586 VOLUME 87 NUMBER 5 | MAY 2010 | www.nature.com/cpt ARTICLES nature publishing group Human epidermal growth factor receptor 2 (HER2) is involved in cell survival, cell proliferation, cell maturation, metastasis, and angiogenesis, as well as exerting antiapoptotic efects. 1 Targeting of HER2 with the monoclonal antibody trastuzumab (Herceptin) is a well-established therapeutic strategy in the metastasized and adjuvant setting, and it has positively afected the prognosis of patients with breast cancer characterized by HER2-protein overexpression and/or ampliication. 2,3 HER2 status is routinely determined using immunohisto- chemistry or luorescence in situ hybridization at the time of diagnosis of the primary tumor. However, there are data indicat- ing that the HER2 status of a tumor can vary during the course of the disease. 4 In addition, there can be a discordance in HER2 expression across tumor lesions in the same patient. 5–7 herefore, clinical guidelines encourage the use of repeated biopsies during the course of the disease. 8,9 Physicians and patients are never- theless frequently reluctant to use this invasive technique; in addition, technical problems can arise when lesions are poorly accessible. 10 Noninvasive HER2 imaging using single-photon emission computed tomography (SPECT) and positron emission tomog- raphy (PET) could be a strategy to determine HER2 expression and localization of HER2-overexpressing tumor lesions, includ- ing inaccessible distant metastases. his strategy, which could potentially guide HER2-targeted therapies, led to the develop- ment of 111 In-trastuzumab. Using this SPECT tracer, we have shown HER2-speciic uptake in patients with HER2-positive metastatic breast cancer. 111 In-trastuzumab imaging discovered new HER2-positive lesions in 13 of 15 patients and was therefore considered to be of potential value as a clinical diagnostic tool in metastatic disease. 11 It was only ater our 111 In-trastuzumab clinical study was completed that the long-lived PET isotope zirconium-89 ( 89 Zr) became available for clinical immunoPET imaging with 89 Zr-labeled antibodies. 12 For immunoPET 1 Department of Hospital and Clinical Pharmacy, University of Groningen, Groningen, The Netherlands; 2 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, Groningen, The Netherlands; 3 Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 4 Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. Correspondence: EG de Vries (e.g.e.de.vries@int.umcg.nl) Received 24 November 2009; accepted 21 January 2010; advance online publication 31 March 2010. doi:10.1038/clpt.2010.12 Biodistribution of 89 Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer EC Dijkers 1,2 , TH Oude Munnink 3 , JG Kosterink 1 , AH Brouwers 2 , PL Jager 2 , JR de Jong 2 , GA van Dongen 4 , CP Schröder 3 , MN Lub-de Hooge 1,2 and EG de Vries 3 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.