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- Alhuseinalkhudhur, Ali, et al.
(author)
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Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
- 2023
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 64:9, s. 1364-1370
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Journal article (peer-reviewed)abstract
- Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.
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| 2. |
- Alhuseinalkhudhur, Ali, et al.
(author)
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Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
- 2020
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In: EJNMMI Research. - : SPRINGEROPEN. - 2191-219X. ; 10:1
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Journal article (peer-reviewed)abstract
- Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.
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| 7. |
- Sandberg, Dan T, et al.
(author)
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Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.
- 2017
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 44:8, s. 1337-1346
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Journal article (peer-reviewed)abstract
- PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.
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- Sandström, Mattias, et al.
(author)
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Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients
- 2016
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:6, s. 867-871
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Journal article (peer-reviewed)abstract
- Ga-68-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 Ga-68-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 Ga-68-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 Ga-68-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 Ga-68-labeled tracers, such as 0.021 +/- 0.003 mSv/MBq for Ga-68-DOTATATE and Ga-68-DOTATOC, mainly because of higher uptake in liver and kidney.
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- Sörensen, Jens, et al.
(author)
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First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the In-111-ABY-025 Affibody Molecule
- 2014
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:5, s. 730-735
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Journal article (peer-reviewed)abstract
- The expression status of human epidermal growth factor receptor type 2 (HER2) predicts the response of HER2-targeted therapy in breast cancer. ABY-025 is a small reengineered Affibody molecule targeting a unique epitope of the HER2 receptor, not occupied by current therapeutic agents. This study evaluated the distribution, safety, dosimetry, and efficacy of In-111-ABY-025 for determining the HER2 status in metastatic breast cancer. Methods: Seven patients with metastatic breast cancer and HER2-positive (n = 5) or - negative (n 5 2) primary tumors received an intravenous injection of approximately 100 mu g (similar to 140 MBq) of In-111-ABY-025. Planar gamma-camera imaging was performed after 30 min, followed by SPECT/CT after 4, 24, and 48 h. Blood levels of radioactivity, antibodies, shed serum HER2, and toxicity markers were evaluated. Lesional HER2 status was verified by biopsies. The metastases were located by F-18-FDG PET/CT 5 d before In-111-ABY-025 imaging. Results: Injection of In-111-ABY-025 yielded a mean effective dose of 0.15 mSv/MBq and was safe, well tolerated, and without drug-related adverse events. Fast blood clearance allowed high-contrast HER2 images within 4-24 h. No anti-ABY025 antibodies were observed. When metastatic uptake at 24 h was normalized to uptake at 4 h, the ratio increased in HER2-positive metastases and decreased in negative ones (P, < 0.05), with no overlap and confirmation by biopsies. In 1 patient, with HER2- positive primary tumor, In-111-ABY-025 imaging correctly suggested a HER2negative status of the metastases. The highest normal-tissue uptake was in the kidneys, followed by the liver and spleen. Conclusion: In-111-ABY- 025 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic breast cancer, regardless of ongoing HER2-targeted antibody treatment.
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