Phase I study of ⁶⁸Ga-HER2-Nanobody for PET/CT assessment of HER2-expression in breast carcinoma

Abstract

The 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 has repeatedly been described between primary tumor and metastasis, resulting in the need to reassess HER2-status during the disease course. In order to avoid repeated biopsy with potential bias due to tumor heterogeneity, nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies are the smallest antigen-binding antibody fragments derived from unique heavy-chain-only antibodies, with ideal characteristics for positron emission tomography (PET) imaging. Aim: the primary aims were assessment of safety, biodistribution and dosimetry. The secondary aim was to investigate tumor targeting potential. Methods: In total, 20 female patients with primary or metastatic breast carcinoma (HER2 IHC 2+ or 3+) were included. Anti-HER2 Nanobody is labeled with ⁶⁸Ga 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 post 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 1h post injection. Uptake was mainly seen in 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 background was demonstrated in the majority of identified sites of disease. Primary lesions were more variable in tracer accumulation. Conclusion: ⁶⁸Ga­-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 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 to normal surrounding tissues, and warrants further assessment in a phase II trial.