Fluoroestradiol Research Articles

Radiosynthesis and Preclinical Evaluation of 18F-Labeled Estradiol Derivatives with Different Lipophilicity for PET Imaging of Breast Cancer.

About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER- MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60-90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer.

Uterine Uptake of Estrogen and Progestogen-Based Radiotracers in Rhesus Macaques with Endometriosis.

Endometriosis is an estrogen-dependent disorder of menstruating primates where tissues similar to the inner lining of the uterus exist "ectopically" outside of the uterus. The ectopic endometrium, like the endometrium within the uterus, expresses estrogen receptors (ER) and progesterone receptors (PR) and undergoes hormone-dependent cell proliferation and bleeding each menstrual cycle. The goal of this study was to conduct abdominopelvic positron emission tomography (PET) scans with computed tomography (CT) imaging of rhesus macaques (Macaca mulatta) using radiotracers that target ER and PR [16α-[18F]fluoroestradiol (FES) and 12-[18F]fluoro-furanyl-nor-progesterone (FFNP)] in individuals with and without endometriosis. We also aimed to determine if menstrual cycle phase and/or the presence of endometriosis affected the uptake of these radiotracers. Rhesus macaques with either clinically diagnosed endometriosis (n = 6) or no endometriosis (n = 4) underwent PET/CT scans with FES. A subset of the animals also underwent PET/CT scans with FFNP. Standard uptake values corrected for body weight (SUVs) were obtained for each radiotracer in target and background tissues (e.g., intestinal). We performed repeated measure analysis of variance tests to determine how uterine and background uptake differed with scan time, phase of the menstrual cycle, and disease state. Abdominopelvic PET/CT could not resolve small, individual endometriotic lesions. However, macaques with endometriosis displayed higher uterine uptake compared to those without the disorder. Radiotracer uptake differed by menstrual cycle phase with increased uterine uptake of both radiotracers in the proliferative phase of the menstrual cycle. Background intestinal uptake of FFNP increased over time after infusion, but only during the proliferative phase. PET/CT with FES and FFNP support the concept that ER and PR levels are altered in individuals with endometriosis. This highlights the impact of the disease on typical reproductive tract function and may provide a novel pathway for the identification of individuals with endometriosis.

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.

18F-Fluoroestradiol: Current Applications and Future Directions

In the United States, breast cancer is the second leading cause of cancer death in all women and the leading cause of cancer death in Black women. The breast cancer receptor profile, assessed with immunohistochemical staining of tissue samples, allows prediction of outcomes and direction of patient treatment. Approximately 80% of newly diagnosed breast cancers are hormone receptor (HR) positive, which is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positive. Patients with ER-positive disease can be treated with therapies targeting the ER; however, the assessment of ER expression with immunohistochemical staining of biopsy specimens has several limitations including sampling error, false-negative results, challenging or inaccessible biopsy sites, and the inability to synchronously and serially assess all metastatic sites to identify spatial and/or temporal ER heterogeneity. In May 2020, after decades of research, the U.S. Food and Drug Administration approved the PET radiotracer fluorine 18 (18F) fluoroestradiol (FES) for clinical use in patients with ER-positive recurrent or metastatic breast cancer as an adjunct to biopsy. FES binds to the ER in the nucleus of ER-expressing cells, enabling whole-body in vivo assessment of ER expression. This article is focused on the approved uses of FES in the United States, including identification of a target lesion for confirmatory biopsy, in vivo assessment of biopsy-proven ER-positive disease, and evaluation of spatial and temporal ER heterogeneity. FES is an example of precision medicine that has been leveraged to optimize the care of patients with breast cancer. © RSNA, 2023 See the invited commentary by Fowler in this issue. Quiz questions for this article are available through the Online Learning Center.

Imaging for illuminating actionable pathways in breast cancer.

Nuclear medicine has the potential to explore and illuminate several pathways in breast cancer (BC) offering different radiopharmaceuticals for positron emission tomography (PET) designed to target specific tumor characteristics. The aim of this critical review is to give an overview about emerging opportunities in PET imaging, underlining the future potential contribution in the management of BC patients. Beside 2-deoxy-2-[ 18 F]-fluoro- d -glucose (FDG), new generation tracers for PET imaging have been recently proposed to investigate specific characteristics in breast cancer, both targeting tumor cells and the tumor micro-environment (TME). FDG-PET is a procedure that received extensive clinical validation. However, its role in BC is still suboptimal due to the low-FDG avidity of specific tumor subtypes. Human epidermal growth receptor-2 and integrin targeted PET radiotracers might provide useful information selecting patients more likely to respond to target therapy. FluoroEstradiol (FES) is a FDA-approved PET radiotracer targeting the estrogen receptor (ER), useful to investigate metastatic ER+ patients, to assess in vivo ER heterogeneity and to evaluate hormonal therapy efficacy. Inhibitors of the fibroblast activation protein (FAPi) targeting the cancer-associated fibroblast can explore the TME with PET imaging. FAPi is also proposed a theranostic agent for radio-ligand therapy.

