Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review

Abstract

Greater understanding of the underlying etiology and biology of breast cancer is enabling the clinical development of targeted therapies for metastatic breast cancer (MBC). Following the successful introduction of trastuzumab, the first human epidermal growth factor receptor (HER) biologically targeted therapy to become widely used in MBC patients, other agents have been developed. Novel agents include monoclonal antibodies such as pertuzumab, which bind to receptors on the cell surface, and tyrosine kinase inhibitors (TKIs) such as lapatinib, which target intracellular pathways such as that of the epidermal growth factor receptor. There is also growing clinical experience with antiangiogenic agents, particularly in combination with chemotherapy. These include the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor receptor, and multitargeted TKIs with antiangiogenic and antiproliferative activities, such as sunitinib. Combination treatment with multiple agents targeting both the HER family and angiogenic pathways (e.g., trastuzumab plus bevacizumab) is also showing activity in the clinical setting. Despite recent advances, there are unanswered questions regarding the management of MBC with targeted agents. Future studies are necessary to determine the optimal combinations, doses, and schedules required to maximize clinical activity while minimizing toxicity. Despite the temptation to use a targeted agent in all patients, identification of patient subgroups most likely to benefit must be a key goal and will be critical to the successful future use of these treatments. The aim of this review is to summarize some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for MBC.

Figure 1.

Key targets for breast cancer treatment. Abbreviations: DAG, diacyl glycerol; EGFR, epidermal growth factor receptor; ERK, extracellular signal–related kinase kinase; HER-2, human epidermal growth factor receptor 2; IP3, inositol 1,4,5-trisphosphate; mTOR, mammalian target of rapamycin; PDGFR-β, platelet-derived growth factor receptor β; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; VEGFR, vascular endothelial growth factor receptor.

Figure 2.

HER-activated signaling pathways. Abbreviations: BAD, Bcl-2-associated death promoter; EGFR, epidermal growth factor receptor; GSK3, glycogen synthase kinase 3; HER-2, human epidermal growth factor receptor 2; HIF-1α, hypoxia inducible factor 1α; MAPK, mitogen-activated protein kinase; MDM2, murine double minute 2; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLC, phospholipase C. Adapted from Atalay G, Cardoso F, Awada A et al. Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer. Ann Oncol 2003;14:1346–1363, by permission of Oxford University Press.

Figure 3.

Extracellular and intracellular targets of therapies at various stages of development for breast cancer. Abbreviations: EGFR, epidermal growth factor receptor; ERK, extracellular signal–related kinase kinase; HER-2, human epidermal growth factor receptor 2; MEK, mitogen-activated protein kinase/ERK kinase; mTOR, mammalian target of rapamycin; PDGFR-β, platelet-derived growth factor receptor β; PI3K, phosphatidylinositol 3-kinase; TK tyrosine kinase; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.