Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

McLarty, Kristin; Cornelissen, Bart; Scollard, Deborah A.; Done, Susan J.; Chun, Kathy; Reilly, Raymond M.

doi:10.1007/s00259-008-0923-x

Cited by 112 publications

(141 citation statements)

References 35 publications

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“…1B). These flow cytometry results correlated well with saturation radioligand binding assays performed with 111 In-diethylenetriaminepentaacetic acid (DTPA)-trastuzumab, which demonstrated that MDA-MB-231 and MDA-MB-361 cells have 5.4 6 0.7 · 10 4 and 5.1 6 1.7 · 10 5 HER2 receptors per cell, respectively (24).…”

Section: Relative Her2 Expression Of Bc Cellssupporting

confidence: 60%

¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

McLarty¹,

Fasih²,

Scollard³

et al. 2009

J Nucl Med

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Breast cancers (BCs) with high human epidermal growth factor receptor type 2 (HER2) expression are most likely to respond to trastuzumab; however, the mechanisms of action of trastuzumab are complex and there are no established biomarkers to accurately monitor treatment outcome in individual patients. Therefore, our aim was to determine, in human BC xenografts in athymic mice treated with trastuzumab, whether there were any changes in 18 F-FDG uptake that were associated with response to the drug and that could have utility in monitoring response in patients. Methods: Baseline tumor uptake of 18 F-FDG was measured in mice with MDA-MB-361 HER2-overexpressing xenografts and MDA-MB-231 xenografts with low HER2 expression by small-animal PET imaging on day 0. Mice were treated with phosphate-buffered saline (PBS) or trastuzumab (4 mg/kg), and small-animal PET was repeated 2 d after treatment. Maintenance doses of trastuzumab (2 mg/kg) or PBS were administered on days 7 and 14, and mice were imaged again on days 9 and 16. Tumor uptake was measured as percentage injected dose per gram (%ID/g) by volume-of-interest analysis on days 0 (baseline), 2, 9, and 16, followed by biodistribution studies on day 16. Tumor growth was measured, and a tumor growth index was calculated. Results: The treatment of mice with trastuzumab, compared with control mice treated with PBS, resulted in a significant decrease in tumor uptake of 18 F-FDG in HER2-overexpressing MDA-MB-361 xenografts after 16 d of treatment (2.6 6 0.8 %ID/g vs. 4.6 6 1.8 %ID/g, respectively; P , 0.03) but not after 2 or 9 d of treatment (P 5 0.28-0.32). In contrast, there was no significant change in the tumor uptake of MDA-MB-231 xenografts with low HER2 expression during the entire course of therapy (4.4 6 1.7 %ID/g vs. 3.6 6 1.1 %ID/g, respectively; P 5 0.31). Trastuzumab treatment, compared with PBS treatment of controls, resulted in significant growth inhibition of MDA-MB-361 xenografts as early as 10 d from the initiation of treatment (tumor growth index, 0.7 6 0.2 vs. 1.7 6 0.3, respectively; P , 0.0005), whereas no tumor growth inhibition was observed for MDA-MB-231 xenografts (5.3 6 2.7 and 5.2 6 3.0; P 5 0.95). Conclusion: Changes in the tumor uptake of 18 F-FDG after therapy accurately identified responding and nonresponding human BC xenografts in athymic mice treated with trastuzumab; however, diminished glucose utilization did not precede changes in tumor volume.

