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16α-18F-fluoro-17β-estradiol (18F-FES) is a positron emission tomography (PET) tracer characterizing the expression of the estrogen receptor (ER). As therapy can interfere with the kinetics and biodistribution of 18F-FES, the aim of this study was to describe the biodistribution of 18F-FES in patients with metastatic ER+ breast cancer undergoing treatment with rintodestrant (G1T48), a novel selective ER degrader. Methods: Eight patients underwent 18F-FES PET/CT imaging at baseline, 4-6 weeks during treatment with rintodestrant (interim) and after treatment. After intravenous administration of 200 MBq (+/- 10%) 18F-FES, a 50-min dynamic PET/CT scan of the thorax was performed, followed by a whole body PET/CT scan 60 min post-injection. Blood samples were drawn for measuring whole blood and plasma activity concentration and the parent fraction of 18F-FES. Volumes of interest (VOIs) were placed in the aorta ascendens and in healthy tissues on both dynamic and whole body PET scans. Standard uptake values (SUVs) and target-to-blood ratios (TBR) were calculated. Area under the curves (AUCs) of input functions and time-activity curves were calculated as a measure of uptake in different regions. Results:18F-FES concentration in whole blood (and plasma) significantly (P

Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200-1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received ≥2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in ≥10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for ≥24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (±8%) at doses ≥ 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored ≥1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, -3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270). Citation Format: Philippe Aftimos, Patrick Neven, Mark Pegram, Catharina Willemien Menke-van der Houven van Oordt, E. Claire Dees, Carolien Schröder, Agnes Jager, Iurie Bulat, Linnea Chap, Marina Maglakelidze, Erika Hamilton, Massimo Cristofanilli, Susanna Ulahannan, Jorianne Boers, Ramsha Iqbal, Adrian Crijanovschi, Curt D Wolfgang, Wenli Tao, Christina Sipes, Rajesh Malik, Sarika Jain. Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection [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 PS12-04.

BackgroundAccurate staging of early breast cancer (BC) patients is essential for tailored treatment. Currently, the preferred imaging modality for staging is positron emission tomography with [18F]Fluorodeoxyglucose (FDG PET) combined with a diagnostic computed tomography (CT) scan of the thorax/abdomen. However, FDG PET might be insufficient for detection of malignant lesions in grade 1–2, estrogen receptor positive (ER+) BC, due to its low metabolic activity. The main aim of this study was to retrospectively investigate the diagnostic accuracy of FDG PET in this patient population.Methods74 patients diagnosed with grade 1–2, ER + clinical stage IIB/III or locoregional recurrent BC were included. Suspect tumor lesions detected on conventional imaging (mammography, ultrasound, magnetic resonance imaging, diagnostic CT, bone scintigraphy) and FDG PET were confirmed with pathology or follow-up. FDG PET-positive lesions were (semi)quantified with standardized uptake values (SUV) and total lesion glycolysis (TLG), and these FDG PET parameters were correlated with pathological features such as histological subtype, grade, ER, PR and HER2 expression and mitotic activity index.ResultsPre-operative imaging identified 155 lesions that were pathologically verified. Based on pathology, 115/155 (74.2%) lesions identified on FDG PET were classified as true positive, i.e. malignant (in 67 patients) and 17/155 (10.8%) lesions as false positive, i.e. benign (in 9 patients); 7/155 (4.5%) as false negative (in 7 patients) and 16/155 (10.3%) as true negative (in 14 patients). FDG PET incorrectly staged 16/70 (22.9%) patients: 3/70 (4.3%) were downstaged whereas 13/70 (18.6%) were upstaged. SUV did not help to discriminate between true- and false positive lesions (median SUVmax 4.23, IQR: 2.54–6.37 vs. 3.07, IQR: 2.14–5.58, P = 0.44 respectively). For true positive lesions, FDG uptake correlated with histological subtype, showing higher uptake in ductal carcinoma compared to lobular carcinoma (P

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABAA receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-β estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17β-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further.

1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .

The target of the current study is to formulate letrozole loaded nanoemulsion (LET-NE) for the direct nose to brain delivery to reduce peripheral effects of letrozole (LET). LET-NE is compared against intraperitoneally administered free LET in kainic acid (KA) induced status epilepticus (SE) in mice. LET loaded nanoemulsion (LET-NE) was prepared by aqueous microtitration method using Triacetin, Tween 80 and PEG-400 as the oil phase, surfactant, and co-surfactant. Nanoemulsion was studied for droplet size, polydispersity index (PDI), zeta potential, percentage transmittance, drug content, surface morphology. TEM images of developed formulation demonstrated spherical droplets with a mean diameter of 95.59 ± 2.34 nm, PDI of 0.162 ± 0.012 and zeta potential of −7.12 ± 0.12 mV respectively. In in-vitro and ex-vivo drug release, LET-NE showed prolonged drug release profile as compared to suspension. SE was induced by KA (10 mg/kg, i.p.) in Swiss albino mice. Behavioral seizure monitoring, biochemical estimations, and histopathological examination were performed. The onset time of SE was significantly enhanced and % incidence of SE was reduced by intranasal administration of LET-NE as compared to KA and LET administered intraperitoneally. Biochemical estimations revealed that LET-NE effectively decreased levels of 17-β estradiol while the levels of 5α-Dihydrotestosterone (5α-DHT) and 3α-androstanediol (3α-Diol) were significantly increased in the hippocampus. In cresyl violet staining LET-NE showed better protection of the hippocampus from neurotoxicity induced by KA as compared to LET. Also, in gamma scintigraphy of mouse brain, intranasal administration of nanoemulsion exhibited the presence of high concentration of LET. The study demonstrates the anticonvulsant and neuroprotective effect of LET-NE probably by inhibition of aromatization of testosterone into 17-β estradiol, proconvulsant, and diverting the pathway into the synthesis of testosterone metabolites, 3α-Diol with known anticonvulsant and neuroprotective action. Brain targeting of LET-NE showed better anticonvulsant and neuroprotective action than LET.

Pitavastatin inhibits 3 hydroxy 3 methyl glutaryl coenzyme A (HMGCoA) reductase enzyme, preventing cholesterol synthesis along with elevating high density apolipoprotein A1 (Apo-A1). The present study was designed to evaluate cardioprotective potential of pitavastatin at 1 mg/kg/day and 3 mg/kg/day dose for 14 days in low dose isoproterenol (ISO) (5 mg/kg/day for 7 consecutive days) induced myocardial damage. ISO administration induced significant reduction in endogenous antioxidant enzymes like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and raised thiobarbituric acid reactive substances (TBARS) indicating activated lipid peroxidation. Along with this, a significant increase in level of cardiac injury biomarkers vie, creatine kinase (CK-MB), lactate dehydrogenase (LDH), aspartate amino transferase (AST), tumor necrosis factor (TNF-α) and transforming growth factor (TGF-β) as well as brain natriuretic peptide (BNP). Histological examination also revealed marked myocardial tissue damage in ISO treated rats. However, pretreatment with pitavastatin (3 mg/kg/day) significantly maintained nearly normal levels of cardiac biomarkers and oxidant antioxidant status as well as lipid peroxidation in ISO induced MI rats. Cardiac histological assessment and infarct size assessment also showed marked reduction in myocardial architecture alteration including infarct size as well as collagen deposition by pitavastatin that strongly supported biochemical findings. These observations strongly corroborate that pitavastatin prevents myocardial damages via up regulation of endogenous oxidants along with its hypocholesterolemic activity.

Background The SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC. Methods Postmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose. Results Currently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant). Conclusions The oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270). Clinical trial identification NCT03455270. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics. Disclosure E.C. Dees: Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): H3Biosciences; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): Meryx; Advisory / Consultancy, Research grant / Funding (institution): Novartis. P.G. Aftimos: Advisory / Consultancy: Boehringer Ingleheim; Advisory / Consultancy: Macrogenics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Amcure; Honoraria (self), Research grant / Funding (institution): Synthon; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Radius; Research grant / Funding (institution): Servier. C.W. Menke-van der Houven van Oordt: Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Novartis. E.G..E. De Vries: Research grant / Funding (institution): G1 Therapeutics; Advisory / Consultancy: NSABP; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Nordic Nanovector; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Synthon. M.D. Pegram: Advisory / Consultancy: G1 Therapeutics. J. Xiao: Full / Part-time employment: G1 Therapeutics. C. Sipes: Full / Part-time employment: G1 Therapeutics. C. Li: Full / Part-time employment: G1 Therapeutics. J.A. Sorrentino: Full / Part-time employment: G1 Therapeutics. R. Malik: Full / Part-time employment: G1 Therapeutics. A.P. Beelen: Full / Part-time employment: G1 Therapeutics. All other authors have declared no conflicts of interest.

Background: Accurate staging of patients with primary breast cancer is essential for an optimal treatment plan. The current imaging standard for staging, positron emission tomography/computed tomography with [18F]Fluorodeoxyglucose ([18F]FDG PET/CT), might be insufficient for detection of distant metastases, specifically in low grade, estrogen receptor positive (ER+) breast cancer, due to lower metabolic activity. The aim of this study was to investigate the efficacy of [18F]FDG PET/CT in staging patients with low-intermediate grade, ER+ breast cancer. Methods: 79 patients diagnosed with grade 1-2, ER+ clinical stage IIB/III or locoregional recurrent breast cancer were retrospectively included. Visual analysis was performed, comparing the lesions detected on conventional imaging modalities (mammography, ultrasound, magnetic resonance imaging, computed tomography, bone scintigraphy) with lesions detected on [18F]FDG PET/CT. Conventional imaging and/or pathology outcomes were considered as the gold standard for this comparison. Tracer uptake in each PET-positive lesion was (semi)quantified: volumes of interest were defined on the PET scan to determine standardized uptake values (SUVmax, SUVmean, SUVpeak), total lesion glycolysis (TLG) and metabolic tumor volume (MTV). These quantitative parameters were correlated with pathological features of tumors (i.e. histological subtype, grade, ER/PR/HER2 expression and mitotic activity index) to assess whether tracer uptake is influenced by these features. Results: Scans were analyzed visually and (semi)quantitatively. 370 lesions could be identified with all imaging modalities (primary lesions: 80, locoregional lymph nodes: 161, distant lesions: 129). Based on the gold standard, 226/370 (61.1%) lesions were interpreted as “true positive” on [18F]FDG PET, 134/370 (36.2%) as “false positive” and 10/370 (2.7%) as “false negative” on [18F]FDG PET (p = 0.016). “False positive” lesions were mainly located in the axilla region (e.g. reactive lesions), gynecological and gastro-intestinal tract (e.g. adenomas) whereas “false negative” lesions were predominantly located in osseous tissue. The average SUVmax for “true positive” and “false positive” lesions was 4.24 ± 2.97 and 3.96 ± 2.03, respectively. For “true positive” lesions SUVmax, SUVpeak, SUVmean and MTV correlated with histological subtype, showing higher uptake in ductal carcinoma compared to lobular carcinoma (p Conclusion: These preliminary data indicate that [18F]DGG PET/CT might not correctly identify a substantial amount of lesions and therefore could lead to incorrect staging of patients with low grade, ER+ breast cancer. This suggests that there is a need to improve current staging procedures. Citation Format: Ramsha Iqbal, Tuba Aras, Lemonitsa Mammatas, Wouter V. Vogel, Daniela E. Oprea-Lager, Hendrik M. Verheul, Ronald Boellaard, Catharina W. Menke-van der Houven van Oordt. Staging with [18F]FDG PET/CT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1415.