title: Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pedram
authors.initials: P
authors.lastname: Heidari
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Francis
authors.initials: F
authors.lastname: Deng
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Shadi A
authors.initials: SA
authors.lastname: Esfahani
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Leece
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shoup
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. umahmood@mgh.harvard.edu.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods; D011960:Receptors, Estrogen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D065171:Estrogen Receptor Antagonists; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol