ThyroidVol. 32, No. S1 American Thyroid Association 2022 Annual MeetingFree AccessLate Breaking AbstractsPublished Online:11 Oct 2022https://doi.org/10.1089/thy.2022.29140.lb.abstractsAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail THURSDAY, OCTOBER 20, 2022LATE BREAKING ORAL 46Thyroid Cancer Clinical OralOUTCOMES OF ATA LOW‐RISK PEDIATRIC THYROID CANCER PATIENTS NOT TREATED WITH RADIOACTIVE IODINE THERAPYMya Bojarsky*1,2, Julia Baran3, Stephen Halada3, Amber Isaza3, Ken Kazahaya3,2, N Adzick3,2, Sogol Mostoufi‐Moab3,2, Andrew Bauer3,21Children's Hospital of Philadelphia, USA,2University of Pennsylvania, USA,3Children's Hospital of Philadelphia, USAObjective: To limit radiation exposure, the 2015 American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) mostly confined to the thyroid (N0 or minimal N1a disease). The impact of limiting RAIT on rates of remission for ATA low‐risk patients is not well described. This study explores remission rate with and without RAIT one‐year post‐initial treatment in ATA low‐risk pediatric DTC patients.Methods: Medical history, surgical pathology, somatic oncogenic alterations, and remission status were retrospectively reviewed for DTC patients who underwent thyroid surgery between 2010‐2020 at the Children's Hospital of Philadelphia. Clinical outcomes were compared between ATA low‐risk pediatric DTC patients treated with and without RAIT. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and one‐year disease status.Results: Of the 119 ATA low‐risk DTC patients (97 females), 47% and 53% were treated with and without RAIT, respectively. RAIT was used to treat 83% (35/42) of patients pre‐2015 compared to 27% (21/77) of patients post‐2015 (p < 0.01). Primary histologic subtype (p = 0.565) and regional lymph node staging (p = 0.151) demonstrated no significant differences. Patients treated without RAIT received more lobectomies (p < 0.01). Surgery pre‐2015 [OR = 18.2 95%CI(17.1‐19.3)], dominant tumor size [OR = 1.05 95%CI(1.02‐1.09)], and N1a disease [OR = 6.4 95%CI(5.2‐7.6)] were independent factors for receiving RAIT. No significant difference in one‐year remission status (p = 0.1059) was found between patients treated with (77%, 43/56) and without RAIT (78%, 49/63) over the course of the study. Post‐2015, 81% (17/21) treated with RAIT and 77% (43/56) treated without RAIT achieved one‐year remission (p = 0.740). RAIT administration, N1a disease, and surgery pre‐2015 were not independent risk factors for evidence of disease or indeterminate status; increasing dominant tumor size incurred clinically minimal risk [OR = 1.03 95%CI(1.00‐1.06)]. Forty‐five patients demonstrated somatic driver variants, including 15 RET/NTRK3 fusions (33%), 16 BRAFV600E (36%), 7 RAS (16%), 5 DICER1 (11%) and 2 PTEN (4%).Conclusion: Withholding RAIT for pediatric patients with minimal to no evidence of extrathyroidal DTC (ATA low‐risk) is clinically beneficial, avoiding exposure to radiation without a negative impact on remission rates one‐year after surgery. Continued surveillance is recommended to ensure stable, long‐term remission.LATE BREAKING ORAL 47Disorders of Thyroid Function Clinical OralLONG‐TERM MORTALITY AND CARDIOMETABOLIC EFFECTS OF TREATMENT FOR HYPERTHYROIDISM: EGRET STUDYBarbara Torlinska1, Jonathan Hazlehurst1, Krishnarajah Nirantharakumar1, G Thomas1, Julia Priestley2, Keith Abrams3, Kristien Boelaert*11University of Birmingham, United Kingdom,2British Thyroid Fundation, United Kingdom,3University of Warwick, United KingdomObjectives: Hyperthyroidism has been linked to long‐term cardiovascular and metabolic morbidity and increased mortality. Current evidence indicates differential