HER2-Targeted Therapy-From Pathophysiology to Clinical Manifestation: A Narrative Review

Abstract

Trastuzumab is the primary treatment for all stages of HER2-overexpressing breast cancer in patients. Though discovered over 20 years ago, trastuzumab-induced cardiotoxicity (TIC) remains a research topic in cardio-oncology. This review explores the pathophysiological basis of TIC and its clinical manifestations. Their understanding is paramount for early detection and cardioprotective treatment. Trastuzumab renders cardiomyocytes susceptible by inhibiting the cardioprotective NRG-1/HER2/HER4 signaling pathway. The drug acts on HER2-receptor-expressing cardiomyocytes, endothelium, and cardiac progenitor cells (see the Graphical Abstract). The activation of immune cells, fibroblasts, inflammation, and neurohormonal systems all contribute to the evolution of TIC. A substantial amount of research demonstrates that trastuzumab induces overt and subclinical left ventricular (LV) systolic failure. Data suggest the development of right ventricular damage, LV diastolic dysfunction, and heart failure with preserved ejection fraction. Further research is needed to define a chronological sequence of cardiac impairments to guide the proper timing of cardioprotection implementation.

Keywords: cardiotoxicity; clinical manifestation; pathophysiology; trastuzumab.

Figure 1

Pathophysiology of TIC. The adverse effects of trastuzumab within the myocardium involve interactions among various cell types that express HER2 receptors—cardiomyocytes, endothelial cells, and cardiac progenitor cells. By blocking the heterodimerization of HER2/HER4, trastuzumab inhibits downstream prosurvival pathways. In addition, immune cell activation, inflammation, reactive oxygen species generation, fibroblast stimulation, and collagen deposition in the extracellular matrix all play a role in myocardial injury. Furthermore, anthracycline exposure promotes these changes, making cardiomyocytes susceptible to damage and reliant on the NRG-1/HER2/HER4 pathway. Sympathetic and angiotensin II activation exert complementary roles in the evolution of cardiac damage. Akt—protein kinase B; CMC—cardiomyocyte; EC—endothelial cell; eNOS—endothelial nitric oxide synthase; ERK1/2—extracellular signal-regulated kinase 1/2; CPC—cardiac progenitor cell; Fbl—fibroblast; HER2—human epidermal growth factor receptor 2; HER4—human epidermal growth factor receptor 4; IL-1—interleukin-1; ICAM-1—intercellular adhesion molecule 1; MEK—mitogen-activated protein kinase; NO—nitric oxide; NRG1—neuregulin-1; PI3K—phosphoinositide 3-kinase; Raf—Raf kinase; Ras—Ras protein; ROS—reactive oxygen species; TGF-β—transforming growth factor-β; TNF—tumor necrosis factor; VEGFR—vascular endothelial growth factor receptor (created by Svetoslava Slavcheva using BioRender.com).