title: Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  (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.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium marleen.keyaerts@vub.ac.be.
authors.forename: Marleen
authors.initials: M
authors.lastname: Keyaerts
authors.affiliation: In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Catarina
authors.initials: C
authors.lastname: Xavier
authors.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium.
authors.forename: Johannes
authors.initials: J
authors.lastname: Heemskerk
authors.affiliation: In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: Devoogdt
authors.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Everaert
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Chloé
authors.initials: C
authors.lastname: Ackaert
authors.affiliation: Department of Oncological Surgery, UZ Brussel, Brussels, Belgium.
authors.forename: Marian
authors.initials: M
authors.lastname: Vanhoeij
authors.affiliation: Medical Oncology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Duhoux
authors.affiliation: Department of Radiation Therapy, UZ Brussel, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gevaert
authors.affiliation: Gynecology Senology, Université Libre de Bruxelles Hôpital Erasme, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Simon
authors.affiliation: Department of Medical Oncology, UZ Brussel, Brussels, Belgium; and.
authors.forename: Denis
authors.initials: D
authors.lastname: Schallier
authors.affiliation: Department of Medical Oncology, UZ Brussel, Brussels, Belgium; and.
authors.forename: Christel
authors.initials: C
authors.lastname: Fontaine
authors.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Vaneycken
authors.affiliation: Infinity Laboratory, MEDISIP, IbiTech, Ghent University, and iMinds Medical IT, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: Department of Medical Oncology, UZ Brussel, Brussels, Belgium; and.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Greve
authors.affiliation: Department of Oncological Surgery, UZ Brussel, Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Lamote
authors.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Vicky
authors.initials: V
authors.lastname: Caveliers
authors.affiliation: Nuclear Medicine Department, UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Tony
authors.initials: T
authors.lastname: Lahoutte
mesh_terms: D000328:Adult; D000368:Aged; D001692:Biological Transport; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005710:Gallium Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D064847:Multimodal Imaging / Q000009:adverse effects / Q000379:methods*; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism*; D012449:Safety; D061905:Single-Domain Antibodies / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D005710:Gallium Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D061905:Single-Domain Antibodies; C508053:ERBB2 protein, human
keywords: HER2; Nanobody; PET/CT; breast carcinoma; phase I