Dataset Information

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).

SUBMITTER: Yadav K

PROVIDER: S-EPMC8841320 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

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.

Yadav Kritika K Lim Joline J Choo Joan J Ow Samuel Guan Wei SGW Wong Andrea A Lee Matilda M Chan Ching Wan CW Hartman Mikael M Lim Siew Eng SE Ngoi Natalie N Tang Siau Wei SW Ang Yvonne Y Chan Gloria G Chong Wan Qin WQ Tan Hon Lyn HL Tan Sing Huang SH Goh Boon Cher BC Lee Soo Chin SC

Breast cancer research and treatment 20211220 1

<h4>Purpose</h4>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 com ...[more]

PMID: 34928481

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Project description:Background: We examined changes in the tumor immune microenvironment during neoadjuvant chemotherapy by comparing immune gene mRNA expression, tumor infiltrating lymphocyte (TIL) count and PD-L1 protein expression in pre- and post-treatment tissues. Methods: Paired pre- and post- treatment tumor samples from 60 patients were profiled using the Nanostring Immune Oncology 360 platform to measure the expression of 770 immune-related genes that also allowed us to test 14 immune cell type and 27 previously published prognostic and immuno therapy response predictive gene signatures. All samples were also assessed for TIL counts and PD-L1 protein expression by immunohistochemistry. Gene expression levels were compared by paired t-test with Bonferroni correction. TIL count, PD-L1 protein expression and immune gene signatures were compared using Wilcoxon signed-rank test. Baseline immune markers were correlated with pathologic complete response (pCR) using estrogen receptor (ER) and treatment adjusted logistic regression. Results: TIL counts were significantly lower in post- compared to pre-treatment samples (17% vs 7%, p=0.013) but stromal PD-L1 protein expression was not significantly different. At baseline, higher TIL count and PD-L1 expression were associated with pCR. High expression of a mast cell metagene was associated with residual disease (RD). No individual genes or VEGF gene signature were associated with benefit from bevacizumab. In patients with RD (n=31), genes involved with tissue repair and inflammation (DUSP1, EGR1, IL6, ATF3, CD36, CXCL2, CD69, NGFR, KLF2, THBD, DAB2) showed significantly higher expression after therapy while most other immune markers decreased. The T effector, T-reg, MHC-I, MHC-II, IFNgamma, STAT-1 and M1 macrophage gene signatures were all significantly lower in post- versus pre-treatment samples and only the IL8/VEGFR and T-helper gene signatures showed higher expression after therapy. Conclusions: High mast cell gene expression is associated with lower pCR rate. TIL counts and most immune parameters decrease after neoadjuvant chemotherapy.

Dataset Information

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.

Purpose

Methods

Results

Conclusion

Trial registry

Publications

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.

Similar Datasets

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