cardio‐metabolic effects from antithyroid drugs (ATD) and definitive treatment options (radioiodine or thyroidectomy). We aimed to assess differences in mortality and cardiometabolic outcomes depending on treatment modality to better inform patient‐clinician decision‐making.Methods: We identified 62,474 patients with newly diagnosed hyperthyroidism, treated with ATD, radioiodine or thyroidectomy from a UK population‐based electronic health record database (>2,000 contributing primary care practices, >16M patients). Health records were linked with Office for National Statistics (ONS) mortality data, (Hospital Episode Statistics) HES, and Index of Multiple Deprivation. All‐cause mortality, major cardiovascular events (MACE: cardiovascular death, heart failure or stroke) and post‐treatment obesity diagnosis were studied. A “target trial” approach was used to allow to elucidate causal effects from observational data; average treatment effects (ATE) were estimated. Confounding was controlled for using inverse‐probability weights (IPW) with regression adjustment. Mortality was assessed as time‐to‐event; other outcomes were modelled as binary (funded by NIHR RfPB, NIHR200772).Results: Patients treated with ATD comprised 73.4% of the cohort; 19.5% were treated with radioiodine, and 7.1% with thyroidectomy. Patients were followed for a median of 10 years (IQR: 6‐15). Estimated mean survival was 11.7 years with ATD treatment. Definitive treatment increased survival: radioiodine by 1.7y. (95%CI: 1.1‐2.4; P < 0.001) and thyroidectomy by 1.4y. (0.5‐2.4; P = 0.003). The estimated risk of MACE if the population were treated with ATD was 9.9% (9.6‐10.3), which increased by an additional 0.7% (0.1‐1.3; P = 0.02) with radioiodine but not with thyroidectomy (0.02% [‐0.8 ‐ 1.2], P = 0.7). The estimated risk of post‐treatment obesity was 7.6%, which increased by 0.9% (0.3‐1.6, P = 0.005) with radioiodine and 1.7% (0.5‐2.8, P = 0.003) with thyroidectomy.Conclusion: EGRET is the first large study using population‐based linked community and hospital data to elucidate the long‐term consequences of treatment modalities for hyperthyroidism. We confirmed a decreased mortality in patients undergoing definitive treatment whereas a slightly increased risk of obesity was found in patients treated with radioiodine and surgery. Compared to medical treatment, a small increase in cardiovascular events was noted with radioiodine.LATE BREAKING ORAL 48Thyroid Cancer Clinical OralBRAF/MEK INHIBITOR PLUS IMMUNOTHERAPY FOR BRAFV600E‐MUTATED ANAPLASTIC THYROID CARCINOMAMaria Cabanillas*, Naifa Busaidy, Mark Zafereo, Maria Gule‐Monroe, Suyu Liu, Renata Ferrarotto, Charles Lu, Neil Gross, Bryan Fellman, Horiana Grosu, Michelle Williams, Priyanka Iyer, Anastasios Maniakas, Jennifer Wang, Ramona DaduThe University of Texas MD Anderson Cancer Center, USABackground: Dabrafenib/trametinib (DT) is a BRAF/MEK inhibitor combination approved for BRAFV600E mutated ATC (BRAFm‐ATC) based on a phase 2 clinical trial. The median overall survival (OS) for patients on the DT trial was 14 months. Single‐agent immunotherapy (anti‐PD1, spartalizumab) has a median OS of 5.9 months. We sought to improve OS by combining a BRAF/MEK inhibitor + anti‐PDL1 immunotherapy in BRAFm‐ATC.Methods: BRAFm‐ATC patients with performance status <3 were enrolled on a prospective, single institution, non‐randomized trial. Patients had to be naïve to kinase inhibitors and immunotherapy. Patients received vemurafenib 960mg BID/cobimetinib 60mg daily for 28 day run‐in, followed by addition of atezolizumab 840mg IV Q2 weeks, at which time vemurafenib dose was decreased to 720mg BID. Patients unable to