18F-FES PET Research Articles

The Application of 18F-FES PET in Clinical Cancer Care: A Systematic Review.

[18F]fluoroestradiol (FES) can be used for the noninvasive visualization and quantification of tumor estrogen receptor (ER) expression and activity and was FDA-approved as a diagnostic agent in May 2022 for detecting ER-positive lesions in patients with recurrent or metastatic breast cancer. PET imaging was also used to detect ER-positive lesions and malignancy among patients with uterine, ovarian, and other ER-positive solid tumors. We conducted a systemic review of the studies on FES PET imaging used among patients with cancer not limited to breast cancer to better understand the application of FES PET imaging. PubMed/MEDLINE and Cochrane Library databases were used to perform a comprehensive and systematic search and were updated until August 15, 2022. Two authors independently reviewed the titles and abstracts of the retrieved articles by using the search algorithm and selected the articles based on the inclusion and exclusion criteria. All statistical analyses were conducted using R statistical software. Forty-three studies with 2352 patients were included in the qualitative synthesis, and 23 studies with 1388 patients were included in the quantitative analysis, which estimated the FES-positive detection rate. Thirty-two studies (77%) included breast cancer patients in 43 included studies. The FES SUVmean was higher in patients with endometrial cancer (3.4-5.3) than in those with breast cancer (2.05) and uterine sarcoma (1.1-2.6). The pooled detection rates of FES PET imaging were 0.80 for breast and 0.84 for ovarian cancer patients, both similar to that of 18F-FDG. The FES uptake threshold of 1.1 to 1.82 could detect 11.1% to 45% ER heterogeneity, but the threshold of FES uptake did not have consistent predictive ability for prognosis among patients with breast cancer, unlike uterine cancer. However, FES uptake can effectively predict and monitor treatment response, especially endocrine therapy such as estradiol, ER-blocking agents (fulvestrant and tamifoxen), and aromatase inhibitors (such as letrozole and Z-endoxifen). [18F]fluoroestradiol PET is not only a convenient and accurate diagnostic imaging tool for detecting ER-expressing lesions in patients with breast and ovarian cancer but also among patients with uterine cancer. [18F]fluoroestradiol PET is a noninvasive predictive and monitoring tool for treatment response and prognosis.

Negative estrogen receptor expression assessed by 18F-FES PET in metastatic breast cancer with ER-positive primary tumor.

1034 Background: The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesion but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. Methods: This study enrolled MBC patients with ER-positive primary tumor who received 18F-FES PET/CT in our center. Descriptive statistics were used in clinicopathologic characteristics and compared with Chi square test or t test. Progression‐free survival (PFS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: 16.46% (52/314) patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy. The rate of ER-negativity tested by 18F-FES was negatively co-related with levels of ER expression in early stage, with a positive to negative conversion in 2 of 3 (46.3%) ER-low (ie, ER 1%-9%) tumors, 7 of 10 (70.0%) ER-moderate (ie, ER 10%-49%) tumors, 16 of 114 (14.0%) ER-high (ie, ER 50%-95%) tumors, and 1 of 8 (12.5%) ER-very high (ie, ER > 95%) tumors (p < 0.001). Chemotherapy (83.33%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (64.29%, 27/42) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 vs 6.21 months, p = 0.035). Conclusions: 18F-FES could identify negative conversion of ER in MBC which occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, chemotherapy was the primary choice by most physicians and capecitabine monotherapy had shown good efficacy.

Summary: Appropriate Use Criteria for Estrogen Receptor-Targeted PET Imaging with 16α-18F-Fluoro-17β-Fluoroestradiol.

