Dataset Information

¹⁸F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-? Mutations in Breast Cancer.

ABSTRACT: The purpose of this study was to determine the effect of estrogen receptor-? gene (ESR1) mutations at the tyrosine (Y) 537 amino acid residue within the ligand binding domain on ¹⁸F-fluoroestradiol (¹⁸F-FES) binding and in vivo tumor uptake compared with wild-type (WT)-estrogen receptor ? (ER). Methods: ER-negative MDA-MB-231 breast cancer cells were used to generate stable cell lines that express WT-ER, Y537S, or Y537C mutant ER. Receptor expression and localization were confirmed by Western blot and immunofluorescence, respectively. ER transcriptional function was measured using an estrogen response element-luciferase reporter gene assay and quantitative polymerase chain reaction analysis of ER-regulated endogenous target genes. Saturation binding and competition assays were performed to determine equilibrium dissociation constant (K_d) and half maximal inhibitory concentration (IC50) values. ¹⁸F-FES uptake was measured in tumor xenografts grown in female athymic nude mice by small-animal PET/CT imaging and tissue biodistribution using 5.55 MBq (150 ?Ci) of ¹⁸F-FES. A 10-fold-lower injected dose of 0.555 MBq (15 ?Ci) of ¹⁸F-FES was also used for tissue biodistribution. Statistical significance was determined using ANOVA. Results: Y537S and Y537C mutations resulted in increased ER transcriptional activity in the absence of estrogen compared with WT-ER (11.48 ± 2.42 fold; P = 0.0002, and 5.89 ± 0.94 fold; P = 0.04, respectively). Constitutive ER activation of two target genes (PGR and TFF1) in the absence of estrogen was also observed in Y537S- and Y537C-ER cells compared with WT-ER. K_d values for ¹⁸F-FES were 0.98 ± 0.54 nM for Y537S-ER (P = 0.27) and 0.24 ± 0.03 nM for Y537C-ER (P = 0.95) compared with 0.07 ± 0.03 nM for WT-ER. IC50 values were 0.22 ± 0.09 nM for Y537S-ER (P = 0.97), 0.18 ± 0.09 nM for Y537C-ER (P = 0.99), and 0.19 ± 0.11 nM for WT-ER. Tumor xenografts expressing Y537S-ER (mean percentage injected dose per gram, 1.45 ± 0.06; P = 0.77) and Y537C-ER (2.09 ± 0.20; P = 0.21) had similar ¹⁸F-FES uptake compared with WT-ER (1.68 ± 0.12). Comparable ¹⁸F-FES uptake between Y537S-, Y537C-, and WT-ER xenografts was also observed using a 10-fold-lower injected dose with the tissue biodistribution assay. Conclusion: Since tumoral uptake of ¹⁸F-FES is not significantly impacted by Y537S-ER or Y537C-ER mutations, the potential diagnostic utility of ¹⁸F-FES PET imaging is expected to be equally valid for patients with or without these activating ESR1 mutations.

SUBMITTER: Kumar M

PROVIDER: S-EPMC6735277 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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18F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-α Mutations in Breast Cancer.

Kumar Manoj M Salem Kelley K Michel Ciara C Jeffery Justin J JJ Yan Yongjun Y Fowler Amy M AM

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20190308 9

The purpose of this study was to determine the effect of estrogen receptor-α gene (ESR1) mutations at the tyrosine (Y) 537 amino acid residue within the ligand binding domain on 18F-fluoroestradiol (18F-FES) binding and in vivo tumor uptake compared with wild-type (WT)-estrogen receptor α (ER). Methods: ER-negative MDA-MB-231 breast cancer cells were used to generate stable cell lines that express WT-ER, Y537S, or Y537C mutant ER. Receptor expression an ...[more]

PMID: 30850489

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Project description:Introduction16α-[18F]Fluoroestradiol (FES), a PET radiotracer for the estrogen receptor (ER) in breast cancer, was the first receptor-targeted PET radiotracer for oncology and is continuing to prove its value in clinical research, antiestrogen development, and breast cancer care. The story of its conception, design, evaluation and use in clinical studies parallels the evolution of the whole field of receptor-targeted radiotracers, one greatly influenced by the research and intellectual contributions of William C. Eckelman.Methods and resultsThe development of methods for efficient production of fluorine-18, for conversion of [18F]fluoride ion into chemically reactive form, and for its rapid and efficient incorporation into suitable estrogen precursor molecules at high molar activity, were all methodological underpinnings required for the preparation of FES. FES binds to ER with very high affinity, and its in vivo uptake by ER-dependent target tissues in animal models was efficient and selective, findings that preceded its use for PET imaging in patients with breast cancer.Advances in knowledge and implications for patient careComparisons between ER levels measured by FES-PET imaging of breast tumors with tissue-specimen ER quantification by IHC and other methods show that imaging provided improved prediction of benefit from endocrine therapies. Serial imaging of ER by FES-PET, before and after dosing patients with antiestrogens, is used to determine the efficacious dose for established antiestrogens and to facilitate clinical development of new ER antagonists. Beyond FES imaging, PET-based hormone challenge tests, which evaluate the functional status of ER by monitoring rapid changes in tumor metabolic or transcriptional activity after a brief estrogen challenge, provide highly sensitive and selective predictions of whether or not there will be a favorable response to endocrine therapies. There is sufficient interest in the clinical applications of FES that FDA approval is being sought for its wider use in breast cancer.ConclusionsFES was the first PET probe for a receptor in cancer, and its development and clinical applications in breast cancer parallel the conceptual evolution of the whole field of receptor-binding radiotracers.

Project description:PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5?±?2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0?±?2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p?<?0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5?±?0.2 compared to 1.3?±?0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7?±?2.3 h), and achieving a consistent final distribution volume averaging 1.4?±?0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57?±?51 min), with an average distribution volume of 3.2?±?1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

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¹⁸F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-? Mutations in Breast Cancer.

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<sup>18</sup>F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-α Mutations in Breast Cancer.

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Dataset Information

18F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-? Mutations in Breast Cancer.

Publications

<sup>18</sup>F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-α Mutations in Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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¹⁸F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-? Mutations in Breast Cancer.