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      Pilot study of 68Ga-DOTA-F(ab′) 2-trastuzumab in patients with breast cancer

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          Abstract

          Objective

          68Ga-1,4,7,10-Tetraazacyclododecane- N, N′, N′′, N′′′-tetraacetic acid (DOTA)-F(ab′) 2-trastuzumab [ 68Ga-DOTA-F(ab′) 2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab′) 2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously.

          Materials and methods

          A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab′) 2-trastuzumab was excluded from analysis. Both HER2-negative ( n=7) and HER2-positive ( n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not.

          Results

          It was determined that 68Ga-DOTA-F(ab′) 2-trastuzumab was well tolerated, with a T ½ of ∼3.6±0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.

          Conclusion

          The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

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          Most cited references 23

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          Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer.

          We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium-89 ((89)Zr)-trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)-positive lesions. Fourteen patients with HER2-positive metastatic breast cancer received 37 MBq of (89)Zr-trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab-naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of (89)Zr-trastuzumab uptake by tumors was 4-5 days after the injection. For optimal PET-scan results, trastuzumab-naive patients required a 50 mg dose of (89)Zr-trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of (89)Zr-trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean +/- SEM) were 12.8 +/- 5.8, 4.1 +/- 1.6, and 3.5 +/- 4.2 in liver, bone, and brain lesions, respectively, and 5.9 +/- 2.4, 2.8 +/- 0.7, 4.0 +/- 0.7, and 0.20 +/- 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of (89)Zr-trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2-positive lesions in patients with metastatic breast cancer.
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            Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations.

            The goal of this review is to systematically address a number of issues raised in the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines on testing for the human epidermal growth factor receptor 2 (HER-2) alteration. A group of investigators who are experienced in the conduct and interpretation of HER-2 assay methods reviewed the ASCO-CAP guidelines and address several areas of the HER-2 testing guidelines with a particular emphasis on biologic and methodologic considerations. Although HER-2 status determined by immunohistochemistry (IHC) and the status determined by fluorescent in situ hybridization (FISH) are significantly correlated, we feel that standard considerations of laboratory testing, including test accuracy, reproducibility, and precision, as well as the current data favor FISH over IHC assay methods for determining HER-2 status. These considerations are clearly important in clinical practice because HER2 amplification is directly linked to protein expression levels in breast cancer. However, this protein is not consistently analyzed in formalin-fixed tissues as a result of variability in fixation methods and times and the impact of fixation on HER-2 protein antigenicity. Conversely, gene amplification and FISH are significantly less dependent on tissue fixation methods, making this assay more reproducible between central and peripheral laboratories than IHC. Moreover, review of the existing data demonstrate that FISH is more strongly correlated with responsiveness to either trastuzumab or lapatinib treatment. Until other methods achieve similar test accuracy, reproducibility, and predictive value, we suggest FISH as the primary HER-2 testing modality for women with breast cancer who are candidates for HER-2-targeted therapies.
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              Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging.

              The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already. Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice. Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972). Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.
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                Author and article information

                Journal
                Nucl Med Commun
                Nucl Med Commun
                MNM
                Nuclear Medicine Communications
                Lippincott Williams & Wilkins
                0143-3636
                1473-5628
                December 2013
                06 November 2013
                : 34
                : 12
                : 1157-1165
                Affiliations
                [a ]Department of Radiology, Molecular Imaging and Therapy Service
                [b ]Department of Medicine, Breast Cancer Medicine Service
                [c ]Human Oncology and Pathogenesis Program
                [d ]Department of Medical Physics
                [e ]Radiochemistry and Molecular Imaging Probes Core Facility, Memorial Sloan-Kettering Cancer Center
                Departments of [f ]Radiology
                [g ]Medicine, Weill Cornell Medical College, New York, New York, USA
                Article
                10.1097/MNM.0b013e328365d99b
                3815146
                24100444
                © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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                breast cancer, f(ab′)2-trastuzumab, 68ga, herceptin, pet/ct

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