swallow used alternative drug administration (ADA; crushed vemurafenib, suspension cobimetinib; po or feeding tube). Response rate (RR) was measured by RECISTv1.1. Patients could undergo surgery and radiation while on trial. The primary endpoint was OS, estimated by Kaplan‐Meier method. In a post‐hoc analysis we compared the OS in our trial to the OS in the DT trial. To perform side‐by side comparison we reconstructed the survival data from the Kaplan‐Meier curve from the DT trial.Results: Between August 2017‐March 2020, 18 BRAF‐mutated ATC patients were enrolled. 82% of patients had distant metastasis at time of trial enrollment; two patients required ADA. Median follow‐up time was 33 months (range: 17.5‐54). Response rate (RR) was 76%: CR 1/18 (6%), PR 12/18 (66%), SD 4/18 (22%: all with regression of target lesions), 1 PD (6%). Seven (41%) patients had complete tumor resection after treatment with vemurafenib/cobimetinib/atezolizumab. Median OS was not reached in our trial, but the 2‐year OS was estimated to be 0.72 (95% CI: 0.46, 0.87). This was higher than the 2‐year OS of 0.32 (95% CI: 0.16, 0.48) in patients on DT trial (p = 0.0092).Conclusions: The addition of immunotherapy to BRAF/MEK inhibitor improves OS in BRAFm‐ATC. A significant number of patients were able to undergo resection of primary tumor due to favorable response to treatment which could have contributed to the improvement in OS.LATE BREAKING ORAL 49Thyroid Cancer Clinical OralBIOCHEMICAL RESPONSE OF DONAFENIB IN LOCALLY ADVANCED/METASTATIC, RADIOACTIVE IODINE‐REFRACTORY, DIFFERENTIATED THYROID CANCER PATIENTS (DIRECTION)Yansong Lin*1, Shukui Qin2, Hui Yang3, Feng Shi4, Aimin Yang5, Xingmin Han6, Bin Liu7, Zhiyong Li8, Qinghai Ji9, Lijun Tang10, Zhiyong Deng11, Yong Ding12, Wei Fu13, Xianhe Xie14, Linfa Li15, Xiaohui He16, Zhongwei Lv17, Qingjie Ma18, Zan Shen19, Zhuming Guo20, Zhendong Chen21, Yali Cui22, Jian Tan23, Zairong Gao24, Shanghua Jing25, Keyi Lu26, Xianyang Luo27, Yuan Zhang28, Yong Fang29, Zhendong Li30, Yizhuang Cheng31, Shangtong Lei32, Xia Luan33, Guang Chen34, Guihua Wang35, Liqing Wu36, Lingling Liu361State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & PUMC, China,2Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, China,3The Affiliated Cancer Hospital of Zhengzhou University, China,4Hunan Cancer Hospital, China,5The First Affiliated Hospital of Xi'an Jiaotong University, China,6The First Affiliated Hospital Of Zhengzhou University, China,7West China Hospital of Sichuan University, China,8The Affiliated Hospital of Xuzhou Medical University, China,9Fudan University Shanghai Cancer Center, China,10The First Affiliated Hospital of Nanjing Medical University, China,11Yunnan Cancer Hospital, China,12The Fifth Medical Center of Chinese PLA General Hospital, China,13Affiliated Hospital of Guilin Medical University, China,14The First Affiliated Hospital of Fujian Medical University, China,15Zhejiang Cancer Hospital, China,16Cancer Hospital Chinese Academy of Medical Sciences, China,17Shanghai Tenth People's Hospital, Tongji University School of Medicine, China,18China‐Japan Union Hospital of Jilin University, China,19Affiliated Sixth People's Hospital, Shanghai Jiaotong University, China,20Sun Yat‐sen University Cancer Center, China,21The Second Hospital of Anhui Medical University, China,22Harbin Medical University Cancer Hospital, China,23Tianjin Medical University General Hospital, China,24Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, China,25The Fourth Hospital of Hebei Medical University, China,26The First Hospital of Shanxi Medical University, China,27The First Affiliated Hospital of Xiamen University, China,28Jiangsu