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            In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

Gaykema, Sietske B.M.; Jong, Johan R. de; Perik, Patrick J.; Brouwers, Adrienne H.; Schröder, Carolien P.; Munnink, Thijs H. Oude; Bongaerts, Alphons H.H.; Vries, Elisabeth G.E. de; Hooge, Marjolijn N. Lub-de

doi:10.2310/7290.2014.00011

Cited by 43 publications

(45 citation statements)

References 17 publications

(24 reference statements)

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“…For imaging of a number of antibodies without dose-dependent PK, such as bevacizumab, fresolizumab or the mesothelin-targeting antibody MMOT0530A, a dose of 5 or 10 mg unlabeled antibody was already sufficient for optimal PET imaging (24,29,32,42). However, for HER2 imaging with 89 Zr-trastuzumab, an antibody with clear dose-dependent PK, an additional dose of 50 mg unlabeled trastuzumab is needed for optimal imaging (43, 44).…”

Section: Discussionmentioning

confidence: 99%

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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# These authors contributed equally to this work. AbstractPurpose-We evaluated biodistribution and tumor targeting of 89 Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental design-20 patients with histologically confirmed HER3-expressing tumors received 89 Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, 89 Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results-Optimal PET conditions were found to be 4 and 7 days after administration of 89 Zrlumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab.Conclusions-PET imaging showed biodistribution and tumor specific 89 Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89 Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.

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Section: Discussionmentioning

confidence: 99%

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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“…One such approach is the use of trastuzumab labeled with 111 In (half-time, 2.8 d) (9) or 89 Zr (3.3 d) (10) for use with SPECT and PET, respectively, but the slow kinetics of antibodies require imaging several days after administration. One promising method of fast, safe, and accurate imaging that specifically binds to a site on the receptor not occupied by current targeting therapeutic drugs (11)(12)(13) is to use the Affibody (Affibody AB) molecule ABY-025.…”

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confidence: 99%

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

et al. 2016

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68 Ga-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of 68 Ga-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD 68 Ga-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 ± 0.003 mSv/MBq for LD and 0.028 ± 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of 68 Ga-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other 68 Ga-labeled tracers, such as 0.021 ± 0.003 mSv/MBq for 68 Ga-DOTATATE and 68 Ga-DOTATOC, mainly because of higher uptake in liver and kidney. Forwomen,br east cancer is currently the most common cancer.Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 1 of 6 cases (1-3) at initial diagnosis and is associated with poor survival (1,3). Treatments targeted to HER2, such as with the anti-HER2 antibody trastuzumab, have considerably improved overall survival (1,3,4). Today, assessment of HER2 status is based on tumor biopsy. However, HER2 expression can vary between the primary tumor and metastases in up to 40% of cases (2,5,6) and metastatic HER2 expression can change over time, which could necessitate a change of therapy (7,8). Follow-up using biopsies cannot always be performed due to practical reasons or patient discomfort.Molecular imaging using SPECT and PET might be a noninvasive, whole-body-based way to evaluate HER2 expression quantitatively. One such approach is the use of trastuzumab labeled with 111 In (half-time, 2.8 d) (9) or 89 Zr (3.3 d) (10) for use with SPECT and PET, respectively, but the slow kinetics of antibodies require imaging several days after administration. One promising method of fast, safe, and accurate imaging that specifically binds to a site on the receptor not occu...

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“…These data showed that molecular antibody imaging can help identify tumor lesions that are missed by conventional imaging techniques. Second, serial SPECT imaging with 111 In-trastuzumab before and after 12 wk of trastuzumab treatment showed persistent uptake in all tumor lesions, with only a 20% decrease in tumor tracer uptake (17). These data indicated that HER2 is constantly available at the tumor cell surface to bind to trastuzumab and that the tumor is not completely saturated by trastuzumab treatment.…”

Section: Use Of Theranostics In Clinical Decision Makingmentioning

confidence: 72%

Theranostics Using Antibodies and Antibody-Related Therapeutics

et al. 2017

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In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibodyrelated therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89 Zr. In this review, we provide an overview of ongoing research on mAbs and antibodyrelated theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required.

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¹¹¹ In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

Cited by 43 publications

References 17 publications

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

Theranostics Using Antibodies and Antibody-Related Therapeutics

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111 In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

Cited by 43 publications

References 17 publications

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule 68Ga-ABY-025 in Breast Cancer Patients

Theranostics Using Antibodies and Antibody-Related Therapeutics

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Product

Resources

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¹¹¹ In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients