)and arrhythmias. The aim of this article is to review current research on trastuzumab-induced cardiotoxicity in the treatment of HER2-positive breast cancer and strategies for monitoring and preventing cardiotoxicity. The aim is to provide a basis for selecting future directions in basic research and optimising clinical management strategies for the use of trastuzumab.

Key words: Breast cancer, Human epidermal growth factor receptor 2, Trastuzumab, Cardiotoxicity, Risk factors

中图分类号:

R541

程跃启,王斐,于理想,郑超,余之刚. 曲妥珠单抗致HER2阳性乳腺癌患者心脏毒性的研究进展[J]. 山东大学学报 (医学版), 2025, 63(1): 17-24.

CHENG Yueqi, WANG Fei, YU Lixiang, ZHENG Chao, YU Zhigang. Progress in the study of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients[J]. Journal of Shandong University (Health Sciences), 2025, 63(1): 17-24.

参考文献

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] Martin AP, Downing J, Cochrane M, et al. Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies[J]. Crit Rev Oncol Hematol, 2018, 130: 92-107. doi:10.1016/j.critrevonc.2018.07.012.
[3] von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer[J]. N Engl J Med, 2017, 377(2): 122-131.
[4] DUva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation[J]. Nat Cell Biol, 2015, 17(5): 627-638.
[5] Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer[J]. N Engl J Med, 2011, 365(14): 1273-1283.
[6] Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel(ACP)with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer[J]. J Clin Oncol, 2012, 30(31): 3792-3799.
[7] Advani PP, Ballman KV, Dockter TJ, et al. Long-term cardiac safety analysis of NCCTG N9831(alliance)adjuvant trastuzumab trial[J]. J Clin Oncol, 2016, 34(6): 581-587.
[8] Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant(HERA)trial[J]. Lancet, 2017, 389(10075): 1195-1205.
[9] Conte P, Frassoldati A, Bisagni G, et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study?[J]. Ann Oncol, 2018, 29(12): 2328-2333.
[10] Pivot X, Suter T, Nabholtz JM, et al. Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study[J]. Eur J Cancer, 2015, 51(13): 1660-1666.
[11] Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer(NeoALTTO): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet, 2012, 379(9816): 633-640.
[12] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2[J]. N Engl J Med, 2001, 344(11): 783-792.
[13] Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group[J]. J Clin Oncol, 2005, 23(19): 4265-4274.
[14] Ebrahim N, Al Saihati HA, Mostafa O, et al. Prophylactic evidence of MSCs-derived exosomes in doxorubicin/trastuzumab-induced cardiotoxicity: beyond mechanistic target of NRG-1/erb signaling pathway[J]. Int J Mol Sci, 2022, 23(11): 5967. doi:10.3390/ijms23115967.
[15] Miyamoto S, Murphy AN, Brown JH. Akt mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue[J]. J Bioenerg Biomembr, 2009, 41(2): 169-180.
[16] Mohan N, Jiang JS, Dokmanovic M, et al. Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers[J]. Antib Ther, 2018, 1(1): 13-17.
[17] Jiang ZG, Zhou MD. Neuregulin signaling and heart failure[J]. Curr Heart Fail Rep, 2010, 7(1): 42-47.
[18] Pentassuglia L, Timolati F, Seifriz F, et al. Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes[J]. Exp Cell Res, 2007, 313(8): 1588-1601.
[19] Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?[J]. Cell Cycle, 2009, 8(8): 1168-1175.
[20] Shirasaki K, Taguchi K, Unno M, et al. NF-E2-related factor 2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice[J]. Hepatology, 2014, 59(6): 2371-2382.
[21] Murakami S, Kusano Y, Okazaki K, et al. NRF2 signalling in cytoprotection and metabolism[J]. Br J Pharmacol, 2023. doi:10.1111/bph.16246.
[22] Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress[J]. Circ Res, 2000, 87(10): 840-844.
[23] Zeglinski M, Ludke A, Jassal DS, et al. Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’[J]. Exp Clin Cardiol, 2011, 16(3): 70-74.
[24] Sun L, Wang H, Yu SS, et al. Herceptin induces ferroptosis and mitochondrial dysfunction in H9c2 cells[J]. Int J Mol Med, 2022, 49(2): 17. doi:10.3892/ijmm.2021.5072.
[25] Ye T, Yang W, Gao TL, et al. Trastuzumab-induced cardiomyopathy via ferroptosis-mediated mitochondrial dysfunction[J]. Free Radic Biol Med, 2023, 206: 143-161. doi:10.1016/j.freeradbiomed.2023.06.019.
[26] Pinto AR, Ilinykh A, Ivey MJ, et al. Revisiting cardiac cellular composition[J]. Circ Res, 2016, 118(3): 400-409.
[27] Dugaucquier L, Feyen E, Mateiu L, et al. The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling[J]. Am J Physiol Heart Circ Physiol, 2020, 319(2): 443-455.
[28] Xu ZF, Gao ZZ, Fu HX, et al. PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications[J]. Cardiovasc Res, 2023, 119(5): 1250-1264.
[29] Wang Y, Wei JL, Zhang P, et al. Neuregulin-1, a potential therapeutic target for cardiac repair[J]. Front Pharmacol, 2022, 13: 945206. doi:10.3389/fphar.2022.945206.
[30] 陈威丞, 芮蕾, 温汉春, 等. 血管紧张素Ⅱ对人心脏微血管内皮细胞神经调节蛋白1表达和分泌的影响[J]. 中国民族民间医药, 2015, 24(3): 18-19. CHEN Weicheng, RUI Lei, WEN Hanchun, et al. Effects of angiotensin Ⅱ on expression and secretion of neuregulin-1 in human cardiac microvascular endothelial cells[J]. Chinese Journal of Ethnomedicine and Ethnopharmacy, 2015, 24(3): 18-19.
[31] Hoffman RK, Kim BJ, Shah PD, et al. Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity[J]. Cardiooncology, 2021, 7(1): 15. doi:10.1186/s40959-021-00100-3.
[32] Wilkinson EL, Sidaway JE, Cross MJ. Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability[J]. Biol Open, 2016, 5(10): 1362-1370.
[33] Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia[J]. Nat Rev Cardiol, 2020, 17(8): 474-502.
[34] Piotrowski G, Gawor R, Stasiak A, et al. Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 — a prospective study[J]. Arch Med Sci, 2012, 8(2): 227-235.
[35] Tanriverdi O, Meydan N, Barutca S. Long-term effect of trastuzumab on QT dispersion in adjuvant treatment for patients with Her2 receptor positive breast cancer: a pilot study[J]. Med Oncol, 2012, 29(5): 3265-3271.
[36] Yoshida A, Kamata T, Iwasa T, et al. Myocardial sleeve tissues in surgical lung specimens[J]. Am J Surg Pathol, 2015, 39(10): 1427-1432.
[37] 杨延宗.肌袖性房性心律失常——一种独特的房性心律失常?(Ⅰ)[J]. 中华心律失常学杂志, 2002, 6(2): 111-115. YANG Yanzong. Myocardial sleeve mediated atrial tachyarrhythmias—a specific atrial arrhythmia?(Ⅰ)[J]. Chinese Journal of Cardiac Arrhythmias, 2002, 6(2): 111-115.
[38] Chang JH, Cheng CC, Lu Y, et al. Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling[J]. Iran J Basic Med Sci, 2020, 23(7): 865-870.
[39] Pretorius L, Du XJ, Woodcock EA, et al. Reduced phosphoinositide 3-kinase(p110alpha)activation increases the susceptibility to atrial fibrillation[J]. Am J Pathol, 2009, 175(3): 998-1009.
[40] Clusin WT. Calcium and cardiac arrhythmias: DADs, EADs, and alternans[J]. Crit Rev Clin Lab Sci, 2003, 40(3): 337-375.
[41] Altomare C, Lodrini AM, Milano G, et al. Structural and electrophysiological changes in a model of cardiotoxicity induced by anthracycline combined with trastuzumab[J]. Front Physiol, 2021, 12: 658790. doi:10.3389/fphys.2021.658790.
