PURPOSE: Estrogen receptor (ER) targeting is key in management of 
receptor-positive breast cancer. Currently, there are no methods to optimize 
anti-ER therapy dosing. This study assesses the use of 16α-(18)F-fluoroestradiol 
((18)F-FES) PET for fulvestrant dose optimization in a preclinical ER(+) breast 
cancer model.
EXPERIMENTAL DESIGN: In vitro, (18)F-FES retention was compared with ERα protein 
expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER(+)) 
after treatment with different fulvestrant doses. MCF7 xenografts were grown in 
ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 
mg), or high-dose (5 mg) fulvestrant treatment groups (5-7 per group). Two and 3 
days after fulvestrant treatment, PET/CT was performed using (18)F-FES and 
(18)F-FDG, respectively. ER expression was assessed by immunohistochemistry, 
ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 
immunohistochemistry.
RESULTS: In vitro, we observed a parallel graded reduction in (18)F-FES uptake 
and ER expression with increased fulvestrant doses, despite enhancement of ER 
mRNA transcription. In xenografts, ER expression significantly decreased with 
increased fulvestrant dose, despite similar mRNA expression and Ki67 staining 
among the treatment groups. We observed a significant dose-dependent reduction 
of (18)F-FES PET mean standardized uptake value (SUV(mean)) with fulvestrant 
treatment but no significant difference among the treatment groups in (18)F-FDG 
PET SUV(mean).
CONCLUSIONS: We demonstrated that (18)F-FES uptake mirrors the dose-dependent 
changes in functional ER expression with fulvestrant resulting in ER degradation 
and/or blockade; these precede changes in tumor metabolism and proliferation. 
Quantitative (18)F-FES PET may be useful for tracking early efficacy of ER 
blockade/degradation and guiding ER-targeted therapy dosing in patients with 
breast cancer.