PET imaging with 16α-18F-fluoro-17β-fluoroestradiol (18F-FES), a radiolabeled form of estradiol, allows whole-body, noninvasive evaluation of estrogen receptor (ER). 18F-FES is approved by the U.S. Food and Drug Administration as a diagnostic agent "for the detection of ER-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer." The Society of Nuclear Medicine and Molecular Imaging (SNMMI) convened an expert work group to comprehensively review the published literature for 18F-FES PET in patients with ER-positive breast cancer and to establish appropriate use criteria (AUC). The findings and discussions of the SNMMI 18F-FES work group, including example clinical scenarios, were published in full in 2022 and are available at https://www.snmmi.org/auc Of the clinical scenarios evaluated, the work group concluded that the most appropriate uses of 18F-FES PET are to assess ER functionality when endocrine therapy is considered either at initial diagnosis of metastatic breast cancer or after progression of disease on endocrine therapy, the ER status of lesions that are difficult or dangerous to biopsy, and the ER status of lesions when other tests are inconclusive. These AUC are intended to enable appropriate clinical use of 18F-FES PET, more efficient approval of FES use by payers, and promotion of investigation into areas requiring further research. This summary includes the rationale, methodology, and main findings of the work group and refers the reader to the complete AUC document.

ER status conversion and subsequent treatment: an assessment of negative ER expression detected by 18F-FES PET in metastatic breast cancer patients with ER-positive primary tumors.

The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesions but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. This study aimed to characterize the primary ER-positive patients with advanced-stage FES negativity and investigate the real-world treatment decisions made by physicians subsequently, and compare the efficacy between different regimens. This observational cohort study was conducted at Fudan University Shanghai Cancer Center, enrolling breast cancer patients with ER-positive primary tumors who showed advanced-stage FES negativity. Descriptive statistics were used in clinicopathologic characteristics and compared with a chi-square test or t-test. In addition, progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared by log-rank test. 16.6% (52/314) of patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy, among whom adjuvant endocrine therapy was prevalently utilized (86.5%, 45/52). The rate of FES negativity in the advanced stage was negatively correlated with levels of ER expression of primary tumors. Chemotherapy (83.3%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (62.5%, 25/40) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 versus 6.21 months, p = 0.029). Negative conversion of ER in MBC detected by 18F-FES occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, most physicians primarily opted for chemotherapy, with capecitabine monotherapy being a commonly selected regimen. ClinicalTrials.gov identifier: NCT05797987.

Chemotherapy Shows a Better Efficacy Than Endocrine Therapy in Metastatic Breast Cancer Patients with a Heterogeneous Estrogen Receptor Expression Assessed by 18F-FES PET.

Simple SummaryAbout 10–20% of breast cancer patients have a heterogeneous estrogen receptor expression. The diagnosis and treatment strategy remains controversial in these patients, especially regarding the metastatic pattern. The aim of our study was to investigate the occurrence and properties of estrogen receptor heterogeneity and to evaluate the following treatment efficacy among a certain group of metastatic breast cancer patients. We found the novel 18F-FES PET/CT method could identify patients with estrogen receptor heterogeneity, and chemotherapy showed a better efficacy compared with endocrine therapy in these patients. Our findings could give valuable suggestions to physicians and researchers in clinical practice.Background: The heterogeneity of estrogen receptor (ER) expression has long been a challenge for the diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient method of ER detection using 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received 18F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression-free survival (PFS) was estimated using the Kaplan–Meier method and was compared using the log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty; 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET), and 10 (19.6%) patients received combined therapy (CT + ET). CT showed a better progression-free survival (PFS) compared with ET (mPFS 7.1 vs. 4.6 months, HR 0.44, 95% CI 0.20–0.93, p = 0.03). CT + ET did not improve PFS compared with either CT or ET alone (mPFS 4.4 months, p > 0.2). All three treatment options were well tolerated. Conclusions: 18F-FES PET/CT could identify patients with ER heterogeneity. Patients with bone metastasis are more likely to have ER heterogeneity. Patients with ER heterogeneity showed better sensitivity to CT rather than ET. Combined therapy of CT + ET did not improve the treatment outcome.

PET Imaging of Estrogen Receptors for Gynecological Tumors.