Cancer Hospital, China,29Sir Run Run Shaw Hospital Zhejiang University School of Medicine, China,30Liaoning Cancer Hospital and Institute, China,31The First Affiliated Hospital of University of Science and Technology of China, China,32Nanfang Hospital, Southern Medical University, China,33The Fourth Affiliated Hospital of Harbin Medical University, China,34The First Hospital of Jilin University, China,35Changsha Central Hospital, China,36Suzhou Zelgen Biopharmaceuticals Co., Ltd, ChinaObjective Donafenib, a deuterated derivative of sorafenib, has shown good efficacy and tolerability in phase II study on the treatment of locally advanced/metastatic radioiodine refractory differentiated thyroid cancer (RAIR‐DTC). In this phase III study, we primary report herein biochemical response (BR) of donafenib in Chinese RAIR‐DTC patients.Methods This randomized, double‐blind, placebo‐controlled, multi‐center trial, were conducted in 37 Chinese sites. Eligible patients were randomized (2:1) to receive donafenib (300 mg) or placebo twice daily until intolerable toxicity or disease progression. The primary endpoint was progression‐free survival (PFS), the second endpoints including BR in terms of the change of thyroglobulin (Tg/TgAb), safety, et al. BR was defined as decreased Tg level ≥25%.Results Between July 2018 and February 2021, 191 patients were randomized to donafenib (n = 128) or placebo (n = 63). The study was terminated early because the results of the pre‐set second interim analysis met the criteria for effective early termination. The PFS of donafenib was significantly longer than placebo (12.9 vs. 6.4 months, HR 0.39, 95% CI 0.25‐0.61, p < 0.0001). The BR rate was significantly higher in the donafenib group than placebo (61.72% vs. 12.7%, p < 0.0001). The median time to BR was 0.95 months (95% CI 0.92‐0.95), while according to RECIST 1.1 evaluation, the median time to structural response (SR) was 1.84 months (95% CI 1.81–2.83). The median duration of BR was not reached in donafenib group (12.02‐NE), and was 1.84 months (0.95‐5.55) in placebo group, p < 0.0001, while the median duration of SR was 16.53 months (10.97‐NE) and NE, respectively, suggesting BR might be more sensitive than the SR, and could be a convenient responsive marker for RAIR‐DTC patients receiving TKI therapy. Treatment‐related adverse events of Grade ≥3 occurred in 43.8% patients in donafenib group, the most common were hypertension (13.3%) and palmar‐plantar erythrodysaesthesia syndrome (12.5%), while the occurrence rate of grade ≥3 proteinuria was only 1.6%, which was common in patients with TKIs, such as lenvatinib in SELECT trial (10%). No treatment‐related death was observed, indicating the more favourable safety profile of donafenib.Discussion Donafenib demonstrated clinical benefit with higher and rapid biochemical response, suggesting biochemical response is more sensitive than structural response to reflect the efficacy of donafenib.LATE BREAKING ORAL 50Thyroid Cancer Clinical OralBRAF +/‐ MEK INHIBITOR THERAPY INBRAF V600E‐MUTATED DIFFERENTIATED THYROID CARCINOMA: DOES THE PRESENCE OF ATERTPROMOTER MUTATION INFLUENCE THERAPEUTIC RESPONSE?Sasan Fazeli*1,2, Marie‐Claude Hofmann1, Maria Gule‐Monroe1, Elena McBeath1, Maria Cabanillas1, Naifa Busaidy1, Steven Waguespack1, Mimi Hu1, Camilo Jimenez1, Steven Sherman1, Mouhammed Habra1, Gilbert Cote1, Roland Bassett1, Michelle Williams1, Ramona Dadu11MD Anderson Cancer Center, USA,2City of Hope Cancer Center, USABackground: Coexisting BRAFV600E and TERTpromoter (pTERT) mutations are associated with poor prognosis in differentiated thyroid carcinoma (DTC). In preclinical models, coexisting BRAF/pTERT mutations correlated with an increased sensitivity to BRAF/MEK inhibitors(i) compared with tumors harboring BRAFV600E only.Objective: To assess the efficacy and safety of BRAFi monotherapy versus the combination BRAF+MEKi in patients with BRAF‐mutated DTC with or without pTERT mutations.Methods: A retrospective analysis of patients with BRAF‐mutated DTC who were treated with BRAF+/‐MEKi and whose tumor samples were tested for pTERT mutations. The endpoints were objective response rate (ORR), progression free survival (PFS), and safety. Response evaluation was assessed by a single radiologist using RECIST v1.1 (SD = stable disease; PR = partial response).Results: 56 patients were included; median age 53; female (52%); distant metastases at diagnosis (23%); prior surgery (96%), RAI (84%), neck radiation (25%), multikinase inhibitors (14%); 21(37%) had BRAF only and 35(63%) had BRAF+pTERT. Baseline characteristics were similar in BRAF only vs BRAF+pTERT, except for more females in BRAF only group (71% vs 40%, p = 0.02). Time from diagnosis to initiating systemic therapy was shorter in BRAF+pTERT compared with BRAF only (median 3.8 vs 8.7 years, p = 0.021). BRAFi monotherapy included dabrafenib (n = 27) and vemurafenib (n = 9) and BRAF+MEKi combination included dabrafenib+trametnib (n = 20). In BRAF only group, 15 patients received BRAFi (PR 40%, SD 60%, median PFS 23.1 months) and 6 patients received BRAF+MEKi (PR 67%, SD 33%, median PFS 31.4 months). In BRAF+pTERT group, 21 patients received BRAFi (PR 33%, SD 62%, median PFS 25.5 months) and 14 patients received BRAF+MEKi (PR 36%, SD 64%, median PFS 19.2 months). No statistically significant differences in ORR, PFS and adverse events were noted among groups. Median follow‐up time was 27 months.Discussion/Conclusion: Coexisting BRAF and pTERT mutations are prevalent (63%) in patients with advanced DTC requiring systemic therapy. The time to initiating systemic therapy was 5 years earlier in patients with coexisting mutations. In contrast to preclinical models, coexisting mutations did not correlate with a better response to BRAF+/‐MEKi therapy, in our study. Further prospective studies are needed to clarify if combination therapy should be used in patients with BRAF + pTERT mutations.LATE BREAKING HIGHLIGHTED POSTER 130Thyroid Hormone Action, Metabolism and Regulation Basic Highlighted PosterCHARACTERIZATION AND TRANSPLANTATION OF THYROID FOLLICULAR CELLS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLSHendrik Undeutsch*1, Alberto Posabella2,3, Andrea Alber2, Anita Kurmann2, Darrell Kotton2,4, Anthony Hollenberg11Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, USA,2Center for Regenerative Medicine, Boston University and Boston Medical Center, USA,3University Center of Gastrointestinal and Liver Diseases ‐ Clarunis, University of Basel, Switzerland,4The Pulmonary Center and Department of Medicine, Boston University School of Medicine, USAThe development of stem cell‐based models of thyroid replacement would greatly facilitate both the treatment and our understanding of the causes of congenital hypothyroidism. To generate thyroid follicular cells from human induced pluripotent stem cells (hiPSCs), we optimized our directed differentiation approach through activation of endogenous signaling pathways previously identified in the mouse. To facilitate tracking and purification of human thyroid progenitors, we engineered a hiPSC line carrying a GFP reporter targeted to the NKX2‐1 locus and tdTomato reporter under the PAX8 locus.Using our direct differentiation protocol, GFP/tdTomato co‐expressing cells first develop around day 9 of culture and can persist for