Abstract 477: Evaluation of tumor uptake and retention in a mouse model of breast cancer brain metastases by I-124 positron emission tomography (PET) imaging

The central nervous system (CNS) is emerging as the first site of metastatic disease in women with breast cancer. Women with hormone unresponsive tumors and/or HER-2 overexpressing tumors are disproportionately affected. Breast cancer brain metastasis represents a unique therapeutic challenge because of the limited access to the CNS of many anticancer drugs. Radioiodide (131I) therapy may provide a therapeutic alternative since over 70% of invasive breast cancers, and some brain metastases express the sodium-iodide symporter (NIS). The rationale for this approach is based on the success of 131I radioablative therapy for thyroid cancers. Objectives: To evaluate CNS permeability, kinetics of radioiodine uptake and retention in our NIS expressing breast cancer brain metastasis (BCBM) mouse model. Methods: A brain-seeking clone of the hormone independent ((ER-/PR-/HER2-) human breast cancer cell line MDA-MB-231 (231BR) was transduced with a lentiviral vector carrying a bicistronic cassette with NIS and the firefly luciferase (Fluc) genes separated by an internal ribosomal entry site (IRES). Single cell clones were selected and characterized for iodide uptake and bioluminescence. 1 Million NIS-Fluc-MDAMB231 cells were implanted subcutaneously in the mammary fat pad (mfp) of nude mice (NCr nude) and tumor growth was monitored by serial in vivo bioluminescent imaging and external tumor volume measurements. NIS-Fluc mfp tumor xenografts were then explanted, 1×1 mm pieces excised and inserted stereotactically into the basal ganglia of the mouse. Bioluminescence imaging was used to follow intracranial tumor growth over time. Kinetics of 123I uptake and biodistribution in mfp xenografts mice was evaluated by ex vivo radioactive count and biodistribution of 124I was evaluated in vivo by positron emission tomography (PET) imaging on BCBM mice. Results: Brain tumors 124I uptake was evident on the PET 1 hour post injection of the tracer, with values ranging from 1.60 to 3.25 % injected dose/gram of tissue (%ID/g) whereas thyroid uptake was between 6.99 and 11.19 %ID/g. At 20 hours post injection, the brain tumors showed a sustained 124I retention while uptake in most other organs (except thyroid and stomach) was close to background levels; brain tumor to normal brain tissue mean uptake ratio was ranging from to 217.12 to 541.50 (versus 2.02 to 2.68 at 1 hour post injection). The kinetics of 124I uptake was in agreement with the data obtained from the ex vivo counts in mfp xenografts. Conclusions: We have characterized the kinetics of iodide uptake and retention in a model of breast cancer brain metastases. We showed that NIS expressing BCBM are able to concentrate and retain 124I for prolonged period of time. These results together with dosimetric calculations will allow us to adjust the dosage and timing for 131I therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 477.