Radiosynthesis and validation of [18 F]fluoroestradiol in a Synthra plus research platform for use in routine clinical practice.

In this practitioner protocol, the optimization of the radiochemical synthesis of [18 F]fluoroestradiol (FES) on the Synthra RNplus research automated platform is described in detail and a quality control (QC) summary of three validation productions is presented. In comparison with published synthesis methods developed on other platforms, the yield was considerably improved (40%-45% ndc). The other important improvement is the reduction of the required concentration of H2 SO4 avoiding the production of high concentrations of acidic vapors that can deteriorate the module. Purification was achieved by solid phase extraction, and the required adaptation of an external heating plate to the module to evaporate the ethanol is also described. The product was obtained with high radiochemical purity and fulfilled all the requirements of current Good Manufacturing Practice (cGMP). The final product is formulated as a sterile, pyrogen-free solution suitable for human injection. To the best of our knowledge, this is the first report of FES production using this type of module.

Abstract P3-02-02: FES-dedicated breast PET uptake in early-stage ER+ breast cancers

Abstract BACKGROUND: Patients with ER+ breast cancer may have a recurrence risk of aggressive disease. While clinical evidence suggests that ER+ tumors are responsive to endocrine therapy, up to one-third of patients with early-stage ER+ disease may not respond to endocrine therapy. Tumor biologic factors such as ER functionality, cell proliferation, and molecular traits may influence endocrine treatment responsiveness and long-term recurrence risk. More comprehensive tools are needed to depict the primary breast tumor. [18F]fluoroestradiol (FES) is a radiotracer developed for positron emission tomography (PET) imaging of ER status. We used FES with a high-resolution dedicated breast PET (dbPET) to quantify ER expression in primary ER+ tumors and assessed the relationship between FES uptake and tumor characteristics. METHODS: With IRB approval, patients with biopsy-proven ER+/HER2- breast cancer were imaged using dbPET with 5 mCi of FES before treatment. FES uptake (SUVmax, SUVmean, and SUVpeak), background parenchymal uptake (BPU), tumor uptake volume (TUV), and tumor to background ratio (TBR) were calculated. Background values (SUVbkg) were obtained from the normal region of the ipsilateral breast. Lesions with background-corrected SUVmax 2 times higher than SUVbkg were considered FES avid. Tumor size (longest diameter) was measured by MRI. The histologic subtype, ER expression, tumor grade, and Ki67 were obtained from core biopsies before treatment. Ki67 was dichotomized to low and high using a 20% cutoff. Spearman’s rank correlation was used to assess the correlation between FES uptake and tumor size. Differences between FES uptake, histologic subtype, and Ki67 were compared using a Wilcoxon rank-sum test. RESULTS: 19 treatment-naïve patients were included in this analysis as part of an ongoing study. Patient and tumor characteristics are listed in Table 1. While all patients had ER positivity >90% by immunohistochemistry (IHC), we observed varying FES avidity in ER+ breast cancers, with 14 FES avid and 5 non-FES avid lesions. There was a statistically significant difference between FES avid vs. non-avid lesions measured by all uptake metrics except BPU. FES uptake in invasive ductal carcinoma was similar to invasive lobular carcinoma. FES uptake correlated with tumor size, with the highest correlation ρ = 0.58, 95% CI (0.17, 0.84), p=0.012, detected in TUV. FES uptake was associated with Ki67, with all uptake metrics except BPU showing a statistically significant difference between high and low Ki67 expression (Table 2). CONCLUSION: We found that not all lesions that were highly ER+ by IHC were FES avid. FES-dbPET captures information from the entire tumor, providing a more comprehensive assessment of functional ER status than IHC of a limited tumor sample. Moreover, FES uptake correlates with tumor size and cell proliferation. This is an ongoing study; additional data may help to guide endocrine therapy decisions. Future studies with a larger cohort are planned to assess the relationship between FES uptake and tumor grade and molecular risk profiles. Table 1.Patient and tumor characteristicsCharacteristicsNo. of patientsTotal N=19Age (median (IQR))56.0 (21.5)Pre-menopausal7Post-menopausal12Histologic subtypeInvasive ductal carcinoma (IDC)6Invasive lobular carcinoma (ILC)13Tumor size (N=18) (MRI LD (cm), median (IQR))3.2 (4.1)Tumor grade1421332Ki67Low12High6Unknown1FESNon-avid5Avid14 Table 2.Summary of baseline FES uptake valuesTumor Size (cm)FES AvidityHistologic SubtypeKi67Spearman CorrelationAvid vs. Non-avidILC vs. IDCHigh vs. Lowρ (95%CI)P-valueMedian Diff (95%CI)P-valueMedian Diff (95%CI)P-valueMedian Diff (95%CI)P-valueSUVmax0.51 (0.054, 0.79)0.0318.02 (3.55, 11.9)0.0010.187 (-8.04, 6.32)0.976.38 (2.36, 11.6)0.017SUVmean0.31 (-0.18, 0.68)0.2042.42 (1.47, 3.49)0.001-0.477 (-1.96, 1.37)0.571.61 (0.81, 2.77)0.028SUVpeak0.46 (-0.0053, 0.76)0.0533.16 (1.42, 5.2)0.003-0.583 (-3.76, 2.61)0.633.16 (1.32, 4.66)0.013BPU-0.09 (-0.53, 0.39)0.723-0.33 (-1.25, 0.46)0.3790.226 (-0.58, 1.19)0.40-0.49 (-1.49, 0.28)0.122TUV (cm3)0.58 (0.15, 0.82)0.0125.45 (1.09, 12.5)0.005-2.82 (-12.5, 4.06)0.405.9 (0.98, 12.66)0.021TBR0.5 (0.047, 0.79)0.0333.48 (2.2, 13.5)0.001-0.295 (-11.9, 7.42)0.9010.2 (1.47, 13.49)0.028 Citation Format: Ella F. Jones, Deep K. Hathi, Julissa Molina-Vega, David C. Newitt, Courtney Lawhn-Heath, Kimberly M. Ray, Bonnie N. Joe, Diane Heditsian, Susie Brain, Rita A. Mukhtar, A. Jo Chien, Hope S. Rugo, I-SPY 2 TRIAL Consortium, I-SPY 2 TRIAL Imaging Working Group, Laura J. Esserman, Nola M. Hylton. FES-dedicated breast PET uptake in early-stage ER+ breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-02.