at least 2 months of culture in media containing TSH. We profiled all cells derived from hiPSCs (regardless of fluorochrome expression) by single cell RNA sequencing on days 12 and 29 of differentiation, looking at time‐dependent changes as well as the impact of sustained exposure to BMP4 (BMP4+) vs. BMP4‐withdrawal (BMP4‐) after specification (day 4‐14). At day 12, tdTomato/GFP co‐expression was observed in 12% of cells, co‐expressing NKX2‐1, PAX8, FOXE1, and HHEX. By day 29 tdTomato+/GFP+ cells represented 69.7% (BMP4‐) and 91.3% (BMP4+) of all cells and also co‐expressed thyroglobulin (TG), TSHR and thyroidperoxidase. In contrast expression of NIS at day 29 was only detected in a small subset of BMP4‐ cells indicating that BMP4 is not required for follicular cell maturation.While the cultured organoids produce TG at the protein level at both day 29 and day 45 no T4 production can be measured at either timepoint. When transplanted into radioablated, immunocompromised mice with confirmed hypothyroidism grafts from day 30 and day 47 organoids sustain TG production in vivo for up to 12 weeks post‐engraftment but fail to synthesize and secrete T4. We hypothesize that stronger induction of NIS expression will be crucial to achieve TH synthesis in our iPSC‐derived thyroid organoids.In conclusion, we have employed a novel hiPSC line to optimize a protocol allowing us to generate human thyroid progenitors and follicular cells. However, further protocol optimization is needed to develop fully mature, functional thyroid follicular cells.LATE BREAKING HIGHLIGHTED POSTER 131Autoimmunity Clinical Highlighted PosterINFLAMMATORY MARKERS AND REMISSION FROM GRAVES' DISEASEAnn‐Elin Meling Stokland*1,2, Bjørn Gunnar Nedrebø3, Siri Carlsen4, Lars Breivik2, Marie Austdal5, Kristian Løvås6, Hans Olav Ueland7, Eystein Sverre Husebye2,6,8, Grethe Ueland61Stavanger University Hospital, Department of Endocrinology, Norway,2University of Bergen, Department of Clinical Science, Norway,3Haugesund Hospital, Department of Medicine, Norway,4Stavanger University Hospital, department of Endocrinology, Norway,5Stavanger University Hospital, Department of Research, Norway,6Haukeland University Hospital, Department of Medicine, Norway,7Haukeland University Hospital, Department of Ophthalmology, Norway,8K.G Jebsen Center for Autoimmune Disorders, Unitversity of Bergen, NorwayObjective Antithyroid drugs (ATD) are considered as first line treatment for Graves' disease (GD). After a course of therapy, about half of the patients may undergo remission, but the mechanism remains unclear. We aimed to investigate a large panel of inflammatory biomarkers in patients with GD, and their relation to disease course, treatment, and outcome.Design and Methods Eighty‐two GD patients that participated in a randomized ATD‐treatment trial 1997‐2001 were studied. Samples taken at baseline (n = 69), after three (n = 50) and 12 months (n = 30) of ATD treatment, were analysed for 92 different inflammatory biomarkers using the proximity extension assay (Olink). Plasma samples from 82 age‐ and sex‐matched blood donors were used as control subjects.Results Significant (p < 0.05) changes in 61/92 inflammatory markers were found in GD patients compared with healthy controls (47 elevated and 14 decreased). At baseline interleukin 6 (IL‐6) and tumor necrosis factor receptor superfamily member 9 (TNFRS9) were significantly higher in 34 (49%) patients that completed 12 months of ATD therapy and relapsed within two years compared to 31 (45%) patients that went into remission (p = 0.049 and p = 0.018). During treatment, TNFRSF9, Interleukin‐15 receptor subunit alpha (IL‐15RA) and CD40L