Shortly after discovery of epidermal growth factor receptor (EGFR) as an inducer of increased cell growth , Weinberg et al. characterized Neu oncogene in rat neuro/glioblastomas [2,3] and later its human homolog was called Human Epidermal growth factor Receptor 2 (HER2) . Then amplification was shown in human breast carcinoma cell lines  (Figure 1). Slamon et al. identified that 30% of patients with primary breast cancers harbored HER2 amplification which negatively correlated with survival .
In early 1990s, a humanized monoclonal antibody against domain IV of HER2 (trastuzumab, Herceptin®) was developed and it was found to be safe and active in HER+ breast cancer patients. Soon the Chemotherapy and Antibody Response Evaluation (CARE) trial of trastuzumab in combination with chemotherapy was launched for metastatic breast cancer (MBC). This randomized study showed significant improvement in median time to progression (TTP) in combination with trastuzumab and chemotherapy arm compared with chemotherapy alone arm (4.6–7.4 months) . Based on the results of this randomized phase III trial and a single-arm single agent trastuzumab study , trastuzumab was approved in HER + MBC in combination with paclitaxel in first and as single agent in second-line setting, respectively.
The clear additional benefit of trastuzumab to chemotherapy was also shown in neo-adjuvant , and adjuvant settings [10,11]. Laptinib, a dual tyrosine kinase inhibitor (inh) against EGFR and HER2, is the second agent that has been approved by FDA for HER+ patients with MBC in combination with capecitabine [12,13] or letrozole . The additional benefit of laptinib to trastuzumab in heavily pretreated HER2+ MBC improved PFS from 8.1 to 12 months .
Homo- and heterodimerization of HER receptors are essential for the signaling and HER2-HER3 heterodimer is the most potent pair in downstream signaling . Pertuzumab is a humanized monoclonal antibody against domain II of HER2 that inhibits HER2 dimerization and the activation of the signaling pathway . CLEOPATRA was a randomized phase III study that launched to test the efficacy of adding pertuzumab to trastuzumab plus chemotherapy (docetaxel) in first-line setting and the results clearly showed the significant improved median progression-free survival (PFS) (18.5 versus 12.4 months) in HER2+ MBC patients .
Despite this progress in the treatment of HER2+ breast cancer, the median PFS in CLEOPATRA study was reported to be 18.5 months, which means that half of the patients in <2 years. Therefore, clearly, further research is needed. Several other targets in EGFR/HER2 signaling pathways are currently being studied. Neratinib (Pan-HER irreversible inh), trastuzumab-MCC-DM1 (T-DM1), phosphatidylinositol 3-kinase (PI3K) inhibitors, AKT inhibitors, mammalian target of rapamycin (mTOR) inhibitors, heat shock protein 90 (HSP90) inhibitors, histone deacetylase (HDAC) inhibitors, and vaccines are examples of drugs under development that have reached phase II or III in the drug development process .
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