Marleen Keyaerts1, Catarina Xavier2, Johannes Heemskerk3, Nick Devoogdt4, Hendrik Everaert3, Chloé Ackaert5, Marian Vanhoeij6, Francois P Duhoux7, Thierry Gevaert8, Philippe Simon9, Denis Schallier10, Christel Fontaine10, Ilse Vaneycken11, Christian Vanhove12, Jacques De Greve10, Jan Lamote6, Vicky Caveliers11, Tony Lahoutte11. 1. Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium marleen.keyaerts@vub.ac.be. 2. In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium. 3. Nuclear Medicine Department, UZ Brussel, Brussels, Belgium. 4. In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. 5. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. 6. Department of Oncological Surgery, UZ Brussel, Brussels, Belgium. 7. Medical Oncology, Cliniques universitaires Saint-Luc, Brussels, Belgium. 8. Department of Radiation Therapy, UZ Brussel, Brussels, Belgium. 9. Gynecology Senology, Université Libre de Bruxelles Hôpital Erasme, Brussels, Belgium. 10. Department of Medical Oncology, UZ Brussel, Brussels, Belgium; and. 11. Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium. 12. Infinity Laboratory, MEDISIP, IbiTech, Ghent University, and iMinds Medical IT, Ghent, Belgium.
Abstract
UNLABELLED: Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. METHODS: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. RESULTS: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. CONCLUSION: (68)Ga-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase II trial.
UNLABELLED: Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinomapatients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. METHODS: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. RESULTS: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. CONCLUSION: (68)Ga-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase II trial.
Authors: Zhengyuan Zhou; Ganesan Vaidyanathan; Darryl McDougald; Choong Mo Kang; Irina Balyasnikova; Nick Devoogdt; Angeline N Ta; Brian R McNaughton; Michael R Zalutsky Journal: Mol Imaging Biol Date: 2017-12 Impact factor: 3.488
Authors: Ganesan Vaidyanathan; Darryl McDougald; Jaeyeon Choi; Eftychia Koumarianou; Douglas Weitzel; Takuya Osada; H Kim Lyerly; Michael R Zalutsky Journal: J Nucl Med Date: 2016-02-18 Impact factor: 10.057
Authors: Matthias D'Huyvetter; Jens De Vos; Catarina Xavier; Marek Pruszynski; Yann G J Sterckx; Sam Massa; Geert Raes; Vicky Caveliers; Michael R Zalutsky; Tony Lahoutte; Nick Devoogdt Journal: Clin Cancer Res Date: 2017-07-27 Impact factor: 12.531
Authors: Gary A Ulaner; Serge K Lyashchenko; Christopher Riedl; Shutian Ruan; Pat B Zanzonico; Diana Lake; Komal Jhaveri; Brian Zeglis; Jason S Lewis; Joseph A O'Donoghue Journal: J Nucl Med Date: 2017-11-16 Impact factor: 10.057
Authors: Adriaan Verhelle; Wouter Van Overbeke; Cindy Peleman; Rebecca De Smet; Olivier Zwaenepoel; Tony Lahoutte; Jo Van Dorpe; Nick Devoogdt; Jan Gettemans Journal: Mol Imaging Biol Date: 2016-12 Impact factor: 3.488