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Clin Cancer Res. 2017 Jun 15;23(12):3053-3060. doi: 10.1158/1078-0432.CCR-16-2197. Epub 2016 Dec 23.

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.

Author information

1
Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
2
Department of Radiology and Radiological Science, Vanderbilt University Medical Center, Nashville, Tennessee.
3
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
6
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
7
Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
8
Genentech, Inc., South San Francisco, California.
9
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. ulanerg@mskcc.org.

Abstract

Purpose: Evaluate 18F-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.

PMID:
28011460
PMCID:
PMC5474190
DOI:
10.1158/1078-0432.CCR-16-2197
[Indexed for MEDLINE]
Free PMC Article

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