In the past few decades, PET with 18F-FDG has been used for the diagnosis of gynecological malignancies and is considered to be superior to conventional imaging methods in diagnostic accuracy for detecting metastatic lesions and local recurrence and in evaluating the treatment response. On the other hand, several gynecological tumors, such as endometrial cancer and leiomyoma, and breast cancer are estrogen-dependent, in which estrogen is essential for their development and progression. 18F-FES is an 18F-labeled compound of estradiol, the most bioactive type of estrogen, and 18F-FES PET has been well-established for diagnosis, staging, and posttherapeutic follow-up in patients with estrogen receptor-positive breast cancer. Compared with in vitro assessment of tumor biopsy material, PET imaging has the advantages of being able to measure in vivo tumor behavior, characterize the entire tumor burden, and capture the heterogeneity of the tumor phenotype. In this article, we review the phenotyping of estrogen-related gynecological tumors other than breast cancer using 18F-FES PET and demonstrate the additional value of 18F-FES PET to 18F-FDG PET in their diagnosis and prognostication. Moreover, promising PET tracers other than 18F-FES and 18F-FDG for the evaluation of estrogen-related gynecological tumors are introduced.

Heterogeneity of estrogen receptor based on 18F-FES PET imaging in breast cancer patients

Heterogeneity of estrogen receptor based on 18F-FES PET imaging in breast cancer patients

18F-Fluoroestradiol Tumor Uptake Is Influenced by Structural Components in Breast Cancer.

Estrogen receptor (ER) is expressed in the majority of invasive breast cancer and is an important prognostic indicator. The tumor stroma also plays an important role in disease progression. This study evaluated the effect of stromal components on 16α-[18F]-fluoro-17β-estradiol (18F-FES) uptake in breast cancer and proposed a partial-volume correction method for 18F-FES PET based on histopathological analyses. Fifteen patients with biopsy-confirmed breast cancer underwent preoperative 18F-FES PET. Estrogen receptor expression in biopsy specimens was assayed by immunohistochemistry, cellular components in surgical specimens were measured using hematoxylin-eosin staining, and nuclear components in surgical and biopsy specimens were measured using Azan-Mallory staining. The relationship between 18F-FES SUV of the primary tumor and histopathological findings including ER expression, the Allred score, ER-positive cellular component ratio, and ER-positive nuclear component ratio (NCR) was examined. The relationship between stroma-free 18F-FES SUV and ER expression was also examined. 18F-FES uptake was not significantly positively correlated with ER expression (r = 0.44, P = 0.10). 18F-FES uptake was significantly correlated with the Allred score, ER-positive cellular component ratio, and ER-positive NCR in surgical specimens (ρ = 0.60, P = 0.02; r = 0.55, P = 0.03; and r = 0.65, P = 0.01, respectively). 18F-FES uptake was predominantly correlated with ER-positive NCR in biopsy specimens (r = 0.84, P < 0.001). Stroma-free 18F-FES SUV was significantly correlated with ER expression (r = 0.78, P < 0.01). 18F-FES PET predominantly demonstrates the level of ER expression in breast cancer cell nucleus. Although tumor 18F-FES uptake is affected by the degree of stromal components, the partial volume effect on the uptake can be corrected by stroma-volume fraction in Azan-Mallory staining.

Value of 18F-FES PET in Solving Clinical Dilemmas in Breast Cancer Patients: A Retrospective Study.