Abstract P3-02-01: Initial experience of FES-dedicated breast PET imaging of early-stage ER+ invasive lobular carcinoma

Abstract BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, representing 15% of all invasive breast cancers. Most ILC tumors are estrogen receptor-positive (ER+) and may respond to endocrine therapy. However, tumor biologic factors such as ER functionality, cell proliferation, and molecular traits may influence endocrine treatment response and long-term recurrence risk, thus necessitating a comprehensive approach to characterize the primary breast tumor. [18F]fluoroestradiol (FES) is a radiotracer developed for positron emission tomography (PET) imaging of ER status. For this work, we studied the utility of imaging FES uptake in early-stage primary ER+ ILC lesions, using high-resolution dedicated breast PET (dbPET) to assess the relationship between FES uptake and tumor characteristics. METHODS: With institutional review board approval, patients with biopsy-proven ER+/HER2- ILC were prospectively imaged using dbPET with 5 mCi of FES before treatment. FES uptake (SUVmax, SUVmean, and SUVpeak), tumor uptake volume (TUV), and background parenchymal uptake (BPU) values were calculated. Background values (SUVbkg) were obtained from the normal region of the ipsilateral breast. Lesions with background-corrected SUVmax 2 times higher than SUVbkg were considered FES-avid. Tumor grade, Ki67 cell proliferation index, and ER expression were obtained from core biopsies before treatment. Ki67 was dichotomized to low and high using a 20% cutoff1. Tumor size (longest diameter) was measured by magnetic resonance imaging (MRI). Spearman rank correlation was used to assess the relationship between FES uptake and tumor size. Differences between FES uptake at high and low Ki67 were compared using a Wilcoxon rank-sum test. RESULTS: 13 treatment-naïve ILC patients aged 32-82 years were included in this analysis (Table 1). Despite all lesions exhibiting strongly positive ER expression >90% by immunohistochemistry (IHC), we observed varying FES avidity with 9 FES avid and 4 FES non-avid ILC lesions. SUVmax, TUV, and TBR had substantial median differences between Ki67 high and low lesions (5.9, 4.3, and 9.6, respectively), but the difference did not achieve statistical significance. FES tumor uptake also correlated with tumor size, with the highest correlation observed for SUVpeak (ρ = 0.71 (95% CI: 0.22, 0.91), p=0.010) (Table 2). CONCLUSION: We found that not all highly ER expressing ILC by IHC were FES-avid. As FES-dbPET captures information from the entire tumor, it provides a more comprehensive assessment of functional ER status than IHC of a limited tumor sample. FES uptake in ILC also relates to tumor size and Ki67. This is an ongoing study; additional data may help to guide endocrine therapy decisions. Future studies with a larger cohort are planned to assess the relationship between FES uptake and tumor grade and molecular risk profiles. 1. Acs, B. et al. Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy. Diagn Pathol 12, 20, doi:10.1186/s13000-017-0608-5 (2017). Patient and tumor characteristicsCharacteristicsNumber of patients (Total N=13)Age (median (range))56.0 (32-80)Pre-menopausal3Post-menopausal10MRI tumor size (median (interquartile range)4.1 (2.4-6.8)Tumor grade132931Ki6712Low/High3/9FES13Avid/Non-avid9/4 Summary of FES uptake values and correlation coefficients.FES avidity (N=13)Ki67 (N=12)MRI tumor size (N=12)Avid vs Non-avidHigh vs LowSpearman rank correlationMedian Difference (95% CI)P-valueMedian Difference (95% CI)P-valueSpearman ρ (95% CI)P-valueSUVmax8.68 (2.86, 12)0.0075.9 (-19.5, 11.6)0.140.67 (0.16, 0.9)0.017SUVmean2.56 (1.43, 4.86)0.0071.34 (-4.14, 3.1)0.200.6 (0.042, 0.87)0.039SUVpeak2.86 (1.14, 4.59)0.0112.15 (-14.4, 3.72)0.190.71 (0.22, 0.91)0.01BPU-0.31 (-1.89, 1.02)0.82-0.73 (-2.34, 0.28)0.0960.01 (-0.57, 0.58)0.98TUV (cm3)5.45 (1.04, 10)0.014.3 (-185, 10)0.190.70 (0.21, 0.91)0.011TBR3.61 (2.2, 13)0.0079.57 (-19.6, 12.4)0.0640.66 (0.13, 0.89)0.02 Citation Format: Ella F Jones, Deep K Hathi, Natalia Konovalova, Julissa Molina-Vega, David C Newitt, Courtney Lawhn-Heath, Kimberly M Ray, Bonnie N Joe, Diane Heditsian, Susie Brain, I-SPY 2 TRIAL Imaging Working Group, I-SPY 2 TRIAL Consortium, A. Jo Chien, Laura J Esserman, Nola M Hylton, Rita A Mukhtar. Initial experience of FES-dedicated breast PET imaging of early-stage ER+ invasive lobular carcinoma [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-01.

Utility of [18F]-fluoroestradiol (FES) PET/CT with dedicated brain acquisition in differentiating brain metastases from posttreatment change in estrogen receptor-positive breast cancer.

Utility of [18F]-fluoroestradiol (FES) PET/CT with dedicated brain acquisition in differentiating brain metastases from posttreatment change in estrogen receptor-positive breast cancer.

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging.

Many breast and prostate cancers are driven by the action of steroid hormones on their cognate receptors in primary tumors and in metastases, and endocrine therapies that inhibit hormone production or block the action of these receptors provide clinical benefit to many but not all of these cancer patients. Because it is difficult to predict which individuals will be helped by endocrine therapies and which will not, positron emission tomography (PET) imaging of estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer, and androgen receptor (AR) in prostate cancer can provide useful, often functional, information on the likelihood of endocrine therapy response in individual patients. This review covers our development of three PET imaging agents, 16α-[18F]fluoroestradiol (FES) for ER, 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for PgR, and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) for AR, and the evolution of their clinical use. For these agents, the pathway from concept through development tracks with an emerging understanding of critical performance criteria that is needed for successful PET imaging of these low-abundance receptor targets. Progress in the ongoing evaluation of what they can add to the clinical management of breast and prostate cancers reflects our increased understanding of these diseases and of optimal strategies for predicting the success of clinical endocrine therapies.

Cross-Species Physiological Assessment of Brain Estrogen Receptor Expression Using 18F-FES and 18F-4FMFES PET Imaging.

A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) and its comparison with 16α-[18F]-fluoroestradiol (FES) in mice, rats, and humans with a focus on the brain uptake. Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field of view, brain uptake of discernable foci was measured and reported as SUVMax. Regardless of the species studied, 4FMFES and FES uptake were relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates thatthe signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

Abstract PD7-05: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer

Abstract Background: Modulation of estrogen activity and/or synthesis is a mainstay therapeutic strategy for ER+ breast cancer (BC). However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand-binding domain, that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that robustly suppress ER signaling in both ESR1 wild-type and mutant tumors may be of substantial therapeutic benefit. GDC-9545 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2−) advanced or metastatic BC (mBC). Patients were eligible if they had advanced or mBC that had progressed while being treated with adjuvant endocrine therapy for ≥ 24 months and/or endocrine therapy in the advanced or mBC setting for ≥ 6 months. No more than 2 prior treatments for advanced or mBC. Primary objective was to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-9545. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans and, when feasible, by performing biomarker analysis of pre- and on-study tumor biopsies. Plasma samples were collected for PK analyses and imaging for response assessment (CT and bone scans) were repeated every 8 weeks. Results: From November 27 2017 to February 1 2019 patients (n = 29) with a median age of 58 years (range 42-75) and a median number of prior therapies for mBC of 2 (range 1-4) were enrolled at 4 total daily dose levels (10, 30, 90 and 250 mg) given once daily (QD) while fasting. Increases in GDC-9545 exposure were approximately dose proportional and t1/2 was ~30 hours. Treatment related adverse events (AEs) were all Grade 1 or 2. The most common treatment-related AEs in ≥10% of patients were fatigue (21%, n=6), nausea (21%, n=6), hot flushes (17%, n=5), diarrhea (17%, n=5), arthralgia (17%, n=5), constipation (10%, n=3) and dyspepsia (10%, n=3). No dose-limiting toxicities, treatment-related serious adverse events (SAEs), Grade ≥ 3 events, or fatal events have been reported. Treatment interruption was required for 3 patients: one patient for a short episode of dyspepsia, vomiting, diarrhea, and dizziness; and two patients due to unrelated SAEs. In 14 patients with FES-PET avid disease at baseline and post-baseline scans, 11 (78%) showed complete or near complete (> 90%) suppression of FES uptake to background levels, including patients with ESR1 mutations. Evidence of reduced ER, PR, and Ki67 IHC values and an ER activity signature was observed in paired pre- and on-treatment biopsies (n = 7). Twelve of 27 patients (10 mg [n=2], 30 mg [4], 90 mg [4], 250 mg [2]) had either confirmed partial responses (n = 3) or were on study ≥ 24 weeks (CBR = 44%), including patients pretreated with CDK4/6i, fulvestrant or harboring baseline ESR1 mutations. The R2PD was 100 mg QD and was selected for dose-expansion in post- and pre/peri-menopausal women with and without palbociclib, which is ongoing. Updated results will be presented. Conclusions: GDC-9545 is well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in patients with advanced or ER+ mBC, including patients with ESR1 mutations. Dose expansion cohorts of GDC-9545 with or without palbociclib in post-menopausal and pre/peri-menopausal women with mBC are ongoing. Citation Format: Komal Jhaveri, Eric Paul Winer, Elgene Lim, Jose AlejandroPerez Fidalgo, Meritxell Bellet, Ingrid Alina Mayer, Valentina Boni, Jaymin M Patel, Aditya Bardia, Jose Manuel Garcia, Peter Kabos, Mary Gates, Ya-Chi Chen, Jill Fredrickson, Xiaojing Wang, Lori Sickels Friedman, Jill Spoerke, Steven Gendreau, Ciara Metcalfe, Lichuan Liu, Ching-Wei Chang, Sharareh Monemi, Monica Gonzalez, Ursula McCurry, Sandra Milan, Eric William Humke, Sherene Loi. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) 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 PD7-05.

Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol

Dedicated breast positron emission tomography (dbPET) is an emerging technology with high sensitivity and spatial resolution that enables detection of sub-centimeter lesions and depiction of intratumoral heterogeneity. In this study, we report our initial experience with dbPET using [F-18]fluoroestradiol (FES) in assessing ER+ primary breast cancers. Six patients with >90% ER+ and HER2− breast cancers were imaged with dbPET and breast MRI. Two patients had ILC, three had IDC, and one had an unknown primary tumor. One ILC patient was treated with letrozole, and another patient with IDC was treated with neoadjuvant chemotherapy without endocrine treatment. In this small cohort, we observed FES uptake in ER+ primary breast tumors with specificity to ER demonstrated in a case with tamoxifen blockade. FES uptake in ILC had a diffused pattern compared to the distinct circumscribed pattern in IDC. In evaluating treatment response, the reduction of SUVmax was observed with residual disease in an ILC patient treated with letrozole, and an IDC patient treated with chemotherapy. Future study is critical to understand the change in FES SUVmax after endocrine therapy and to consider other tracer uptake metrics with SUVmax to describe ER-rich breast cancer. Limitations include variations of FES uptake in different ER+ breast cancer diseases and exclusion of posterior tissues and axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. Further development to improve the field of view and studies with a larger cohort of ER+ breast cancer patients are warranted.

