Personalized Medicine and Imaging Pharmacodynamic Imaging Guides Dosing of a Selective Estrogen Receptor Degrader

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 16a-F-fluoroestradiol (F-FES) PET for fulvestrant dose optimization in a preclinical ERþ breast cancer model. Experimental Design: In vitro, F-FES retentionwas compared with ERa protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ERþ) after treatment with different fulvestrant doses.MCF7 xenografts were grown in ovariectomized nudemice and assigned to vehicle, low(0.05mg), 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 performedusing F-FES and 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 FFES uptake and ER expression with increased fulvestrant doses, despite enhancement of ERmRNA transcription. In xenografts, ER expression significantly decreasedwith increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of F-FES PET mean standardized uptake value (SUVmean) with fulvestrant treatment but no significant difference among the treatment groups in F-FDG PET SUVmean. Conclusions: We demonstrated that 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 F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patientswithbreast cancer.ClinCancerRes;21(6);1340–7. 2015AACR.