Breast cancer (BC) is a heterogeneous disease in which estrogen receptor (ER) expression plays an important role in most tumors. A clinical dilemma may arise when a metastasis biopsy to determine the ER status cannot be performed safely or when ER heterogeneity is suspected between tumor lesions. Whole-body ER imaging, such as 16α-18F-fluoro-17β-estradiol (18F-FES) PET, may have added value in these situations. However, the role of this imaging technique in routine clinical practice remains to be further determined. Therefore, we assessed whether the physician's remaining clinical dilemma after the standard workup was solved by the 18F-FES PET scan. Methods: This retrospective study included 18F-FES PET scans of patients who had (or were suspected to have) ER-positive metastatic BC and for whom a clinical dilemma remained after the standard workup. The scans were performed at the University Medical Center of Groningen between November 2009 and January 2019. We investigated whether the physician's clinical dilemma was solved, defined either as solving the clinical dilemma through the 18F-FES PET results or as basing a treatment decision directly on the 18F-FES PET results. In addition, the category of the clinical dilemma was reported, as well as the rate of 18F-FES-positive or -negative PET scans, and any correlation to the frequency of solved dilemmas was determined. Results: One hundred 18F-FES PET scans were performed on 83 patients. The clinical dilemma categories were inability to determine the extent of metastatic disease or suspected metastatic disease with the standard workup (n = 52), unclear ER status of the tumor (n = 31), and inability to determine which primary tumor caused the metastases (n = 17). The dilemmas were solved by 18F-FES PET in 87 of 100 scans (87%). In 81 of 87 scans, a treatment decision was based directly on 18F-FES PET results (treatment change, 51 scans; continuance, 30 scans). The frequency of solved dilemmas was not related to the clinical dilemma category (P = 0.334). However, the frequency of solved dilemmas was related to whether scans were 18F-FES-positive (n = 63) or 18F-FES-negative (n = 37; P < 0.001). Conclusion: For various indications, the 18F-FES PET scan can help to solve most clinical dilemmas that may remain after the standard workup. Therefore, the 18F-FES PET scan has added value in BC patients who present the physician with a clinical dilemma.

Abstract PS3-06: Fluoroestradiol F18 positron emission tomography diagnostic performance to characterize estrogen receptor status in breast cancer

Abstract Background Estrogen receptor (ER) status by immunohistochemistry (IHC) of breast cancer tissue is currently used to direct endocrine therapy. Fluoroestradiol F18 (18F-FES) is a noninvasive method to determine the presence and ligand-binding function of the ER in metastatic breast cancer lesions throughout the body. Concordance of imaging and tissue assays should be established for 18F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. Objective We conducted a meta-analysis of published results comparing 18F-FES PET and tissue assays of ER status in patients with breast cancer. Method PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. We used hierarchical summary receiver-operating characteristic (HSROC) curve models for four analyses. -For the first three analyses, IHC was used as the standard for tissue reference assay: i)18F-FES PET performance for nonbreast lesions in patients with metastatic breast cancer; ii)18F-FES PET performance for breast tumors; iii)18F-FES PET performance for all lesions (combined analysis); -The last analysis assesses 18F-FES PET performance with all evaluable studies, which used a variety of standards for the tissue reference. Results PubMed and EMBASE searches identified 103 breast cancer studies involving 18F-FES PET, and 12 studies met the criteria for inclusion in our meta-analysis. Results are presented in Table 1. Tests of homogeneity did not find differences in sensitivity or specificity among the studies in the primary analysis or other analyses with IHC as the tissue reference standard. Examining all tumor sites and all breast cancer stages, our results are consistent with other published meta-analyses (Table 2). Conclusion A strong correlation has been demonstrated between ER status determined by IHC of tissue from a single lesion and 18F-FES PET in this meta-analysis, which validates the accuracy of 18F-FES PET assessment of metastatic ER status. These results suggest that 18F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. Moreover, 18F-FES has been approved by the FDA in May 2020 as an adjunct to biopsy in recurrent and metastatic breast cancer. Table 1: 18F-FES PET test accuracy resultsNumber of studiesPooled number of ER-positive lesionsSensitivity (95% confidence region)Pooled number of ER-negative lesionsSpecificity (95% confidence region)Nonbreast lesions, IHC4690.78 (0.65-0.88)440.98 (0.65-1)Breast lesions, IHC3600.86 (0.73-0.94)180.76 (0.52-0.90)Combined, IHC71430.83 (0.72-.90)640.83 (0.64-0.93)Combined, all reference standards112110.81 (0.73-0.87)1160.86 (0.68-0.94) Table 2: Comparison with other published meta-analysesStudyVan Kruchten 2013 1Evangelista 2016 2Chae 2019 3Combined, IHCSensitivity (95% Confidence Region)0.84 (0.73-0.91)0.82 (0.74-0.88)0.83 (0.72-0.91)0.83 (0.72, 0.90)Specificity (95% Confidence Region)0.98 (0.90-1.00)0.95 (0.86-0.99)0.93 (0.74-0.99)0.83 (0.64-0.93)1Van Kruchten et al., “PET Imaging of Oestrogen Receptors in Patients with Breast Cancer.”2 Evangelista et al., “18F-Fluoroestradiol Positron Emission Tomography in Breast Cancer Patients.”3 Chae et al., « Diagnostic Accuracy and Safety of 16α-[18F]Fluoro-17β-Oestradiol PET-CT for the Assessment of Oestrogen Receptor Status in Recurrent or Metastatic Lesions in Patients with Breast Cancer ». Citation Format: Peter Webner, Brenda F. Kurland, Jay R. Wiggins, Amandine Coche, Charlotte Fontan, Yann Bouvet, Chaitanya Divgi, Hannah M. Linden. Fluoroestradiol F18 positron emission tomography diagnostic performance to characterize estrogen receptor status in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-06.