Abstract P6-01-04: Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol

Abstract Introduction: Breast cancer is a heterogeneous disease encompassing distinct subtypes with variable treatment response, relapse risk and overall prognosis. The majority of breast cancers are estrogen receptor-positive (ER+). While neoadjuvant endocrine therapy trials have been proposed to better identify therapeutic approaches for ER+ breast cancer, accurate quantification of the ER biomarker is necessary to assess the primary tumor and its likelihood of response to treatment. Dedicated breast positron emission tomography (dbPET) is an emerging technology with a high spatial resolution that enables detection of sub-centimeter lesions and depiction of intratumoral heterogeneity. In this study, we report our initial experience with [F-18]fluoroestradiol (FES) dbPET in assessing ER+ primary breast cancers. Materials and Methods: In an IRB-approved protocol, patients with biopsy-confirmed ER+ breast cancers were imaged with dbPET (MAMMI, OncoVision, Valencia, Spain) as a companion diagnostic tool to standard breast MRI. A dose of 5 mCi of FES was administered and patients were imaged in the prone position at 45 min post-injection. As part of routine clinical care, MR images were reviewed by a certified breast radiologist experienced in breast MRI. DbPET was reviewed by a radiologist specialized in nuclear imaging. Results: Five patients with ER+ breast cancers were imaged. Patient ages ranged from 33 to 64. Two patients with infiltrating lobular carcinomas measuring up to 6.7 cm and 5.3 cm at MRI demonstrated corresponding FES tumor-to-normal maximum standard uptake value (SUVmax) ratio at 4.81 and 2.49 respectively. A third patient demonstrated multifocal FES uptake corresponding to multifocal invasive ductal carcinoma and ductal carcinoma in situ with disease foci ranging from 9-13 mm. In this patient, the more posterior disease foci seen on MRI were excluded from the field of view of dbPET. One patient demonstrated an absence of FES uptake in her 3.4 cm infiltrating ductal carcinoma, which was due to estrogen receptor blockade from the recent administration of tamoxifen for a fertility preservation procedure. The final patient had metastatic cervical and axillary lymphadenopathy secondary to a breast primary that was occult on mammography and MRI. FES-dbPET also showed no corresponding uptake in the ipsilateral breast, possibly due to the small size of the primary lesion and/or low tumor to background uptake ratio. Conclusions: FES-dbPET imaging has potential as a diagnostic tool that is complementary to MRI in characterizing ER+ primary breast cancers. Limitations include variations of FES uptake in different ER+ breast cancer diseases and exclusion of posterior breast tissue near the chest wall and the axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. Further development to improve the dbPET field of view and studies with a larger cohort of ER+ breast cancer patients are therefore warranted. Citation Format: Jones EF, Ray KM, Mukhtar R, Li W, Franc BL, Esserman LJ, Joe BN, Pampaloni MH, Hylton NM. Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-01-04.

Abstract OT1-06-04: [18F] fluoroestradiol (FES) PET as a predictive measure for endocrine therapy in women with newly diagnosed metastatic breast cancer

