Here, we sought to develop a PET radioligand based on trastuzumab labeled with 124I, 124I-trastuzumab, to evaluate its distribution, internal dosimetry, and initial PET images of HER2-positive lesions in gastric cancer (GC) patients.
In animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity of 124I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124I-trastuzumab PET imaging, with 18F-FDG PET/CT in each to compare.
In animal studies, PET imaging of 124I-trastuzumab showed significant higher tumor uptake than that of 124I-IgG1 in HER2-positive PDX mouse models at 24 h. The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity. In human clinical studies, 18 HER2-positive lesions and 11 HER2-negative lesions were evaluated in PET imaging analysis. The detection sensitivity of 124I-trastuzumab was 100% (18/18) at 24 h. The PET images showed significant difference in tumor uptake between HER2-positive and HER2-negative lesions at 24 h (SUVmax 7.83 ± 0.55 vs. 1.75 ± 0.29, p < 0.0001). Quite striking difference in tumor uptake was observed between 124I-trastuzumab and 18F-FDG (SUVmax 1.75 ± 0.29 vs. 6.46 ± 0.44, p < 0.0001) in HER2-negative lesions, further confirming the specific binding of 124I-trastuzumab in HER2-positive lesions. The radiation-absorbed dose was calculated to be 0.3011 ± 0.005 mSv/MBq. No toxicities or adverse effects were observed in any of the patients.
The findings described here demonstrated that 124I-trastuzumab was feasible to detect HER2-positive lesions in primary and metastatic gastric cancer patients and to differentiate HER2-positive and HER2-negative lesions quantitatively.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Human epidermal receptor type 2
Gastroesophageal junction cancer
- h :
Silver, chromogenic, or fluorescent in situ hybridization
Single-photon emission computed tomography
Positron emission tomography
Patient-derived tumor xenograft
Radioactive thin-layer chromatography scanner
High-performance liquid chromatography
- d :
The maximum single-voxel standardized uptake value
Regions of interest
Percent injected dose per gram
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2017;67(1):7.
Lin S, Yan-Shen S, Huang-Ming H, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14(12):e535–47.
Van CE, Sagaert X, Topal B, et al. Gastric cancer. J Natl Cancer Inst. 2016;57(1):2654–64.
Shah MA. Update on metastatic gastric and esophageal cancers. J Clin Oncol. 2015;33(16):1760–9.
Stella M, Serventi A, Friedman D. Right portal vein thrombosis after splenectomy for trauma. J Gastrointest Surg. 2005;9(5):646–7.
Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.
Okines AF, Cunningham D. Trastuzumab in gastric cancer. Eur J Cancer. 2010;46(11):1949–59.
Niikura N, Liu J, Hayashi N, et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol. 2012;30(6):593–9.
Pectasides D, Gaglia A, Arapantonidadioti P, et al. HER-2/neu status of primary breast cancer and corresponding metastatic sites in patients with advanced breast cancer treated with trastuzumab-based therapy. Anticancer Res. 2006;26(1B):647.
Altundag K. Role of endocrine therapy in weak estrogen/progesterone receptor expression in HER2 negative breast cancer. Eur J Surg Oncol. 2018;44(4):539.
Altundag K. Digital breast tomosynthesis findings may be different in HER2 positive breast cancer patients according to hormone receptor status. Br J Radiol. 2018;91(1082):20170730.
Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87–100.
Chao WR, Lee MY, Ruan A, et al. Assessment of HER2 status using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques in mucinous epithelial ovarian cancer: a comprehensive comparison between ToGA biopsy method and ToGA surgical specimen method. PLoS ONE. 2015;10(11):e0142135.
Perik PJ, Lub-De Hooge MN, Gietema JA, et al. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24(15):2276–82.
Dijkers EC, Kosterink JG, Rademaker AP, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med. 2009;50(6):974–81.
Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87(5):586–92.
Tamura K, Kurihara H, Yonemori K, et al. 64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer. J Nucl Med. 2013;54(11):1869–75.
Kurihara H, Hamada A, Yoshida M, et al. (64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res. 2015;5:8.
Woo SK, Jang SJ, Seo MJ, et al. Development of 64Cu-NOTA-Trastuzumab for HER2 targeting: radiopharmaceutical with improved pharmacokinetics for human study. J Nucl Med. 2018. https://doi.org/10.2967/jnumed.118.210294.
Guo X, Zhu H, Zhou N, et al. Noninvasive detection of HER2 expression in gastric cancer by (64)Cu-NOTA-trastuzumab in PDX mouse model and in patients. Mol Pharm. 2018;15(11):5174–82.
Knowles SM, Zettlitz KA, Richard T, et al. Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody. J Nucl Med. 2014;55(3):452–9.
Divgi CR, Pandit-Taskar N, Jungbluth AA, et al. Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol. 2007;8(4):304–10.
Hamilton EP, Patel MR, Armstrong AC, et al. A first in human study of the new oral selective estrogen receptor degrader AZD9496 for HR +/HER2- advanced breast cancer. Clin Cancer Res. 2018.
Chen Z, Huang W, Tian T, et al. Characterization and validation of potential therapeutic targets based on the molecular signature of patient-derived xenografts in gastric cancer. J Hematol Oncol. 2018;11(1):20.
Wong JYC, Raubitschek A, Yamauchi D, et al. A Pretherapy biodistribution and dosimetry study of indium-111-radiolabeled trastuzumab in patients with human epidermal growth factor receptor 2-overexpressing breast cancer. Cancer Biother Radiopharm. 2010;25(4):387.
O’Donoghue JA, Lewis JS, Pandit-Taskar N, et al. Pharmacokinetics, biodistribution, and radiation dosimetry for 89Zr-trastuzumab in patients with esophagogastric cancer. J Nucl Med Off Publ Soc Nucl Med. 2017. https://doi.org/10.2967/jnumed.117.194555.
Van Dongen GA, Visser GW, Lub-de Hooge MN, et al. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. 2007;12(12):1379–89.
Conflicts of interests
The authors declare no potential conflict of interests.
All procedures in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. Informed consent, or its equivalent, was obtained from all patients included in the study. The clinical study was approved by the Ethics Committee of the Beijing Cancer Hospital (Ethics Approval License: 2018KT48).
Human and animal rights
All institutional and national guidelines for the care and use of laboratory animals were followed.
Informed consent was obtained from the 6 individual participants included in this study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Guo, X., Zhou, N., Chen, Z. et al. Construction of 124I-trastuzumab for noninvasive PET imaging of HER2 expression: from patient-derived xenograft models to gastric cancer patients. Gastric Cancer (2020) doi:10.1007/s10120-019-01035-6
- Gastric cancer