title: 18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.
abstract: Purpose:Evaluate18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.Experimental Design:In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.Results:Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.Conclusions:FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials.Clin Cancer Res; 23(12); 3053-60. ©2016 AACR.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Yingbing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiology and Radiological Science, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Ayres
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Goldman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maura N
authors.initials: MN
authors.lastname: Dickler
authors.affiliation: Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bardia
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Fredrickson
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Department of Radiology and Radiological Science, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Manning
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. ulanerg@mskcc.org.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Ulaner
mesh_terms: D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002934:Cinnamates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D058990:Molecular Targeted Therapy; D000072078:Positron Emission Tomography Computed Tomography; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: C000606997:3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid; D054316:Biomarkers, Pharmacological; D002934:Cinnamates; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007191:Indazoles; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol