The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer

To date, blockade of growth factor receptors is the mainstay of targeted therapy in metastatic breast cancer (mBC). Monoclonal antibodies such as trastuzumab and bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and the vascular endothelial growth factor (VEGF) antagonists have shown synergism with a broad spectrum of established cytotoxins, thus being approved for first-line treatment of mBC in combination with taxanes. As a next step, tyrosine kinase inhibitors (TKIs) have been integrated into daily routine as an alternative approach for targeting HER2: The dual HER1/2 inhibitor lapatinib demonstrated activity in trastuzumab-pretreated mBC patients in combination with capecitabine. Furthermore, chemotherapy-free regimens (trastuzumab or lapatinib plus aromatase inhibitors) have been identified as additional options for hormone receptor (HR)- and HER2-positive patients. Recently published data indicate that a combination of two biologicals such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab related progression. Multitarget TKIs have the potential to inhibit several signaling pathways involved in breast cancer-related angiogenesis. Until now, they have failed to show a clear benefit in mBC. On the other hand, poly(ADP-ribose) polymerase (PARP) inhibition, mediated by a new class of small molecules, is an interesting area of investigation. Future directions of research in HER2-positive breast cancer focus on the evaluation of novel antibodies (pertuzumab, T-DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt) and of receptor cross-talk (IGFR).