18F-Fluoroestradiol PET guides dosing of selective estrogen receptor degraders

Objectives Estrogen receptor (ER) targeting therapies are key in management of breast cancer (BrCa). Currently, there are no methods to optimize treatment dosing of anti-ER medications. However, ER functional availability may be evaluable using 16α-[18F]-fluoroestradiol (18F-FES) PET. This study assesses the utility of 18F-FES PET in dose optimization of fulvestrant, a selective ER degrader (SERD), in a preclinical model of ER+ BrCa.

Methods Human ER+ BrCa cells, MCF7, were incubated with different doses of fulvestrant for 24 h. Retention of 18F-FES was measured and compared to semiquantitative assays of ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR). MCF7 tumors were grown in ovariectomized nude mice. The mice were assigned to vehicle, low- (0.05mg), medium- (0.45mg) or high-dose (5mg) treatment groups (n=5-7). Two days after fulvestrant treatment, PET/CT was performed using 18F-FES and 18F-FDG. ER expression was assayed by immunohistochemistry (IHC), ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki-67 IHC.

Results In vitro, fulvestrant was equipotent at reducing 18F-FES uptake as ER protein expression, despite stimulating mRNA transcription severalfold. Tumors resected from mice demonstrated decreased ER staining with increasing fulvestrant dose. ER expression significantly decreased with fulvestrant treatment in a dose-dependent manner both in ELISA of tumor lysates and IHC staining, despite similar mRNA expression. No difference in Ki-67 staining was observed among the treatment groups. We observed a significant dose-dependent reduction of 18F-FES PET SUVmean with fuvestrant treatment, but no significant difference among the treatment groups in 18F-FDG PET parameters.

Conclusions We demonstrated that 18F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant treatment which precedes the changes in tumor metabolism and proliferation. Quantitative 18F-FES-PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in BrCa patients.