Abstract 4120: 18F-Fluorothymidine PET at earlier time-point than the evaluation of tumor size for anti-epidermal growth factor receptor antibody in human lung cancer xenograft

Abstract

Abstract Background: Specific inhibition of epidermal growth factor receptor (EGFR) is promising treatment in the clinical setting. Cetuximab, a chimeric monoclonal antibody that binds to the extracellular domain of EGFR, has activity in various types of cancer. Because cetuximab is very expensive and has unique side effects, the development of appropriate evaluation for the therapeutic effects is necessary to use this drug effectively. Measurement of tumor proliferative activity by PET using 18F-Fluorothymidine (18F-FLT) may serve to assess early therapeutic effect. The purpose of this study is to determine whether 18F-FLT positron emission tomography (18F-FLT PET) is useful to evaluate a response to EGFR antibody cetuximab therapy at early time-points in human lung cancer cell xenografts. Methods: Human tumor xenograft model was established in male BALB/c athymic mice with human lung cancer cell line, NCI-H1975. Mice were randomly assigned to four groups; tumor growth follow-up, ex vivo study, PET imaging and non-treated control. Mice were administered saline as control or cetuximab 1.0 mg on day 1. In the tumor growth follow-up group, tumor sizes were measured by caliper on day 3, 5, 8, and 10 after the treatment. Ex vivo study and 18F-FLT PET were performed on day 3 as early therapeutic evaluation. In the ex vivo study group, radioactivity of 18F-FLT in tumor and other tissue samples (%Injected Dose/g/kg) was measured using a γ-counter. In the PET imaging group, mice were imaged by a small animal PET as pre-treatment before administration of cetuximab on day 1, and secondly imaged with the same procedure as post-treatment on day 3. In the PET imaging group, tumor cell proliferative activity (Ki-67) was also determined and was compared with that in the non-treated control group as control value. Results: In the tumor growth follow-up group, there was no difference in tumor volume between control and treatment with cetuximab on day 3, although the difference became significant after day 8. In the ex vivo study, radioactivity of 18F-FLT in tumor was decreased about 70 % by treatment with cetuximab (0.098 ± 0.005 %ID/g/kg in the control group vs. 0.029 ± 0.010 %ID/g/kg in the cetuximab-treated group, p < 0.001). In the PET imaging group, the maximum of standardized uptake value was decreased about 40 % similarly (0.41 ± 0.17 before treatment on day 1 vs. 0.24 ± 0.15 after treatment on day 3, p < 0.01). The decrease of tracer uptake was clearly visualized by 18F-FLT PET. Ki-67 positive cells were also decreased by treatment with cetuximab (12.8 ± 4.0% in the non-treated control group on day 1 vs. 5.0 ± 1.5% in the PET imaging group on day 3, p = 0.01). Conclusions: These results suggest 18F-FLT-PET can be a useful predictor to evaluate a response to molecular targeted drug such as cetuximab at earlier time-point than the evaluation of tumor size. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4120. doi:10.1158/1538-7445.AM2011-4120