Dual Tracers of 16α-[18F]fluoro-17β-Estradiol and [18F]fluorodeoxyglucose for Prediction of Progression-Free Survival After Fulvestrant Therapy in Patients With HR+/HER2- Metastatic Breast Cancer.

ObjectiveThe purpose of this study was to employ dual tracers 16α-[18F]fluoro-17β-estradiol (18F-FES) and [18F]fluorodeoxyglucose (18F-FDG) as imaging biomarkers in predicting progression-free survival (PFS) in ER-positive metastatic breast cancer (MBC) patients receiving fulvestrant therapy.MethodsWe retrospectively analyzed 35 HR+HER2- MBC patients who underwent 18F-FES and 18F-FDG PET/CT scans prior to fulvestrant therapy in our center. The SUVmax across all metastatic lesions on the PET/CT were assessed. The heterogeneity of ER expression was assigned by the presence of any 18F-FES negative lesions for patients with entirely 18F-FES positive lesions categorized into two groups by the median ratio of FES/FDG SUVmax, low FES/FDG, and high FES/FDG. PFS were estimated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazard model.ResultsIn total, 12 patients had both 18F-FES negative and positive lesions, indicating the heterogeneity of ER expression in metastatic lesions. These patients had a low median PFS of 5.5 months (95% CI 2.3–8.7). Of patients with entirely 18F-FES positive lesions, 11 had a low FES/FDG, and 12 had a high FES/FDG. These groups had a median PFS of 29.4 months (95% CI 2.3–56.5) and 14.7 months (95% CI 10.9–18.5), respectively. The patients were stratified in three categories based on incorporating both 18F-FES and 18F-FDG imaging results that were significantly correlated with PFS by univariate analysis (P < 0.001) and multivariate analysis (P = 0.006).Conclusion18F-FES and 18F-FDG PET could serve as prognostic imaging biomarkers for ER-positive MBC patients treated with fulvestrant therapy.