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Section: Relative Her2 Expression Of Bc Cellssupporting

confidence: 60%

¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

McLarty¹,

Fasih²,

Scollard³

et al. 2009

J Nucl Med

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“…The pre-clinical study determined the uptake of 111 In-labelled trastuzumab (72 h after tracer administration) by a panel of breast tumour lines varying in HER-2 receptor density, which were grown as xenografts in mice [17]. When tracer incorporation was expressed as tumour uptake, the relationship between tumour-associated activity and HER-2 receptor density was poor.…”

Section: Single Photon Emission Tomography (Spect)mentioning

confidence: 99%

“…However, when uptake was corrected for blood pooling of tracer and for non-specific uptake determined using 111 In-DTPA-mIgG, HER-2 receptor density was shown to correlate strongly with tumour-associated activity. McLarty et al [17] also determined the sensitivity to trastuzumab of each of the breast tumour cell lines grown as xenografts in nude mice by determining a tumour growth inhibitory ratio, which was based on size after intraperitoneal (IP) trastuzumab treatment (4 mg kg 21 then weekly 2 mg kg 21 for 4 weeks) and the pretreatment size. They found that the only significant growth inhibition was in cells expressing 2+ HER-2 levels.…”

Section: Single Photon Emission Tomography (Spect)mentioning

confidence: 99%

“…Several studies have described the labelling and characterisation of HER-2 targeting molecules with In both a pre-clinical [17] and a clinical [20] study, trastuzumab was labelled with 111 In by conjugation with the chelating group diethylene triamine pentaacetic acid (DTPA). The pre-clinical study determined the uptake of 111 In-labelled trastuzumab (72 h after tracer administration) by a panel of breast tumour lines varying in HER-2 receptor density, which were grown as xenografts in mice [17].…”

Section: Single Photon Emission Tomography (Spect)mentioning

confidence: 99%

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Towards detecting the HER-2 receptor and metabolic changes induced by HER-2-targeted therapies using medical imaging

Smith¹

2010

BJR

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ABSTRACT. HER-2/neu (a receptor for human epidermal growth factor) is involved in cell survival, proliferation, angiogenesis and invasiveness. It is overexpressed in about 25% of breast cancers. Overexpression of HER-2 is associated with response to the anti-HER-2 antibody trastuzumab (herceptin). However, HER-2 expression can be heterogeneous within the primary tumour and can also exhibit discordant expression between a primary tumour and its metastases, bringing into question the practice of HER-2 screening to determine whether a patient is a candidate for trastuzumab using material obtained only from the primary tumour. Medical imaging modalities using HER-2-targeted tracers (or contrast agents) facilitate a global approach to the determination of HER-2 expression across all detectable tumour lesions, and could provide a more reliable indication of the patient's likely response to trastuzumab treatment. Here, I review the development and pre-clinical (and occasional clinical) assessment of HER-2-targeted tracers. I discuss studies in which established imaging tracers, such as 11 C-choline, have been used to determine response to trastuzumab in a range of medical imaging modalities, including positron emission tomography (PET), single photon emission tomography (SPECT), MRI and optical imaging.

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“…This discrepancy was attributed to possible differences in the microenvironment of MCF-7/clone18 xenografts that may have affected the delivery of 18 F-Z HER2:324 Affibody. Interestingly, we recently reported that strong associations between tumor HER2 density and uptake of 111 In-labeled trastuzumab in a panel of 5 HER2-positive breast cancer xenografts in athymic mice were obtained only if tumor uptake was corrected for nonspecific IgG localization or circulating blood-pool radioactivity, factors that presumably reflect differences in the tumor microenvironment (20). Reasonably good correlations between epidermal growth factor receptor density and the accumulation of 64 Cu-labeled anti-epidermal growth factor receptor cetuximab antibodies in epidermal growth factor receptor-positive xenografts in mice have similarly been described (21).…”

mentioning

confidence: 99%

Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

Cited by 112 publications

References 35 publications

¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

Towards detecting the HER-2 receptor and metabolic changes induced by HER-2-targeted therapies using medical imaging

Aiming for a Direct Hit: Combining Molecular Imaging with Targeted Cancer Therapy

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Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

Cited by 112 publications

References 35 publications

18F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

18F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

Towards detecting the HER-2 receptor and metabolic changes induced by HER-2-targeted therapies using medical imaging

Aiming for a Direct Hit: Combining Molecular Imaging with Targeted Cancer Therapy

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Product

Resources

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¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice