Breast cancer is a major cause of morbidity and mortality both locally as well as globally. Approximately 10-15% of newly diagnosed breast cancer patients present with metastatic disease; in addition, a significant proportion of patients who initially present with non-metastatic disease relapse with distant metastases. These patients have no prospect for cure, and systemic therapy remains the mainstay of treatment. In the last few years, several targeted agents have been approved for the treatment of breast cancer. For example, the addition of bevacizumab, an anti-angiogenic agent, to chemotherapy has been shown to improve treatment outcome in metastatic HER2 negative breast cancer and possibly in the neoadjuvant treatment of triple negative breast cancers. Two classes of anti-angiogenic agents are currently available: monoclonal antibodies against vascular endothelial growth factor (VEGF), such as bevacizumab; and small molecule receptor tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of vascular endothelial growth factor receptor (VEGF-R), such as sunitinib and sorafenib.

Small molecule receptor tyrosine kinase inhibitors such as sunitinib and sorafenib are currently being evaluated in clinical trials. Although sunitinib and sorafenib are potent anti-angiogenic agents, the clinical data that has been reported thus far when combined with chemotherapy, has been less promising than what has been predicted in pre-clinical studies. One possible reason is that optimal scheduling of small molecule tyrosine kinase inhibitors with chemotherapy has not yet been determined. Preclinical observations have suggested that anti-angiogenic agents can 'normalize' tumor vasculature. Further continuous administration of anti-angiogenic agent ultimately results in destruction of tumor vasculature, starving the tumor and resulting in tumor necrosis. When combined with chemotherapy, this continuous scheduling may paradoxically result in reduced delivery of chemotherapy to the tumor, causing a relatively chemo-resistant state and may account for the less than optimal results from combination studies, which have largely employed the strategy of continuous dosing of the small molecule tyrosine kinase inhibitor. Intermittent dosing of a small molecule tyrosine kinase inhibitor prior to chemotherapy to transiently 'normalize' tumor vasculature, may make it more efficient for drug and oxygen delivery, and thus potentiate sensitivity to chemotherapy.

The investigators previously studied the addition of low-dose, short-course sunitinib to pre-operative chemotherapy in the neoadjuvant setting in newly diagnosed breast cancer patients with measurable primary breast tumor in a phase Ib/II study at the National University Cancer Institute, Singapore. The study data showed that the addition of sunitinib improved tumor vascularization as hypothesized with enhanced short-term treatment response. However, pathological complete response rate after 4 cycles of chemotherapy was not superior to standard chemotherapy, and may be attributed to dose delays from increased myelosuppression with the addition of sunitinib. The investigators hypothesize that this promising regimen may be further optimized with the use of growth factor support. The investigators thus plan to study the addition of low-dose, short-course sunitinib to dose-dense doxorubicin/cyclophosphamide administered every 14 days, supported by pegfilgrastim.