4FMFES and FDG-PET of a ER+ uterine cancer mouse xenograft model

Objectives: About 80% of uterine cancers overexpress the Estrogen Receptor (ER). While most patients are diagnosed at early stage, those burdened with advanced disease are difficult to assess and follow up with conventional imaging procedures. The ER-targeting FES-PET was already shown to detect ER+ endometrial cancers in the clinical setting. Our group evaluated the improved ER PET tracer 4FMFES in a breast cancer xenograft model and in a breast cancer patient cohort, with both studies showing that 4FMFES-PET outperformed FES-PET for ER+ tumor detection and contrast. Our research group is about to initiate a phase I/II clinical trial evaluating FDG- and 4FMFES-PET in ER+ uterine and ovarian cancer patients. As a result, we seek to first evaluate 4FMFES-PET in a ER+ uterine cancer mouse xenograft model to support our clinical efforts.

Methods: A cohort of 6 female athymic nude mice was subcutaneously injected on the right shoulder with a 50% Matrigel solution containing 5 × 10⁶ RL95-2 cells per 100 µl (ER+ human uterine carcinoma). Tumors were grown up to ~50 mm³ before further experiments. Each animal was anesthetized then injected with 3.6 ± 0.9 MBq FDG via the caudal vein. The next day, the same mice received 3.5 ± 0.4 MBq of intravenous 4FMFES. Following each tracer injection, mice were placed in prone position on the PET scanner bed, then a 15-minute static PET acquisition one-hour post-injection was initiated. Mice were euthanized by CO₂ inhalation following 4FMFES-PET, and organ biodistribution was performed. %ID/g for tissues of interest were calculated from PET images for both tracers, and also from dissected organs for 4FMFES.

Results: RL95-2 tumors reached the appropriate size in 28 days. Despite intense background from brown adipose tissues, muscles and the heart, FDG-PET yielded a tumor uptake of 3.5 ± 0.4 %ID/g, for a tumor-to-muscle ratio of 1.83 ± 0.47. 4FMFES tumor uptake was considerably lower and reached 0.97 ± 0.11 %ID/g according to PET images, and 0.72 ± 0.17 %ID/g from biodistribution. However, muscle uptake was also much lower than for FDG, resulting in a comparable tumor-to-muscle ratio of 1.94 ± 0.52 and 2.20 ± 0.77 from PET images and from dissection respectively.

Conclusions: 4FMFES-PET enables detection of RL95-2 ER+ uterine tumors in a xenografted mouse model with a similar contrast as with FDG-PET. Preclinical data obtained foretell the feasibility of 4FMFES imaging for clinical uterine cancer applications. Orthotopic mouse models for both uterine and ovarian cancers are under development and will be evaluated in the near future.