Abstract Background: The majority of metastatic breast cancer patients have estrogen-receptor positive (ER+) disease. Therapy options include cytotoxic chemotherapy and ER-directed therapy, including endocrine therapy with or without molecularly targeted agents such as CK4/6 inhibitors. ER-targeted therapy is most commonly given first-line due to improved tolerability. However, not all patients will respond to first-line endocrine therapy due to intrinsic endocrine-therapy resistance mechanisms as well as tumor heterogeneity. There are no current methods in standard practice to inform on either of these issues. F-18 fluorestradiol (FES), an estrogen analogue has been considered the most promising ER imaging agent and is widely studied in breast cancer. FES positron emission tomography (PET) evaluates multiple tumor sites simultaneously and, thus, can inform on tumor heterogeneity of ER expression, and can measure ER binding in primary and metastatic sites (e.g., lymph nodes, lung, bone, and soft tissue). Like tissue ER expression, FES positivity, as measured by standardized uptake value (SUV), has been shown to predict response to endocrine therapy with selective ER modulators or aromatase inhibitors in first-line therapy or salvage settings in small studies. Typically, a significantly higher tumor SUV was noted in responders compared with non-responders. Since FES uptake can provide a better assessment of ER expression across all sites of metastatic disease, FES may provide more expansive information on ER expression.. Furthermore, preliminary studies examining FES-PET in metastatic breast cancer have suggested that baseline FES uptake may predict response to endocrine therapy. Trial Design: This is a prospective trial for patients about to start first line endocrine therapy for advanced ER+ breast cancer. Participants will undergo an FDG-PET within six weeks of FES-PET. FES-PET and serum hormone level to be completed prior to endocrine therapy. Patients may opt to have a 2nd FES-PET for test-re-test of FES-PET. Specific Aims: Primary Aim : To assess the relationship between ER expression measured by FES-PET/CT and clinical benefit (response plus stable disease) of newly diagnosed ER+ metastatic breast cancer to endocrine therapy. Secondary Aim: To assess the correlation between FES uptake in ER+ metastatic breast cancer and tissue ER expression. Eligibility: Patients must have confirmed ER+ HER2- metastatic breast cancer and planning to receive endocrine therapy with or without CK 4/6 inhibitors. Patient must NOT have a history of >1 line of administered chemotherapy for metastatic disease and may not have received endocrine therapy for advanced disease. Prior endocrine or chemotherapy in the adjuvant setting is allowed. Methods: Participants will undergo a F-18 fluorodeoxyglucose (FDG)-PET/CT within six weeks of FES-PET/CT. FES-PET/CT will be completed prior to treatment initiation. Patients may opt to have a 2nd FES-PET for test-re-test of FES-PET/CT Present and Target Accrual: A total of 13 out of 99 patients have been enrolled onto this imaging study. Citation Format: Linden H, Clark A, Fowler A, Novakova A, Mankoff D, Dehdashti F. [18F] fluoroestradiol (FES) PET as a predictive measure for endocrine therapy in women with newly diagnosed metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-06-04.

Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC)

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete (> 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10.

Abstract OT3-03-03: Challenges faced across borders to open European academic multicentre projects: The ET-FES program part of the ERA-Net TRANSCAN JTC 2011

Abstract Background The activation of international non-profit clinical trials funded by the European Commission (EC) is challenging given the cross-borders regulations and the need to follow specific timelines according to EC rules. We report here the logistic procedures and challenges faced by 4 academic centres from 4 different countries from the European Union (EU) for the activation of such program in metastatic breast cancer (MBC). Materials and Methods The primary objective of the ET-FES program is to validate the use of a new radiotracer 18F Fluoroestradiol (FES), targeting estrogen receptors, as a tool to better predict endocrine responsiveness in MBC, with PET/CT. The trial is sponsored by EO Galliera (Genoa, Italy) and brings together Italy, Spain, France and Germany. In 10/2012, ET-FES was approved for funding from EC under the Seventh Framework Programme after the first ERA-NET TRANSCAN Joint Transnational Call (JTC) for Proposals (2011) on validation of new biomarkers for personalized cancer medicine. Results The official start of the program was set up on 06/2013 by the Italian Ministry of Health. Time to institutional review board and to competent authority (CA) approvals were 1.5 and 11, 2 and 5, 3 and 16, and 13 and 14+ months in Italy, France, Spain and Germany respectively. Overall, no blocking comment was raised by the ethical committees; only minor clinical and methodological issues were raised in Germany and Spain. Issues from CA were raised in all countries except France (12, 21 and 23 queries in Italy, Spain and Germany respectively), on quality aspects of 18F-FES investigational medicinal product dossier. At the sponsor level, time to final agreement signature with Advanced Accelerator Applications, the 18F-FES manufacturing company, required 13 months. First patient could be enrolled in Italy 14 and 22 months after ethical committee approval and after the official start of the ET-FES project respectively. Conclusions As of May 2016, of 310 patients expected, only 28 have been enrolled from Italy. From a regulatory viewpoint and acknowledging that 18F-FES does not have yet any marketing approval in the EU, the ET-FES program approval process was timely completed at the ethical committee level in Italy, France and Spain. Time to CA approval varied across countries and was timely achieved only in France, due to requirements varying from CA to CA, stressing the serious lack of harmonized procedures although intended by the 2001/20/EC directive. Regarding sponsor's responsibilities (i.e. Italy), the administrative procedures needed to activate this type of EU projects remain critical, appealing for more tolerant time span in order to satisfy all the legal aspects on contracts by public bodies, according to national rules and laws. One needs to be very conscious of these timelines when applying to EU/EC calls, especially when the time allowed for the conduction of research is limited (3 years here), unless jeopardizing the entire multicentre and multinational effort. Citation Format: Brain E, Corradengo D, Oriana N, Piccardo A, Matteucci F, Cortes J, Harbeck N, Würstlein R, Piris A, Alberini J-L, Merlo DF, Degenhardt T, Turbiez I, Madar O, Monti M, Cesaro A, Rivitti E, Rollandi GA, Iacozzi M, Campazzi E, Campora S, Camporese D, Gennari A. Challenges faced across borders to open European academic multicentre projects: The ET-FES program part of the ERA-Net TRANSCAN JTC 2011 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-03-03.

