Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer

Abstract

Purpose Tumor 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. Methods This 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. Results In 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). Conclusion Sunitinib, 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 registry ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Pathological angiogenesis: mechanisms and therapeutic strategies

“…Indeed, a judicious use of angiogenesis inhibitors and in some cases a paradoxical promotion of new tumor blood vessels, can improve the delivery and efficacy of chemotherapeutic drugs. In one example, Sunitinib (a tyrosine kinase inhibitor with activity for VEGFRs) was found to increase tumor vessel normalization and, when combined with chemotherapy, resulted in a greater inhibition of tumor cell proliferation [ 305 ].…”

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors

“…Patients with newly diagnosed HER2− breast cancer were enrolled into this prospective, Phase II open-label study of chemotherapy in combination with low-dose antiangiogenic agents to normalize tumor vasculature, conducted at the National University Cancer Institute, Singapore (NCIS) [ 14 ]. The study was approved by the institution’s ethics review board and all patients signed written informed consent (ClinicalTrials.gov identifier: NCT02790580).…”

“…Our group has previously studied the strategy of pre-treatment with low-dose anti-angiogenic agents to normalize tumor vasculature to improve intra-tumoral delivery of standard neoadjuvant chemotherapy in breast cancer in two clinical trials [ 13 , 14 ]. The first trial tested low-dose short-course sunitinib and confirmed vascular normalization on functional imaging and immunohistochemistry.…”

The mechanistic immunosuppressive role of the tumour vasculature and potential nanoparticle-mediated therapeutic strategies

“…Interestingly, trials employing pre-treatment of sunitinib before chemotherapy in breast cancer patients, demonstrated a statistically significant 12.46% increase in vascular normalisation index (VNI) compared to pre-treatment with bevacizumab ( 113 ). The VNI biomarker is defined by vessel permeability, volume and collagen IV plasma levels (relative to basement membrane thinning) which allows for quantification of vascular normalisation ( 114 , 115 ).…”

“…The VNI biomarker is defined by vessel permeability, volume and collagen IV plasma levels (relative to basement membrane thinning) which allows for quantification of vascular normalisation ( 114 , 115 ). The observed VNI therefore indicates anti-angiogenic pre-treatment may improve chemotherapeutic drug delivery, particularly in cancers where concurrent administration has not proved effective ( 113 ).…”