Abstract P5-11-02: Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer

Abstract Background: Selective estrogen receptor (ER) degraders (SERDs) result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor, palbociclib, in ER-positive (+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). We previously presented preliminary results (ASCO 2019). Here we describe safety, pharmacokinetics (PK), ER gene (ESR1)profiling and updated antitumor activity for SAR439859 monotherapy dose escalation. Methods: Part A of this open-label, Phase 1/2 first-in-human study (NCT03284957; TED14856) assessed SAR439859 dose escalation (3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Dose levels ranged from 20-600 mg once daily (QD). Primary objectives: dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended dose. Secondary objectives: safety, PK, tumor response (RECIST v1.1), pharmacodynamic (PD) inhibition of ER occupancy (18F-fluoroestradiol positron emission tomography[18F-FES PET] scan). Exploratory objective: mutation profiling of ESR1 (circulating tumor DNA was assessed for 12 ESR1 mutations at baseline and end of Cycle 2 using multiplex droplet digital polymerase chain reaction). Results: As of May 29, 2019, 16 patients were treated. Median age: 59.5 years (range 40-79); ECOG performance status: 0 (62.5%) or 1 (37.5%); median prior anticancer therapies in the advanced setting: 3 (range 1-8). All patients had ≥ 1 treatment-emergent adverse event (TEAE), mostly grade 1-2; most frequent were hot flushes, diarrhea, constipation, nausea (all 37.5%) and decreased appetite (31.3%). Most frequent TEAEs related to treatment were hot flushes (31.3%), diarrhea, nausea (both 25%), decreased appetite, constipation, night sweats, asthenia (all 18.8%), arthralgia and fatigue (both 12.5%); no event was grade ≥ 3. There were no DLTs at any of the five dose levels (maximum administered dose 600 mg QD); MTD was not reached. In 18F-FES PET scans, signal inhibition &amp;gt; 87% occurred with plasma concentrations &amp;gt; 100 ng/mL. PK profile showed rapid SAR439859 absorption (median tmax ~ 3 hours) and an apparent terminal half-life of ~ 8 hours after first administration. After repeated QD administration, there was no or low accumulation and exposure (Cmax/AUC0-24h) increased with doses up to 600 mg. Food intake did not have a major effect on exposure. Best overall response (BOR) was confirmed partial response (PR) in one patient at 150 mg QD (6.3%) and stable disease (SD) in eight patients (50.0%) including seven (43.8%) with long-term SD (≥ 24 weeks). Seven had progressive disease (43.8%). Tumor shrinkage &amp;gt; 10% was seen in eight patients (50.0%), without any dose dependency. ESR1 mutations were detected at baseline in 11 patients (68.8%), with five patients harboring &amp;gt; 1 mutation. Similar BOR was seen regardless of ESR1 mutation status with SD seen in 54.5% (6/11) of patients with ESR1 mutations and SD/PR seen in 60.0% (SD: 2/5; PR: 1/5) of patients with wild-type ESR1. Conclusions: SAR439859 demonstrated a favorable safety profile and high ER occupancy in pretreated patients with ER+/HER2- mBC. Most patients had ESR1 mutations. Preliminary antitumor activity was encouraging in both ESR1 mutated and wild-type patients. With no DLTs and no MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK. Additional data on PK, PD, antitumor activity and the ESR1 mutational profile, and any correlations, will be presented. Funding: Sanofi. Citation Format: Mario Campone, Aditya Bardia, Gary A Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Jeffrey Ming, Marina Celanovic, Hannah M Linden. Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-02.

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

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 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 (Kd) 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 μCi) of 18F-FES. A 10-fold-lower injected dose of 0.555 MBq (15 μCi) 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. Kd 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.

Developing a personalized treatment model based on molecular biomarkers and molecular imaging in breast cancer