Abstract CT231: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (>90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease > 6 months while 10 pts remain active on study with followup < 6 months. Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231

Abstract P1-13-01: Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer

Abstract Background: Evidence that ER can signal in both ligand-dependent and independent manner in endocrine resistant breast cancer (BC) provides rationale for therapies that are not only functional antagonists of ER but also reduce ER levels, thus targeting both modes of signaling. Furthermore, mutations in ESR1 affecting the ligand-binding domain (LBD) that drive ER-dependent transcription and proliferation in the absence of estrogen suggest that LBD-mutant forms are involved in mediating clinical resistance and next generation ER modulators with robust activity in both wild type and mutant ER tumors are needed. ARN-810 is a novel, orally bioavailable, ER antagonist that induces proteasomal ER degradation in BC cell lines at picomolar concentrations and tumor regression in tamoxifen-sensitive and resistant BC xenograft models. Methods: ARN-810 was tested using standard 3+3 dose escalation to assess safety, PK, and Recommended Phase 2 Dose (RP2D). Key eligibility criteria included ER+ (HER2-) metastatic BC progressing ≥ 6 months (m) on endocrine therapy and ≤ 2 prior chemotherapies. Pre- and on-study tumor biopsies were obtained when feasible. Pharmacodynamics was assessed by functional imaging with [18F]-fluoroestradiol (FES)-PET, tumor-based ER/PR/Ki67 IHC, and ER target gene expression. Plasma PK was assessed following a single dose and at steady-state. Anti-tumor activity was assessed by clinical benefit rate (CBR) [complete response, partial response, or stable disease ≥ 6m] and progression-free survival (PFS). Results: From April 2013 to June 2014, 32 patients (pts) (median age 61 (range 43 – 75); median number of prior therapies = 3 (range 1 – 7); visceral metastases 54%) were enrolled at 5 doses (100, 200, 400, 600, 800 mg) and 2 different regimens (once [QD] and twice daily) given orally with and without fasting. Increases in ARN-810 exposure were dose-dependent with no apparent food effect. At 4 weeks of treatment, complete reduction in FES uptake consistent with full receptor saturation and/or degradation was seen in 95% pts (21/22 scanned to date), including 2 pts with ESR1 mutations, suggesting ARN-810 exhibits greater ER occupancy than that recently reported for fulvestrant 500 mg (van Krutchen et al, ASCO 2014). Evidence of reduced ER levels and Ki67 staining was observed on treatment. To date, 19 pts (59.4%) remain on study with a preliminary CBR of 41%. RP2D, PFS and gene expression results will be provided at time of meeting. The most common adverse events were grades 1/2 nausea, diarrhea, fatigue, and abdominal pain. There was 1 dose limiting toxicity (grade 3 diarrhea) at 800 mg QD which led to expansion of that cohort, while in parallel, evaluation of the other dose regimens continues. No patients have discontinued the study due to toxicity. Conclusions: ARN-810 appears to be safe and tolerable, with predictable PK, promising anti-tumor activity, and pharmacodynamic evidence of target engagement, ER degradation and reduced tumor proliferation in heavily pre-treated metastatic ER+ BC. In Phase II, ARN-810 will be studied in patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations. Citation Format: Aditya Bardia, Maura N Dickler, Ingrid A Mayer, Eric P Winer, Umar Mahmood, Gary Ulaner, H Charles Manning, Peter Rix, Jeffrey H Hager, Debasish Roychowdhury, Edna Chow Maneval, Carlos L Arteaga, Jose Baselga. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-01.

Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer.

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.