Abstract
PurposeTumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients.MethodsThis prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2.ResultsIn comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004).ConclusionSunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery.Trial registryClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).
Highlights
As per global cancer statistics 2018, breast cancer is the most commonly diagnosed cancer in females, with an incidence rate of 46.2 per 100,000 and representing 24.2% of the total female cancer burden globally
Out of the total 62 patients, a full set of pre-treatment, post-C1 and post-C4 tumor samples were available for IHC analysis for 29 of the 38 patients enrolled into the sunitinib cohort, and 15 of the 24 patients enrolled into the Bevacizumab cohort
Lymphatic vessel density, tumor proliferation index and activated VEGFR2 status of tumor cells in both treatment groups
Summary
As per global cancer statistics 2018, breast cancer is the most commonly diagnosed cancer in females, with an incidence rate of 46.2 per 100,000 and representing 24.2% of the total female cancer burden globally. Breast Cancer Research and Treatment factor (VEGF) monoclonal antibody, while Sunitinib is an orally administered small molecule receptor tyrosine kinase inhibitor that exerts its action by targeting the vascular endothelial growth factor receptors (VEGFR). Both agents have been studied in clinical trials in combination with chemotherapy in breast cancer. Both anti-angiogenic agents have shown promising preclinical results, their effects in breast cancer when combined with chemotherapy have been conflicting in the clinic This could be in part attributed to the fact that optimal dosing schedule of these drugs in combination with chemotherapy are yet to be determined [4,5,6]
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