Risk stratification in breast cancer can be done with either bio markers or 18F FDG a marker of glucose metabolism demonstrating tumor aggressiveness. The receptor status also plays an important role in predicting outcome as well as has a significant role in personalizing treatment protocols. In vivo receptor imaging has also made an inroad from the bench to the bed side. Hormone positivity has an impact on both treatment planning and prognosis and therefore imaging the ER receptor plays an important role. 18F-FES PET CT helps in resolving diagnostic dilemma and also planning further management. Estrogen is involved in the growth of both normal and cancerous breast tissues and a uniform expression of receptor is an exception rather than a rule. At the same time the expression in primary tumor and the metastatic sites may be different which may further prompt the need for imaging. FES PET-CT scan in combination with FDG PET-CT scan can be used as a problem solving modality in deciding the regimen. Our results point to this and a common rule of thumb could be well differentiated hormone positive tumor with FDG uptake less than FES uptake is unlikely to benefit from cytotoxic chemotherapy and would be an ideal candidate to be treated with hormone or vice versa. In the coming years and in future we hope that the treatment of breast cancer has a very high potential to be personalized based on PET scan (both FDG and FES) and other molecular bio markers giving early and clear indications to the treating oncologist as to where the disease is heading and how the treatment regimen needs to be modified. In this presentation I will discuss how a combination of conventional FDG PET-CT and FES PET-CT along with the receptor status can help in precision management of breast cancer based on our work and literature.

18F-Fluoroestradiol Tumor Uptake Is Heterogeneous and Influenced by Site of Metastasis in Breast Cancer Patients.

Heterogeneity of estrogen receptor (ER) expression in breast cancer is recognized. However, knowledge about varying expression across metastases and surrounding normal tissue in patients is scarce. We therefore analyzed 16α-18F-fluoro-17β-estradiol (18F-FES) PET to assess ER expression heterogeneity. Methods:18F-FES PET on accredited PET/CT camera systems performed in patients with ER-positive metastatic breast cancer November 2009-December 2014 was analyzed. Lesions with an SUVmax 1.5 or more were considered ER-positive, but liver lesions were excluded given high background liver signal. CT lesions with a diameter 10 mm or more were included. We used multilevel linear-mixed models to evaluate determinants of 18F-FES uptake. Cluster analysis was performed with different imaging features per patient as input variables. Results: In 91 patients, 1,617 metastases in bone (78%), lymph node (15%), lung (4%), or liver (2%) were identified by CT (11.2%), PET (56.6%), or both (32.2%). Median tumor uptake varied greatly between patients (SUVmax, 0.54-14.21). 18F-FES uptake in bone metastases was higher than in lymph node and lung metastases (geometric mean SUVmax, 2.61 [95% confidence interval (CI), 2.31-2.94] vs. 2.29 [95% CI, 2.00-2.61; P < 0.001] vs. 2.23 [95% CI, 1.88-2.61; P = 0.021]), respectively. Cluster analysis identified 3 subgroups of patients characterized by particular metastatic sites and 18F-FES PET/CT features. SUVmax in surrounding normal tissue, highest in the bones, varied per patient (range, 0.7-3.3). Conclusion:18F-FES uptake is heterogeneous in tumor and normal tissue and influenced by anatomic site. Different patterns can be distinguished, possibly identifying biologically relevant ER-positive metastatic breast cancer patient subgroups.

18F-Fluoroestradiol Positron Emission Tomography in Breast Cancer Patients: Systematic Review of the Literature & Meta-Analysis.

The aim of the study was to determine the correlation between 16α-18F-fluoro- 17β-estradiol (18F-FES) uptake and the expression and functionality of estrogen receptors (ERs), as well as to evaluate the ability of 18F-FES PET to predict the response to hormonal therapy (HT) in patients with locally advanced or metastatic breast cancer (BC). Literature searches in the major literature databases were carried out in order to select English-language articles dealing with 18F-FES PET and BC. Studies that included patients with BC undergoing 18F-FES PET alone or in combination with other imaging modalities and included the absolute numbers of true-positive, true-negative, false-positive and false-negative test results were selected. We found 23 journal articles, published between 1988 and December 2014, that critically evaluated the role of 18F-FES PET in BC patients. Two separate meta-analyses were carried out: 1- to assess the correlation between 18F-FES uptake and ER expression and 2- to determine the predictive value of 18F-FES in response to HT. For the first, we considered nine selected studies with a total of 238 patients. A pooled sensitivity of 82% (95% CI: 74-88%) and a pooled specificity of 95% (95% CI: 86-99%) for the evaluation of ER functional status by 18F-FES PET were found. Seven studies, with a total of 226 patients, were considered eligible for the analysis of prediction for response. The pooled sensitivities and specificities were 63.9% (95% CI: 46.2-79.2%) vs. 66.7% (95% CI: 52.1-79.2%), and 28.6% (95% CI: 17.3-42.2%) vs. 62.1% (95% CI: 48.4-74.5%), for a SUV cutoff of 1.5 and 2.0, respectively. A good correlation between 18F-FES uptake and ER expression by immunohistochemistry emerges, while the role of 18F-FES in predicting the response to endocrine therapy in advanced BC remains undetermined.