receptor (CD40) were among the 32 biomarkers that decreased significantly. Type of ATD‐regimen (block and replace vs titration) did not affect the level or trend of inflammation. After more than 20 years of observation time, long‐term remission was achieved in 31 patients (38%). At the end of treatment, CD40 was significantly lower (p = 0.048) in patients that went into long‐term remission compared to those with relapsing or persisting disease.Conclusion We demonstrate a profound systemic immune response in patients with GD, with significant alterations during remission that is independent of ATD‐regimen. IL‐6, TNFRSF9, IL‐15RA and CD40 emerge as potential biomarkers to predict disease course, and are conceivably novel treatment targets.LATE BREAKING HIGHLIGHTED POSTER 132Autoimmunity Translational Highlighted PosterVRDN‐001, A STRONG ANTAGONIST ANTIBODY TO THE INSULIN‐LIKE GROWTH FACTOR RECEPTOR‐1 (IGF‐1R) IN DEVELOPMENT FOR THYROID EYE DISEASE (TED), BINDS TO A DISTINCT EPITOPE FROM TEPROTUMUMABYang Zhao*, Jordan Tsai, Rachel Newell, Tyler Swanson, Vahe BedianViridian Therapeutics, USAObjective: VRDN‐001 (Viridian Therapeutics, Waltham, MA) is a potent and selective antagonist antibody to insulin‐like growth factor receptor‐1 (IGF‐1R) under development for the treatment of Thyroid Eye Disease (TED). Clinical and preclinical evidence indicates a central role for IGF‐1R antagonism in reducing the inflammation and proptosis that occur in TED. As different anti‐IGF‐1R antibodies may have distinct characteristics, we compared the in vitro binding epitope and antagonist properties of the marketed IGF‐1R antibody teprotumumab to VRDN‐001.Methods: We generated a panel of IGF‐1R extracellular domain (ECD) point mutants of 40 potential IGF‐1 interacting residues and three N‐terminal truncation constructs and assessed the binding pattern of the two antibodies to these variants by Bio‐Layer Interferometry (Octet). Antagonist characteristics were determined by dose‐responses of inhibition of biotinylated IGF‐1 binding to IGF‐1R expressing HEK293FF cells by flow cytometry and by inhibition of IGF‐1 mediated signaling in primary human ocular choroidal fibroblasts.Results: VRDN‐001 and teprotumumab were unable to bind IGF‐1R‐ECD simultaneously, suggesting an overlapping epitope. While teprotumumab and VRDN‐001 had similar sensitivity to N‐terminal truncations, they were sensitive to different point mutations of the IGF‐1R‐ECD, indicating differences in binding epitope. Antagonism studies showed that VRDN‐001 inhibited binding of biotinylated IGF‐1 to cells to a greater extent than teprotumumab. Similarly, VRDN‐001 antagonized IGF‐1 mediated signaling more fully.Discussion/Conclusions: Despite having overlapping epitopes, VRDN‐001 is distinct in both its mutational signature and its strong antagonist properties. VRDN‐001 is a more complete antagonist of IGF‐1 mediated signaling than teprotumumab. It will be important to further explore and understand how these antibody binding and functional characteristics correlate to clinically meaningful efficacy measures in TED.LATE BREAKING HIGHLIGHTED POSTER 133Disorders of Thyroid Function Basic Highlighted PosterOVERACTIVATION OF THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR) BY TARGETED DISRUPTION OF TUBEROUS SCLEROSIS COMPLEX 2 GENE IN THYROCYTES INDUCES FOLLICULAR HYPERPLASIA, INFLAMMATION, AND IMPAIRED THYROID FUNCTIONCamila Rossetti*1, Flavia Pecanha1, Vania Nose2, John Lew1, Shioko Kimura3, Ernesto Bernal‐Mizrachi1, Joao Pedro Werneck‐de‐Castro11University of Miami, USA,2Harvard University, USA,3National Institutes of Health, USAThe serine‐threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, growth, and