Monitoring Afatinib Treatment in HER2-Positive Gastric Cancer with 18F-FDG and 89Zr-Trastuzumab PET

We evaluated the ability of the PET imaging agent Zr-89-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib. Methods: Using Zr-89-trastuzumab, F-18-FDG, or 3 '-deoxy-3 '-F-18-fluorothymidine (F-18-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using Zr-89-trastuzumab and F-18-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies. Results: Although F-18-FDG uptake in NCI-N87 tumors did not change, a decrease in Zr-89-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 +/- 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 +/- 3.4% ID/g, respectively; P < 0.05). Zr-89-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment. Conclusion: Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. Zr-89-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib.