Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting 227Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

Heyerdahl, Helèn; Røe, Kathrine; Brevik, Ellen Mengshoel; Dahle, Jostein

doi:10.1016/j.ijrobp.2013.04.052

Cited by 9 publications

(7 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our observations of increased vascular heterogeneity upon trastuzumab treatment are further supported by other studies which have shown alterations in tumor vasculature and oxygenation in preclinical models of HER2+ cancer in response to trastuzumab therapy [20] , [58] , [59] , [60] , [61] . In a HER2+ murine model of brain cancer, Izumi et al utilized optical imaging to show significant decrease in vascular permeability in response to trastuzumab therapy along with increased rates of survival [20] .…”

Section: Discussionsupporting

confidence: 88%

Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer

et al. 2019

View full text Add to dashboard Cite

The purpose of this study is to investigate imaging and histology-based measurements of intratumoral heterogeneity to evaluate early treatment response to targeted therapy in a murine model of HER2+ breast cancer. BT474 tumor-bearing mice (N = 30) were treated with trastuzumab or saline and imaged longitudinally with either dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) or 18F-fluoromisonidazole (FMISO) positron emission tomography (PET). At the imaging study end point (day 4 for MRI or 7 for PET), each tumor was excised for immunohistochemistry analysis. Voxel-based histogram analysis was performed on imaging-derived parametric maps (i.e., Ktrans and ve from DCE-MRI, SUV from 18F-FMISO-PET) of the tumor region of interest to measure heterogeneity. Image processing and histogram analysis of whole tumor slice immunohistochemistry data were performed to validate the in vivo imaging findings. Trastuzumab-treated tumors had increased heterogeneity in quantitative imaging measures of cellularity (ve), with a mean Kolmogorov-Smirnov (K-S) distance of 0.32 (P = .05) between baseline and end point distributions. Trastuzumab-treated tumors had increased vascular heterogeneity (Ktrans) and decreased hypoxic heterogeneity (SUV), with a mean K-S distance of 0.42 (P < .01) and 0.46 (P = .047), respectively, between baseline and study end points. These observations were validated by whole-slice immunohistochemistry analysis with mean interquartile range of CD31 distributions of 1.72 for treated and 0.95 for control groups (P = .02). Quantitative longitudinal changes in tumor cellular and vascular heterogeneity in response to therapy may provide evidence for early prediction of response and guide therapy for patients with HER2+ breast cancer.

show abstract

Section: Discussionsupporting

confidence: 88%

Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Izumi et al evaluated HER2+ MDA-MB-361 murine model of brain cancer with optical imaging and presented the evidence that trastuzumab increased overall survival rate, while initiating a more normal phenotype in tumor blood vessels [10] through a significant reduction in vessel diameter and vascular permeability. Additionally, Heyerdahl et al revealed that xenograft tumors treated with trastuzumab labeled 227 Th were well perfused and exhibited vascular stability [41] when radiotherapy was expected to damage vascular perfusion.…”

Section: Discussionmentioning

confidence: 99%

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

Sorace

Quarles

Whisenant

et al. 2016

Breast Cancer Res Treat

View full text Add to dashboard Cite

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 Ktrans) and the extravascular extracellular volume fraction (ve) 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 Ktrans (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in ve (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.

show abstract

“…To investigate these anti-angiogenic effects, angiogenesis-related genes were investigated; trastzumab-treated tumors revealed lower levels of VEGF, TGF-α, Ang-1, PAI-1, and higher levels of TSP-1 compared to control tumors [11] , [41] . A study by Heyerdahl et al analyzed changes in DCE-MRI parameters after 227 Th-trastuzumab radiotherapy in xenograft tumors [42] . Although radiotherapy has the potential to increase permeability and damage vasculature, the tumors treated with trastuzumab labeled 227 Th were well perfused and exhibited vascular stability [42] .…”

Section: Discussionmentioning

confidence: 99%

“…A study by Heyerdahl et al analyzed changes in DCE-MRI parameters after 227 Th-trastuzumab radiotherapy in xenograft tumors [42] . Although radiotherapy has the potential to increase permeability and damage vasculature, the tumors treated with trastuzumab labeled 227 Th were well perfused and exhibited vascular stability [42] . This study also revealed a significant increase in k ep (= K trans / v e ; the rate of contrast wash-out from extracellular space to plasma) compared to control tumors on week two and three.…”

Section: Discussionmentioning

confidence: 99%

Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts

Whisenant¹,

Sorace²,

McIntyre³

et al. 2014

Translational Oncology

View full text Add to dashboard Cite

We report longitudinal diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced (DCE)-MRI (7 T) studies designed to identify functional changes, prior to volume changes, in trastuzumab-sensitive and resistant HER2 + breast cancer xenografts. Athymic mice (N = 33) were subcutaneously implanted with trastuzumab-sensitive (BT474) or trastuzumab-resistant (HR6) breast cancer cells. Tumor-bearing animals were distributed into four groups: BT474 treated and control, HR6 treated and control. DW- and DCE-MRI were conducted at baseline, day 1, and day 4; trastuzumab (10 mg/kg) or saline was administered at baseline and day 3. Animals were sacrificed on day 4 and tumors resected for histology. Voxel-based DW- and DCE-MRI analyses were performed to generate parametric maps of ADC, Ktrans, and ve. On day 1, no differences in tumor size were observed between any of the groups. On day 4, significant differences in tumor size were observed between treated vs. control BT474, treated BT474 vs. treated HR6, and treated vs. control HR6 (P < .0001). On day 1, ve was significantly higher in the BT474 treated group compared to BT474 control (P = .002) and HR6 treated (P = .004). On day 4, ve and Ktrans were significantly higher in the treated BT474 tumors compared to BT474 controls (P = .0007, P = .02, respectively). A significant decrease in Ki67 staining reinforced response in the BT474 treated group compared to BT474 controls (P = .02). This work demonstrated that quantitative MRI biomarkers have the sensitivity to differentiate treatment response in HER2 + tumors prior to changes in tumor size.

show abstract

Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting 227Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

Cited by 9 publications

References 19 publications

Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer

Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer

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

Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts

Contact Info

Product

Resources

About