proliferation. In the thyroid gland, the PI3K‐Akt‐mTOR pathway is abnormally overactive in tumors and has been linked to increased aggressiveness in thyroid cancer. In addition, patients suffering from Tuberous Sclerosis (mutations in TSC1 or TSC2 genes) have thyroid gland abnormalities. TSC2 is an intracellular inhibitor of mTOR complex 1 (mTORC1) and deletion of this gene results in mTORC1 activation. To further understand how TSC2 and mTOR activation regulates thyrocyte growth and function, we generated a mouse model with deletion of TSC2 specifically in thyrocytes by crossing TSC2‐floxed mouse with mice expressing Cre recombinase driven by thyroperoxidase (TPO) (TPO‐TSC2KO). TPO‐TSC2KO mice were normal early but stopped gaining weight at 6 months of age, and this was associated with less body fat at 6 and 12 months of age. Examination of the thyroid glands in TPO‐TSC2KO mice revealed 70‐80% less TSC2 protein and mRNA levels, and 4‐6‐fold overactivation of mTORC1 activity in both male and female mice. The thyroid gland size was bigger in the TPO‐TSC2KO mice as early as 1‐month of age and continued to grow throughout life in both genders. At twelve months of age, there was significant heterogeneity in size among thyroid follicles in the TPO‐TSC2KO mice, with extensive follicular breakdown and focal inflammatory response. Thyroids of TPO‐TSC2KO mice exhibit higher thyrocyte proliferation assessed by Ki67 and elevated Cyclin D3 levels. While the thyroid gland was bigger, TPO‐TSC2KO mice were slightly hypothyroid with 20% less plasma thyroxine and a 2‐fold increase in TSH levels at 6 months of age. Overactivation of mTORC1 suppressed the mRNA expression of key genes involved in thyroid hormone biosynthesis such as thyroglobulin, thyroperoxidase, and sodium‐iodide transporter in both male and female mice. At 14 months of age, a fraction of TPO‐TC2KO mice developed thyroid tumors. In summary, overactivation of mTORC1 by targeted disruption of TSC2 in thyrocytes induces follicular hyperplasia, inflammation, and impaired thyroid function. These studies enhance our understanding of the role of mTORC1 in the regulation of thyrocyte growth and function.LATE BREAKING HIGHLIGHTED POSTER 134Disorders of Thyroid Function Basic Highlighted PosterINTRAUTERINE EXPOSURE TO BPA DISRUPTS THE PITUITARY‐THYROID AXIS FUNCTION OF THE OFFSPRING RATS DURING ADULTHOODGuilherme Henrique1, Erica Sousa‐Vidal2, Renata Silva1, Gisele Giannocco1, Caroline Serrano‐Nascimento*11UNIFESP, Brazil,2Hospital Albert Einstein, BrazilBisphenol A (BPA) is commonly used in the production of polycarbonate plastics, and it is a known thyroid disruptor that interferes with thyroid hormone (TH) synthesis and action. However, the impact of the intrauterine exposure to BPA in the programming of thyroid function has never been reported.Objective: To investigate the effects of the maternal exposure to BPA during the gestation period on the pituitary‐thyroid axis gene expression and function of the adult F1 offspring rats.Methods: Pregnant Wistar rats were exposed or not to water supplemented with 0.1 or 1 ppm BPA throughout the gestation. The treatment was interrupted after the birth of the offspring animals. The female and male offspring rats were euthanized at the postnatal day 90 (PND90). Pituitary, thyroid, and serum were collected. Gene and protein expression were evaluated by RT‐qPCR and Western Blotting, respectively. Thyroid global DNA methylation, TH and TSH levels were measured by ELISA and chemiluminescence assays.Results: Intrauterine exposure to both doses of BPA significantly increased the gene and protein expression of the