18F-Fluoroestradiol PET: Current Status and Potential Future Clinical Applications.

Estrogen receptor (ER) expression in breast cancer is associated with a more favorable prognosis and is necessary for a response to endocrine therapies. Traditionally, ER expression is assessed by in vitro assays on biopsied tumor tissue. However, recent advances have allowed in vivo evaluation of ER expression with (18)F-fluoroestradiol ((18)F-FES) PET. Clinical studies have demonstrated the use of (18)F-FES PET as a method for quantifying in vivo ER expression and have explored its potential as a predictive assay and method of assessing in vivo pharmacodynamic response to endocrine therapy. This review outlines the biology and pharmacokinetics of (18)F-FES, highlights the current experience with (18)F-FES in patient studies on breast cancer and other diseases, and discusses potential clinical applications and the possible future clinical use of (18)F-FES PET.

Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader.

Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-(18)F-fluoroestradiol ((18)F-FES) PET for fulvestrant dose optimization in a preclinical ER(+) breast cancer model. In vitro, (18)F-FES retention was compared with ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER(+)) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 mg), or high-dose (5 mg) fulvestrant treatment groups (5-7 per group). Two and 3 days after fulvestrant treatment, PET/CT was performed using (18)F-FES and (18)F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 immunohistochemistry. In vitro, we observed a parallel graded reduction in (18)F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of (18)F-FES PET mean standardized uptake value (SUV(mean)) with fulvestrant treatment but no significant difference among the treatment groups in (18)F-FDG PET SUV(mean). We demonstrated that (18)F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative (18)F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patients with breast cancer.

Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17β-estradiol PET/CT.

The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status. (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

In Vivo Imaging of Brain Estrogen Receptors in Rats: A 16α-18F-Fluoro-17β-Estradiol PET Study

The steroid hormone estrogen is important for brain functioning and is thought to be involved in brain diseases, such as Alzheimer disease and depression. The action of estrogen is mediated by estrogen receptors (ERs). To understand the role of estrogens in brain functioning, it is important to study ERs in the brain. The aims of the present study were to determine whether ERs could be measured in the rat brain by PET with the ER ligand 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) and to evaluate whether tracer uptake was affected by endogenous estrogen. Small-animal PET was used to determine (18)F-FES uptake in female rats in the diestrous phase of the estrous cycle, the proestrous phase, and after ovariectomy. Coinjection of (18)F-FES with 17β-estradiol was performed to determine whether tracer binding was specific for ERs. Additionally, (18)F-FES uptake was quantified with kinetic modeling in female rats in the proestrous phase and after ovariectomy and in male rats. The highest levels of uptake of (18)F-FES were found (in descending order) in the pituitary, hypothalamus, bed nucleus of the stria terminalis, and amygdala. Other brain regions showed low levels of brain uptake. The level of (18)F-FES uptake was higher in the pituitary and hypothalamus in rats after ovariectomy than in rats in the proestrous phase. Coinjection with 17β-estradiol resulted in a decrease in (18)F-FES uptake in the pituitary and hypothalamus. The volume of distribution and binding potential determined with kinetic modeling were higher in the pituitary than in the other brain regions in all 3 groups. No differences were found among the groups. (18)F-FES PET imaging of ER availability in the rat brain is feasible for brain regions with high ER densities.