Role of trastuzumab in the management of HER2-positive metastatic breast cancer

Abstract

Breast cancer is a major health issue in developed countries. Overexpression of HER2, a member of epidermal growth factor receptor family, occurs in 20%-30% of breast cancers. HER2 drives the cancer cells to develop a more aggressive phenotype, to metastasize to viscera and central nervous system, and to be less sensitive to chemotherapeutic agents. Trastuzumab (Herceptin®) is a monoclonal antibody directed against the extracellular domain of HER2. As single agent or with chemotherapy, trastuzumab improves survival of HER2-positive breast cancers. In the past years, trastuzumab has completely revolutionized the scenario of the treatment of HER2-positive breast cancer, representing one of the most remarkable examples of targeted therapy in oncology. However, issues such as the best chemotherapeutic companion to associate with trastuzumab, cardiac toxicities, and clinical resistance still require tremendous efforts by researchers. Here, we review pharmacology, efficacy studies, and toxicities of trastuzumab in metastatic breast cancer. Moreover, we provide some insights on resistance to therapy. Finally, we briefly discuss trastuzumab's place in the clinical setting.

Keywords: HER2; breast cancer; cardiotoxicity; resistance; trastuzumab.

Figure 1

Mechanisms of action of trastuzumab. A) In vitro, trastuzumab is able to disrupt signaling through PI3K/Akt and MAPK signaling pathways; causes a disruption of the binding of Src to HER2, allowing PTEN to inhibit Akt B); induces apoptosis of target cells and C) cell cycle arrest in G0-G1 phase, via modulating the cyclin-dependent kinase (CDK) inhibitor 27 ^Kip1. D) In vivo, trastuzumab binds the Fcγ receptor on NK cells and triggers the antibody-dependent cell-mediated cytotoxicity (ADCC). Abbreviations: HER2, human epidermal growth factor receptor 2; NK, natural killer; FcγR, fragment crystallizable region gamma receptor; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless protein; Ras, small GTPase protein; Raf, Mek, and Erk, serine/threonine-protein kinases; Elk, transcription factor; Src, Rous sarcoma tyrosine kinase; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinases; Akt, serine/threonine protein kinase; mTor, mammalian target of rapamycin; p27 ^Kip−1, cyclin-dependent kinase inhibitor 1B; Cdk2, cyclin-dependent kinase 2a.

Figure 2

Mechanisms of resistance to trastuzumab. A) Loss of PTEN protein can impair efficacy of trastuzumab; B) mutation of PI3KCA gene sequence C) Overexpression of DARPP-32 and its truncated form t-DARPP, leading to increased phosphorylation of Akt; D) HER2 can dimerize with other tyrosine kinase receptors, such as Met or IGF-1R, activating alternative signaling pathways; E) binding of HER2 with trastuzumab can be prevented by other cellular surface proteins, such as Muc4, F) or by the shedding of the extracellular domain of HER2 mediated by metalloproteinases; G) Fcγ-receptor polymorphisms can impair antibody-dependent cell-mediated cytotoxicity (ADCC) in vivo. Abbreviations: HER2, human epidermal growth factor receptor 2; NK, natural killer; FcγR, fragment crystallizable region gamma receptor; Src, Rous sarcoma tyrosine kinase; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinases; Akt, serine/threonine protein kinase; mTor, mammalian target of rapamycin; DARPP-32, dopamine- and cyclic-AMP-regulated phosphoprotein; t-DARPP, truncated form of dopamine- and cyclic-AMP-regulated phosphoprotein; MMP9, matrix metallopeptidase 9; p95, truncated form of HER2; Muc4, mucin 4; IGF-1R, insulin-like growth factor receptor 1; Met, hepatocyte growth factor receptor.