Abstract

It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) antagonist, is sufficient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/computed tomography (PET/CT) at baseline (scan 1), day 28 (scan 2), and day 84 (scan 3) to monitor tumor [(18)F]fluoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefined as <75% decrease in median tumor FES uptake and a residual standardized uptake value (SUVmax) of ≥1.5. In total, 131 FES-positive lesions were identified (median SUVmax of 2.9; range, 1.7-6.5). The median change in patients during fulvestrant treatment was -85% at scan 2, but varied widely (-99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 (38%) of the 16 patients, which was associated with early progression. Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER. FES-PET showed significant residual ER availability in tumors during fulvestrant therapy in 38% of patients, which was associated with early progression.

Highlights

  • Fulvestrant, a pure estrogen receptor (ER) antagonist, is used as treatment for advanced and metastatic ER-positive breast cancer

  • FES uptake at the earlier scan during aromatase inhibitor therapy was higher. If this scan was used as the baseline scan, FES uptake would have decreased by 26% during fulvestrant treatment, correctly identifying this patient as nonresponder. These results suggest that tamoxifen and its metabolites partly block FES uptake in the tumor, even after a 5-week drug-free period

  • When data adjusted for previous tamoxifen use were included, the positive predictive value increased to 89% and negative predictive value remained at 100%. This is the first serial PET imaging study evaluating the effects of fulvestrant 500 mg on FES uptake in patients with metastatic breast cancer

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Summary

Introduction

Fulvestrant, a pure estrogen receptor (ER) antagonist, is used as treatment for advanced and metastatic ER-positive breast cancer. Fulvestrant was shown to completely downregulate tumor ER expression and inhibit estrogen-mediated tumor growth [2]. Serial biopsy studies showed that ER expression is downregulated incompletely at the 250-mg dose [4]. A loading-dose regimen was explored more recently: 500 mg at day 1 and 250 mg at days 14 and 28 and every 4 weeks thereafter, as well as a high-dose regimen consisting of 500 mg at days 1, 14, and 28 and every 4 weeks thereafter. Because of a progression-free survival (PFS) gain in the highdose regimen from 5.5 to 6.5 months in a phase III trial, the high-dose regimen became the current standard

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