Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

Abstract

To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method, following treatment with trastuzumab may provide an opportunity to optimize the scheduling and improve delivery of subsequent cytotoxic therapy.

• Authors: Anna G Sorace, C Chad Quarles, Jennifer G Whisenant, Ariella B Hanker, J Oliver McIntyre, Violeta M Sanchez, Thomas E Yankeelov
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 155 Issue 2 Pg. 273-84 (Jan 2016) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 26791520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor A
• Doxorubicin
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Doxorubicin (pharmacology)
• Drug Therapy, Combination (methods)
• Female
• Magnetic Resonance Imaging (methods)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Receptor, ErbB-2 (metabolism)
• Trastuzumab (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays (methods)