Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Sorace, Anna G.; Syed, Anum; Barnes, Stephanie L.; Quarles, C. Chad; Sánchez, Violeta; Kang, Hakmook; Yankeelov, Thomas E.

doi:10.1007/s11307-016-0994-1

Cited by 30 publications

(35 citation statements)

References 32 publications

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“…Evaluation of immune cell characterization and impact on tumor regression using the present study's treatment regimen is needed to further elucidate mechanisms contributing to enhanced tumor regression in the combination treatment group. Although no signi cant differences were shown in hypoxia or the vascular maturation index, previous studies using longitudinal imaging have indicated that trastuzumab can reduce hypoxia and increase vascular perfusion [17,29]. It is possible, by employing longitudinal imaging methods, windows of heightened oxygenation could be identi ed and that appropriately altered order of dosing could enhance treatment response in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…Additionally, breast tumors can become hypoxic due to the irregular and tortuous vasculature which increases radioresistance [12][13][14]. Previous results in HER2+ breast cancer have revealed that treatment with trastuzumab can increase tumor oxygenation in a preclinical mouse model through stabilization of tumor blood vessels [17]. Although there has been investigation into the potential ability of trastuzumab to radiosensitize breast cancer, data quantifying sensitization over time has been lacking, thereby reducing clinical relevance.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Bloom

Song

Virostko

et al. 2020

Preprint

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Background: Trastuzumab, a clinical antibody targeted to the human epidermal growth factor receptor 2 (HER2), has been shown to sensitize cells to radiation in vitro. Current studies lack longitudinal evaluation of cellular response and in vivo data is limited. The purpose of this study is to quantify the effects of combination trastuzumab and radiation therapy in vitro and in vivo over time to determine if there is a synergistic interaction. Methods: EGFP expressing BT474, SKBR3 and MDA-MB-231 cell lines were treated with 0.1 ng/ml of trastuzumab, 5 or 10 Gy of radiation, or combination treatment, and imaged using fluorescence live cell microscopy for one week. The Bliss independence model was used to quantify the effects of combination treatment. HER2+ tumor bearing mice (female NU/J) (N=34) were treated with saline, 10 mg/kg of trastuzumab, 5 or 10 Gy of radiation, or combination treatment. Tumor size was measured three times per week for four weeks via caliper measurements. Additional mice (N=13) were treated with 10 mg/kg of trastuzumab, 5 Gy of radiation, or combination treatment. Tumors were harvested at one week and evaluated with immunohistochemistry for inflammation (CD45), vascularity (CD31 and α-SMA), and hypoxia (pimonidazole). Results: Altering the order of therapies did not significantly affect BT474 cell proliferation in vitro (P>0.05). The interaction index calculations revealed additive effects of trastuzumab and radiation treatment in all three cell lines in vitro. In vivo results revealed significant differences in tumor response between mice treated with 5 and 10 Gy single agent radiation (P < 0.001); however, no difference was seen in the combination groups when trastuzumab was added to the radiation regimen (P=0.56), indicating a lower dose of radiation could be used without decreasing therapeutic efficacy. Histology results revealed increases in inflammation (CD45+) in mice receiving trastuzumab (P<0.05). Conclusions: Longitudinal evaluation of cell proliferation in vitro showed additive effects of combination therapy. In vivo results show a potential to achieve the same efficacy of treatment with reduced radiation when also administering trastuzumab. Further evaluation of tumor microenvironmental alterations during treatment could identify mechanisms of increased therapeutic efficacy in this regimen.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Bloom

Song

Virostko

et al. 2020

Preprint

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“…Trastuzumab, a monoclonal anti-HER2 antibody, is a targeted therapy used in the treatment of HER2+ breast cancer and has led to reduced recurrence of disease and dramatic improvements in patient survival [12] , [16] , [17] . In addition to its cytotoxic mechanisms, trastuzumab has been shown to alter tumor vasculature and oxygenation as a secondary mechanism of action [18] , [19] , [20] , [21] . Although trastuzumab has improved the treatment of locally advanced HER2+ breast cancer, only 30% of patients respond effectively to trastuzumab therapy in combination with other standard-of-care treatments [12] , [16] , [22] , [23] .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…With the goal of achieving personalized treatment strategies, the well-known inter- and intra-tumor heterogeneity and the upcoming advanced imaging technologies have stimulated various researches on tumor characterization, treatment response assessment, and outcome prediction [ 1 – 10 , 12 – 14 , 16 – 18 ]. Consequently, dose painting strategies that aim to overcome treatment resistance by locally increasing the dose to the potentially more radio-resistant target sub-regions have been conceptually proposed and have been clinically introduced in selected studies for lung and head and neck cancer [ 11 , 15 , 19 , 21 , 22 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…For hypoxia imaging, [ 18 F]fluoromisonidazole ([ 18 F]FMISO) has become a frequently used radiotracer. PET imaging with this tracer has proven to be useful in the assessment and prediction of the outcome of different types of cancer therapy [ 12 , 13 ]. Hypoxia is known to cause radiation treatment resistance and therefore new therapeutic strategies are targeting this crucial tumor feature.…”

Section: Introductionmentioning

confidence: 99%

Changes in Tumor Biology During Chemoradiation of Cervix Cancer Assessed by Multiparametric MRI and Hypoxia PET

et al. 2017

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PurposeImaging biomarkers assessed with magnetic resonance imaging (MRI) and/or positron emission tomography (PET) enable non-invasive tumor characterization in cervix cancer patients. We investigated the spatio-temporal stability of hypoxia, perfusion, and the cell density of tumors over time by repetitive imaging prior to, during, and after radio-chemotherapy.ProceduresThirteen patients were included in this prospective study. The imaging protocol included the following: [18F]fluoromisonidazole ([18F]FMISO)-PET/x-ray computed tomography (CT) and multiparametric (mp)-MRI at four time-points (TP): baseline (BL); and weeks 2 (TP1), 5 (TP2), and 19 after treatment start (follow-up FU). Complete datasets for six patients could be assessed for tumor volume, enhancement kinetics, diffusivity, and [18F]FMISO-avidity (P1–P6). In addition, two patients completed all PET/CT examinations (P7–P8) but not all MR scans; however, one of them had no hypoxia (P8). Descriptive statistics, correlations, and voxel-by-voxel analysis were performed. For various, independent reasons, five patients could not complete the study according to the protocol with all imaging sequences.ResultsMedian tumor ADCs (in ×10−3 mm2/s) were 0.99 ± 0.10 at BL, 1.20 ± 0.12 at TP1, 1.33 ± 0.14 at TP2, and 1.38 ± 0.21 at FU. The median TBRpeak (tumor-to-background) was 2.7 ± 0.8 at BL, 1.6 ± 0.2 at TP1, 1.8 ± 0.3 at TP2, and 1.7 ± 0.3 at FU. The voxel-by-voxel analysis of the [18F]FMISO uptake at BL and TP1 showed no correlation. Between TP2 and TP1 and FU and TP2, weak correlations were found for two patients.ConclusionsLongitudinal mp-MR and PET imaging enables the in vivo tumor characterization over time. While perfusion and cell density decreased, there was a non-uniform change of hypoxia observed during radiotherapy. To assess the potential impact with regard to more personalized treatment approaches, hypoxia imaging-based dose painting for cervix cancer requires further research.

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Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Cited by 30 publications

References 32 publications

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

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

Changes in Tumor Biology During Chemoradiation of Cervix Cancer Assessed by Multiparametric MRI and Hypoxia PET

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