Current approaches and future directions in the treatment of HER2-positive breast cancer

Abstract

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20-30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.

Figure 1

Human epidermal growth fa ctor receptor 2 (HER2) signal transduction pathways. Homodimerization and heterodimerization of HER2 leads to TK activation and downstream signaling via the PI3K/Akt/mammalian target of rapamycin pathway and the Ras/Raf/mitogen-activated protein kinase pathway to stimulate processes involved in cell survival and proliferation. Adapted from Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol. 2007;18:977–984, by permission of Oxford University Press.

Figure 2

Kaplan-Meier analysis of time to progression in patients with activated PI3K pathways (yes; orange curve; n = 24) and nonactivated PI3K pathways (no; blue curve; n = 29) shows that PI3K pathway activation is associated with significantly shorter time to progression after trastuzumab-based therapy (p = 0.007). Reprinted from Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395–402. Copyright 2007, with permission from Elsevier.