A Neoadjuvant Phase II Trial of GW572016 in HER2 Overexpressing Breast Cancer Patients: Biologic Correlative Study

The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play an important role in fundamental cell processes like cell proliferation, differentiation, and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been causally associated with cancer cell proliferation and survival.

HER1 is expressed or over-expressed in many human solid tumors and plays an important role in progression to invasion and metastases.. The association between HER2 overexpression and poor prognosis in node-positive and advanced breast cancer has been shown by a number of studies. Based on this association between the members of HER1/HER2 family and worse clinical outcome, antibodies and small molecules that specifically target these receptor tyrosine kinases were developed for their therapeutic efficacy.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the HER2 receptor. Pivotal multicenter efficacy trials in metastatic patients showed improved response rates and disease-free survival in patients who received trastuzumab in addition to chemotherapy. One of these studies was an open-labeled, multicenter, randomized phase III study evaluating the addition of trastuzumab to standard first-line chemotherapy in metastatic breast cancer. This study randomized 469 patients with metastatic disease to chemotherapy with or without trastuzumab. Results of this study showed survival in patients who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone (7.2 vs. 4.5 months, p<0.0001).

As dimerization is important in signal transduction, therapies that target more than one member of the HER family may have greater anti-tumor effect. Recently, data with trastuzumab plus IMC-C224 in human ovarian cancer cells showed greater growth inhibition compared to either monoclonal antibody alone. GW572016 is an orally active dual HER1/HER2 kinase inhibitor that blocks signal transduction pathways. This dual inhibition is an attractive therapeutic strategy for epithelial cancers, as ligand-induced HER1/HER2 dimerization triggers off potent proliferative and survival signals. In vitro studies with GW572016 have shown marked activity, leading to growth arrest and apoptosis in HER1 and HER2 overexpressing cell lines. GW572016 markedly reduced tyrosine phosphorylation of HER1 and HER2, and activation of MAP kinase and Akt, the downstream effectors of proliferation and survival, respectively. In vitro studies in HER-2 overexpressing cell lines have demonstrated synergistic activity when GW572016 is combined with taxanes. Phase I studies with GW572016 and taxanes have been completed, with results demonstrating that this small molecule inhibitor may be safely combined with chemotherapy with no unanticipated side effects.

The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play an important role in fundamental cell processes like cell proliferation, differentiation, and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been causally associated with cancer cell proliferation and survival.