[42] Aladwani A, Mullen A, Alrashidi M, et al. Comparing trastuzumab-related cardiotoxicity between elderly and younger patients with breast cancer: a prospective cohort study[J]. Eur Rev Med Pharmacol Sci, 2021, 25(24): 7643-7653.
[43] Chavez-MacGregor M, Zhang N, Buchholz TA, et al. Trastuzumab-related cardiotoxicity among older patients with breast cancer[J]. J Clin Oncol, 2013, 31(33): 4222-4228.
[44] Gunaldi M, Duman BB, Afsar CU, et al. Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: an observational single-centre study[J]. J Oncol Pharm Pract, 2016, 22(2): 242-247.
[45] Kaboré EG, Guenancia C, Vaz-Luis I, et al. Association of body mass index and cardiotoxicity related to anthracyclines and trastuzumab in early breast cancer: French CANTO cohort study[J]. PLoS Med, 2019, 16(12): e1002989. doi:10.1371/journal.pmed.1002989.
[46] Hamirani Y, Fanous I, Kramer CM, et al. Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study[J]. Med Oncol, 2016, 33(7): 82. doi:10.1007/s12032-016-0797-x.
[47] Zhang L, Wang Y, Meng WJ, et al. Cardiac safety analysis of anti-HER2-targeted therapy in early breast cancer[J]. Sci Rep, 2022, 12(1): 14312. doi:10.1038/s41598-022-18342-1.
[48] Cochet A, Quilichini G, Dygai-Cochet I, et al. Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer[J]. Breast Cancer Res Treat, 2011, 130(3): 845-854.
[49] Collier P, Phelan D, Klein A. A test in context: myocardial strain measured by speckle-tracking echocardiography[J]. J Am Coll Cardiol, 2017, 69(8): 1043-1056.
[50] van der Linde D, van Hagen I, Veen K, et al. Global longitudinal strain: an early marker for cardiotoxicity in patients treated for breast cancer[J]. Neth Heart J, 2023, 31(3): 103-108.
[51] Lv XF, Pan CL, Guo H, et al. Early diagnostic value of high-sensitivity cardiac troponin T for cancer treatment-related cardiac dysfunction: a meta-analysis[J]. ESC Heart Fail, 2023, 10(4): 2170-2182.
[52] Grothues F, Smith GC, Moon JCC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy[J]. Am J Cardiol, 2002, 90(1): 29-34.
[53] Xu J, Yang WJ, Zhao SH, et al. State-of-the-art myocardial strain by CMR feature tracking: clinical applications and future perspectives[J]. Eur Radiol, 2022, 32(8): 5424-5435.
[54] 徐淑菲, 王志学, 赵森, 等. 心脏磁共振特征追踪技术对乳癌患者化疗期间心脏功能的评估价值[J]. 磁共振成像, 2024, 15(5): 87-93. XU Shufei, WANG Zhixue, ZHAO Sen, et al. Value of cardiac magnetic resonance feature tracking technique in evaluating cardiac function during chemotherapy in breast cancer patients[J]. Chinese Journal of Magnetic Resonance. Imaging, 2024, 15(5): 87-93.
[55] Lewinter C, Nielsen TH, Edfors LR, et al. A systematic review and meta-analysis of beta-blockers and renin-angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer[J]. Eur Heart J, 2022, 43(27): 2562-2569.
[56] Pituskin E, MacKey JR, Koshman S, et al. Multidisciplinary approach to novel therapies in cardio-oncology research(MANTICORE 101-breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity[J]. J Clin Oncol, 2017, 35(8): 870-877.
[57] Abdel-Qadir H, Bobrowski D, Zhou LM, et al. Statin exposure and risk of heart failure after anthracycline- or trastuzumab-based chemotherapy for early breast cancer: a propensity score?matched cohort study[J]. J Am Heart Assoc, 2021, 10(2): e018393. doi:10.1161/JAHA.119.018393.
[58] Hojan K, Procyk D, Horyńska-Kęstowicz D, et al. The preventive role of regular physical training in ventricular remodeling, serum cardiac markers, and exercise performance changes in breast cancer in women undergoing trastuzumab therapy-an REH-HER study[J]. J Clin Med, 2020, 9(5): 1379. doi:10.3390/jcm9051379.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed