title: 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.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA. anna.sorace@vanderbilt.edu.|Vanderbilt Institute of Imaging Science, Vanderbilt University Medical Center, AA-1105 Medical Center North, 1161 21st Ave South, Nashville, TN, 37232-2310, USA. anna.sorace@vanderbilt.edu.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Sorace
authors.affiliation: Division of Neuroimaging Research, Barrow Neurological Institute, Dignity Health, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA. christopher.quarles@dignityhealth.org.
authors.forename: C Chad
authors.initials: CC
authors.lastname: Quarles
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA. j.whisenant@vanderbilt.edu.|Vanderbilt Institute of Imaging Science, Vanderbilt University Medical Center, AA-1105 Medical Center North, 1161 21st Ave South, Nashville, TN, 37232-2310, USA. j.whisenant@vanderbilt.edu.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Whisenant
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA. ariella.hanker@vanderbilt.edu.
authors.forename: Ariella B
authors.initials: AB
authors.lastname: Hanker
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA. oliver.mcintyre@vanderbilt.edu.|Vanderbilt Institute of Imaging Science, Vanderbilt University Medical Center, AA-1105 Medical Center North, 1161 21st Ave South, Nashville, TN, 37232-2310, USA. oliver.mcintyre@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA. oliver.mcintyre@vanderbilt.edu.
authors.forename: J Oliver
authors.initials: JO
authors.lastname: McIntyre
authors.affiliation: Department of Hematology Oncology, Vanderbilt University, Nashville, TN, USA. violeta.sanchez@vanderbilt.edu.
authors.forename: Violeta M
authors.initials: VM
authors.lastname: Sanchez
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA. thomas.yankeelov@vanderbilt.edu.|Vanderbilt Institute of Imaging Science, Vanderbilt University Medical Center, AA-1105 Medical Center North, 1161 21st Ave South, Nashville, TN, 37232-2310, USA. thomas.yankeelov@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA. thomas.yankeelov@vanderbilt.edu.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. thomas.yankeelov@vanderbilt.edu.|Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. thomas.yankeelov@vanderbilt.edu.|Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, USA. thomas.yankeelov@vanderbilt.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Yankeelov
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A; C524056:Erbb2 protein, mouse
keywords: Adriamycin; Angiogenesis; BT474; Herceptin; Immunohistochemistry; MRI; Normalization