Improved Estrogen Receptor Assessment by PET Using the Novel Radiotracer ¹⁸F-4FMFES in Estrogen Receptor–Positive Breast Cancer Patients: An Ongoing Phase II Clinical Trial

Abstract

After encouraging preclinical and human dosimetry results for the novel estrogen receptor (ER) PET radiotracer 4-fluoro-11β-methoxy-16α-F-fluoroestradiol (F-4FMFES), a phase II clinical trial was initiated to compare the PET imaging diagnostic potential of F-4FMFES with that of 16α-F-fluoroestradiol (F-FES) in ER-positive (ER+) breast cancer patients. Patients diagnosed with ER+ breast cancer ( = 31) were recruited for this study, including 6 who underwent mastectomy or axillary node dissection. For each patient, F-FES andF-4FMFES PET/CT scans were done sequentially (within a week) and in random order. One hour after injection of either radiotracer, a head-to-thigh static scan with a 2-min acquisition per bed position was obtained. Blood samples were taken at different times after injection to assess each tracer metabolism by reverse-phase thin-layer chromatography. The SUV of nonspecific tissues and the SUV of the tumor were evaluated for each detected lesion, and tumor-to-nonspecific organ ratios were calculated. Blood metabolite analysis 60 min after injection of the tracer showed a 2.5-fold increase in metabolic stability ofF-4FMFES over F-FES. Although for most fociF-4FMFES PET had an SUV similar to that of F-FES PET, tumor contrast improved substantially in all cases. Lower uptake was consistently observed in nonspecific tissues forF-4FMFES, notably a 4-fold decrease in blood-pool activity as compared with F-FES. Consequently, image quality was considerably improved usingF-4FMFES, with lower overall background activity. As a result, F-4FMFES successfully identified 9 more lesions thanF-FES. This phase II study with ER+ breast cancer patients showed thatF-4FMFES PET achieves a lower nonspecific signal and better tumor contrast than F-FES PET, resulting in improved diagnostic confidence and lower false-negative diagnoses.

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…Moreover, the hepatic uptake and biliary excretion of this tracer additionally complicate the detection of lesions in this region. FES also shows affinity to plasma globulins which results in a reduced amount of tracer available for targeting the ER receptors expressing cells [ 19 ]. A modification of the estradiol to 4-fluoro-11β-methoxy-16α-[ 18 F]FES ([ 18 F]4FMFES) lowers tracer affinity for plasmatic globulins, accelerates blood clearance, and decreases uptake in nonspecific organs compared to [ 18 F]FES [ 19 , 64 ].…”

“…In a Phase II clinical trial, the diagnostic potential of [ 18 F]4FMFES was further evaluated. The tracer showed a similar tumor targeting potential to [ 18 F]FES but had superior imaging properties due to decreased overall background allowing higher detection rates and better sensitivity towards ER + BCa [ 19 ].…”

Recent Advances in Imaging Steroid Hormone Receptors in Breast Cancer

“…Additional phase II data regarding the diagnostic accuracy of 18 F-fluoroestradiol imaging have been published by Paquette et al (13). The performance of a newer ER-targeted radiopharmaceutical, 4-fluoro-11b-methoxy-16a-18 F-fluoroestradiol, or 18 F-4FMfluoroestradiol, was compared with 18 F-fluoroestradiol in 31 patients with ER-positive breast cancer.…”

Positron emission tomography in breast cancer: 18F- FDG and other radiopharmaceuticals

“…Sun Y in 2015 investigated the contribution of FES PET/CT in determining ER positive metastatic lesions from breast cancer, suggesting that 18 F-FES PET/CT by assessing the entire tumor volume receptor Kruchten et al, 2013;Dehdashti et al, 1995;Linden et al, 2006;Peterson et al, 2008;Peterson et al, 2011;Mintun et al, 1988;Sun et al, 2015) 4 status, it may be used to assist the individualized treatment decisions of breast cancer patients (Sun et al, 2015). Paquette et al (2017) took ER imaging a step forward by their phase II clinical trial, which was conducted to compare the PET imaging diagnostic potential of 4-fluoro-11β-methoxy-16α-[ 18 F] fluoroestradiol (4FMFES) to FES in ER positive breast cancer patients. They found that 4FMFES-PET achieves lower non-specific signal and better tumor contrast than FES-PET, promising improved diagnostic confidence and lower false negative diagnoses (Paquette et al, 2017).…”

“…Paquette et al (2017) took ER imaging a step forward by their phase II clinical trial, which was conducted to compare the PET imaging diagnostic potential of 4-fluoro-11β-methoxy-16α-[ 18 F] fluoroestradiol (4FMFES) to FES in ER positive breast cancer patients. They found that 4FMFES-PET achieves lower non-specific signal and better tumor contrast than FES-PET, promising improved diagnostic confidence and lower false negative diagnoses (Paquette et al, 2017).…”