Anaplastic Thyroid Cancer Patients Research Articles

Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.

Abstract 6431: First NGS-based companion diagnostic to aid in the selection of targeted therapy for anaplastic thyroid cancer patients with BRAF V600E mutations

Abstract Introduction: While anaplastic thyroid cancer (ATC) is rare, it is the most aggressive form of thyroid cancer. All ATCs are considered stage IV at diagnosis and response rates to standard systemic therapies are poor with dismal long-term outcomes. As such, molecular profiling of ATCs has increasingly been used to identify therapeutic targets that may inform individualized therapy. Current clinical guidelines recommend molecular profiling, especially BRAF V600E mutation assessment, be performed at the time of ATC diagnosis to inform decisions related to the use of targeted therapies. On September 29, 2023, the FDA granted companion diagnostic approval to the Oncomine™ Dx Target Test (ODxT Test) as an aid in the selection of patients with BRAF V600E-mutated ATC who may be eligible for treatment with dabrafenib in combination with trametinib. Here we report the assay performance data which supports the clinical benefit of the ODxT Test as an aid in the selection of targeted therapy for ATC patients with BRAF V600E mutations. Methods: The ODxT Test is a targeted next-generation sequencing (NGS) in vitro diagnostic assay used to detect somatic changes in human DNA and RNA isolated from FFPE tissue samples. To validate the clinical benefit of the ODxT Test for the selection of ATC patients with BRAF V600E mutations, a retrospective clinical concordance study was performed on 35 patients enrolled in the ATC cohort of the ROAR trial, a phase II study of dabrafenib in combination with trametinib in subjects with rare cancers with BRAF V600E mutations. The study evaluated the overall percent agreement (OPA), positive percent agreement (PPA), and negative percent agreement (NPA) for the detection of BRAF V600E mutations between the ROAR trial central confirmatory assay, bioMerieux THxID™ BRAF test (THxID), and the ODxT Test. Due to the small number of BRAF V600E-mutated ATC patients enrolled in the ROAR trial, 167 commercially-obtained thyroid cancer specimens were also included in the concordance analysis. Results: Of the 202 specimens included in the study with a valid ThxID result, 199 had sufficient material for testing with the ODxT Test and were included in the clinical concordance analysis. The point estimates of PPA, NPA and OPA were 99.0%, 100%, and 99.4%, respectively, when excluding ODxT Test invalid results and the lower bounds of the 95% Wilson Score confidence intervals for PPA, NPA, and OPA were 94.4%, 93.7%, and 96.4% respectively. Conclusion: The ODxT Test was shown to be effective in identifying BRAF V600E mutations in ATC patients through a clinical concordance study using specimens from patients enrolled in the ROAR trial and commercially-sourced samples. The results support the expanded indication to the ODxT Test and marks the first FDA-approved NGS-based companion diagnostic for patients with BRAF V600E-mutated ATC. Citation Format: Thomas Clark, Tristan Nater, Jessica Maxfield, Justin Peterson, Kristina Hotchkiss, Corey Russo, Anne Marie Velasco Roth. First NGS-based companion diagnostic to aid in the selection of targeted therapy for anaplastic thyroid cancer patients with BRAF V600E mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6431.

Comparative study between poorly differentiated thyroid cancer and anaplastic thyroid cancer: real-world pathological distribution, death attribution, and prognostic factor estimation.

The clinic-pathological boundary between poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) is unclear due to a wide spectrum of histopathological features and the rarity of the disease. In addition to that, with the highest mortality rate and non-standard treatment modality, the PDTC/ATC population has not been subjected to comprehensive description and comparison with the extent of histological characteristics, therapeutic response, prognostic factors, and death attribution analysis. A total of 4,947 PDTC/ATC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival curve estimation and Cox proportional hazard regression were applied. Overall, the 5- and 10-year DSS for PDTC were 71.9% and 68.0%, respectively, whereas the 5- and 10-year OS are 59.3% and 51.2%, respectively. The median survival time for ATC patients was 3 months with 1-year OS being 26.9% and 1-year DSS being 31.2%. During the follow-up period, 68.1% of the PDTC/ATC cohort were dead, 51.6% of which were attributed to thyroid malignancies and 16.5% to non-thyroid causes. The top three common non-thyroid causes of death were miscellaneous cancers, lower respiratory system disease, and heart disease. The histological feature of papillary thyroid cancer (PTC) was the leading pathological category for PDTC patients (51.7%), whereas 76.7% of ATC patients' pathological feature was characterized as unidentifiable. Sarcoma histological characteristics found in ATC cases suffer the highest overall mortality (vs. PTC, HR = 2.61, 95% CI 1.68-4.06, P < 0.001). Older age unidentifiable histology feature, more advanced AJCC N1b, AJCC M1, and SEER stage, tumor size larger than 5cm, and more invasive tumor extension were independent bad outcome predictors. The populational analysis of the PDTC/ATC cohort has provided reliable support for better understanding of the difference between PDTC and ATC cases and the guidance of clinical practice and further studies.

The value of multimodal treatment in anaplastic thyroid cancer patients with distant metastasis

BackgroundAnaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with a poor prognosis, particularly in patients presenting with distant metastasis (DM). This study aimed to assess the effect of combination treatment strategies on survival in ATC patients with DM.MethodsA retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database to identify primary ATC cases with DM at diagnosis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent risk factors for survival.ResultsOf the 315 ATC patients with DM included in the study, surgery to the primary tumor, radiotherapy, chemotherapy, and lung metastasis were identified as independent risk factors for survival. Patients who received primary tumor surgery plus chemotherapy or surgery plus chemoradiation exhibited a superior outcome compared to those who received only one treatment modality.ConclusionOur findings suggest that a combination treatment approach, particularly surgery combined with radiotherapy or surgery combined with chemoradiotherapy, may provide the most optimal treatment option for ATC patients with DM. These results may provide some evidence for clinical decision making, but larger sample cohorts are still needed for validation.

Inhibition of MEK Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is highly aggressive and has very limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity in ATC could underlie this recurrence and resistance to treatment. The recent approval by the U.S. Food and Drug Administration of the combined treatment of BRAF and MEK inhibitors for ATC patients has shown some efficacy in patients harboring the BRAFV600E mutation. However, it was unknown whether the combined treatment could affect the CSC activity. This study explores the effects of the BRAF and MEK inhibitors on CSC activity in human ATC cells. Methods: Using three human ATC cells, THJ-11T, THJ-16T, and 8505C cells, we evaluated the effects of dabrafenib (a BRAF kinase inhibitor), trametinib (an MEK inhibitor), or a combined treatment of the two drugs on the CSC activity by tumorsphere formation, Aldefluor assays, expression profiles of key CSC markers, immunohistochemistry, and in vivo xenograft mouse models. Furthermore, we also used confocal imaging to directly visualize the effects on drugs on CSCs by the SORE6-mCherry reporter in cultured cells and xenograft tumor cells. Results: The BRAF inhibitor, dabrafenib, had weak efficacy, while the MEK inhibitor, trametinib, showed strong efficacy in attenuating the CSC activity, as evidenced by suppression of CSC marker expression, tumorsphere formation, and Aldefluor assays. Using ATC cells expressing a fluorescent CSC SORE6 reporter, we showed reduction of CSC activity in the rank order of combined > trametinib > dabrafenib through in vitro and in vivo xenograft models. Molecular analyses showed that suppression of CSC activity by these drugs was, in part, mediated by attenuation of the transcription by dampening the RNA polymerase II activity. Conclusions: Our analyses demonstrated the presence of CSCs in ATC cells. The inhibition of CSC activity by the MEK signaling could partially account for the efficacy of the combined treatment shown in ATC patients. However, our studies also showed that not all CSC activity was totally abolished, which may account for the recurrence observed in ATC patients. Our findings have provided new insights into the molecular basis of efficacy and limitations of these drugs in ATC patients.

Beneficial Role of Multi-Disciplinary Treatment for Anaplastic Thyroid Cancer with Initial Distant Metastasis

Anaplastic thyroid cancer (ATC) is a rare, highly aggressive tumor, with median survival around 5 months. Approximately half of the ATC patients presents with distant metastases at diagnosis, showing even more devastating prognosis, yet no outcome analysis had been reported. In this study, we aim to evaluate the clinical outcome of M1 ATC patients, and to define the group of patients who would benefit from local treatment based on multi-disciplinary approach. A total of 133 histology-confirmed ATC patients underwent protocol-based multidisciplinary treatment including surgery and chemoradiotherapy (CRT) between May 2016 and January 2022. Patients received intensity-modulated radiotherapy of 30 fractions concurrently with paclitaxel on days 1, 8 and 15 every 4 weeks, and lenvatinib was added upon progression. After 18 fractions of CRT, interim response analysis using modified RECIST was conducted for adaptive treatment planning. We reviewed 58 patients with distant metastasis at diagnosis (stage IVC). Overall survival (OS) and progression-free survival (PFS) were measured from the day of diagnosis. Most common metastatic site was lung (91.4%), followed by bone (31.0%) and brain (5.2%). Lenvatinib was added for 35 patients after any sign of progression. Fourteen patients received upfront surgery (16 debulking and 5 total) followed by adjuvant CRT in 16 patients. Thirty-one patients received upfront CRT with 2 patients receiving total resection after sufficient down-staging. Six (10%) patients could not complete radiotherapy but continued receiving systemic treatment. The median follow-up was 5.9 months. The median and 1-year OS were 6.2 months and 20.5%, and PFS were 3.7 months and 3.5%. Total RT dose over 60 Gy significantly improved median OS (7.5 vs 4.1 months, p = 0.012) and median PFS (4.4 vs 3.0, p = 0.010). Patients with less than 10 initial metastatic tumors showed better median OS (9.1 vs 4.6 months, p = 0.002) but not PFS (5.1 vs 3.6, p = 0.485). At interim analysis, early response (CR, PR and SD) of primary tumor was not associated with survival, while progression of distant metastases showed significantly worse median OS (9.8 vs 4.6 months, p = 0.001). More than 10 metastatic tumors (HR 2.73, 95% CI 1.32-5.66) and stable metastasis at interim analysis (HR 2.39, 95% CI 1.04-5.48) remained as significant factor in the multivariable cox regression analysis. Median OS and PFS of patients with less than 10 metastases showing no progression at interim analysis were 9.1 months, and 5.1 months. Local treatment combined with chemotherapy for M1 ATC patients showed outcome comparable to those of non-metastatic ATC results. Active local treatment should be considered especially for patients with less than 10 metastases, and patients without distant progression in early response evaluation.

AKT-independent signaling in PIK3CA-mutant thyroid cancer mediates resistance to dual SRC and MEK1/2 inhibition.

Anaplastic thyroid cancer (ATC) is a rare and aggressive disease with 90% of patients succumbing to this disease 1 year after diagnosis. The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients. However, resistance to therapy remains a major problem. We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response. Herein, we determined that AKT is not a major mediator of sensitivity and instead PIK3CA-mutants that are resistant to combined dasatinib and trametinib have sustained activation of PDK1 signaling. Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.

Development and validation of a nomogram for predicting the early death of anaplastic thyroid cancer: a SEER population-based study.

Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with dismal prognosis. This study aimed to identify the independent risk factors and construct a readily-to-use nomogram to predict the probability of early death in ATC patients. Patients diagnosed with ATC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled in this study for model development and internal validation. Univariate and multivariate logistic regression analyses were conducted to identify independent risk factors for early death of ATC. Nomograms for predicting the probability of all-cause early death (ACED) and cancer-specific early death (CSED) of ATC were subsequently developed. The performance of the nomograms was comprehensively evaluated and validated in an internal cohort. A total of 696 ATC patients were included in this study, of which 488 patients in the training cohort and 208 patients in the validation cohort. The univariate and multivariate logistic regression analyses identified five independent factors (tumor size, M stage, surgery, radiotherapy and chemotherapy) in the ACED model and six variables in the CSED (gender, tumor size, M stage, surgery, radiotherapy and chemotherapy) model for the establishment of the nomograms. Calibration curves and receiver operating characteristic (ROC) curves showed satisfactory efficacy and consistency both in the training (ACED: AUC values: 0.814 (0.776-0.852); CSED: 0.778 (0.736-0.820)) and validation sets (ACED: 0.762 (0.696-0.827); CSED: 0.745 (0.678-0.812)). In addition, the decision curve analysis (DCA) demonstrated the favorable potential of the two nomograms in clinical application. The two nomograms assist clinicians to identify risk factors and predict the early death probability among ATC patients, thus guide individualized treatment to improve the prognosis.

Thyroid hormone receptor α1: a novel regulator of thyroid cancer cell differentiation.

Thyroid hormone receptor α1 (TRα1) mediates the genomic actions of thyroid hormone (T3). The biology of TRα1 in growth and development has been well studied, but the functional role of TRα1 in cancers remains to be elucidated. Analysis of the human thyroid cancer database of The Cancer Genome Atlas (TCGA) showed that THRA gene expression is lost in highly dedifferentiated anaplastic thyroid cancer (ATC). We, therefore, explored the effects of TRα1 on the progression of ATC. We stably expressed TRα1 in two human ATC cell lines, THJ-11T (11T-TRα1 #2, #7, and #8) and THJ-16T (16T-TRα1 #3, #4, and #8) cells. We found that the expressed TRα1 inhibited ATC cell proliferation and induced apoptosis. TCGA data showed that THRA gene expression was best correlated with the paired box gene 8 (PAX8). Consistently, we found that the PAX8 expression was barely detectable in parental 11T and 16T cells. However, PAX8 gene expression was elevated in 11T- and 16T-TRα1-expressing cells at the mRNA and protein levels. Using various molecular analyses, we found that TRα1 directly regulated the expression of the PAX8 gene. Single-cell transcriptomic analyses (scRNA-seq) demonstrated that TRα1 functions as a transcription factor through multiple signaling pathways to suppress tumor growth. Importantly, scRNA-seq analysis showed that TRα1-induced PAX8, via its transcription program, shifts the cell landscape of ATC toward a differentiated state. The present studies suggest that TRα1 is a newly identified regulator of thyroid differentiation and could be considered as a potential therapeutic target to improve the outcome of ATC patients.

Abstract 3915: RNAseq analysis reveals differentiation gene drivers as potential therapeutic targets in anaplastic thyroid cancer

Abstract Papillary thyroid cancer (PTC) is a well-differentiated and highly treatable cancer with a 5-year survival rate of almost 99%. In contrast, anaplastic thyroid cancer (ATC) lacks differentiation and loses its thyroid-like functions, including lack of response to radioiodine therapy. Due to ATC’s aggressive metastatic phenotype, it is always diagnosed as stage IV with a 5 year survival rate of less than 3%. ATC lacks targetable genetic lesions making it a difficult cancer to treat, therefore RNAseq analysis was performed in an effort to investigate the differentially expressed genes between ATC to PTC. Exploration of differential gene expression between ATC and PTC was undertaken to further elucidate the differences in expression that drive the aggressive nature of ATC phenotype. RNA was isolated from human thyroid cancer cell lines T238 (ATC) and K1 (PTC) and RNA sequencing was conducted by Azenta Life Sciences. Our analysis resulted in 4,931 significant differentially expressed genes between ATC and PTC. Looking at the gene ontology analysis, pathways involving cell differentiation, proliferation, and migration revealed 90, 70, and 47 genes differentially expressed in ATC vs PTC respectively. These pathways putatively give rise to ATC’s aggressive phenotype when compared to PTC, therefore, we narrowed down the focus from 4,931 genes to 207. Through RNAseq analysis, Homeobox D4 (HOXD4) was observed to significantly increase in ATC (7.69 log2 fold change) compared to PTC. HOXD4 is a transcription factor that plays a crucial role in cell differentiation and has been associated with a worse prognosis in cancers such as ovarian serous carcinoma. As loss of differentiation is essential to ATC’s refractory nature and therapeutic resistance, targeting pathways involved in differentiation can be crucial in making ATC amenable to therapy. Other differentiation regulatory genes identified include BLK and LAMA5. BLK (3.95 log2 fold change) is a Src family tyrosine kinase proto-oncogene that is not only involved in cell proliferation but also differentiation. LAMA5 (4.76 log2 fold change) is an extracellular glycoprotein that has been linked to differentiation, migration and metastasis. Validation of the RNAseq results was completed via western blot analysis of multiple ATC and PTC cells lines. We found that HOXD4 expression was higher in ATC cell lines T238, 8505C, and SW1736 than PTC cell lines K1, TPC1, and BCPAP. Further validation was carried out by immunohistochemistry of human thyroid tissue. Preliminary IHC on ATC, PTC, and normal thyroid patient samples showed ATC has significantly increased HOXD4 expression (27.5%) compared to PTC (8.7%) and normal thyroid tissue (2.3%). Ongoing studies in the laboratory to identify novel genetic drivers of cell differentiation and proliferation so as to discover a therapeutic target to fulfill an unmet clinical need is underway. Citation Format: Kaci Kopec, Tara Jarboe, Michael Guo, Nicole R. DeSouza, Sarnath Singh, Augustine Moscatello, Humayun K. Islam, Jan Geliebter, Raj K. Tiwari. RNAseq analysis reveals differentiation gene drivers as potential therapeutic targets in anaplastic thyroid cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3915.

Abstract 1406: Long non-coding RNA DUXAP10 is a putative determinant of anaplastic thyroid cancer

Abstract Anaplastic Thyroid Cancer (ATC) is one of the most aggressive forms of cancer, with only a 4% survival rate with metastatic disease. ATC is highly refractory and resistant to both traditional therapeutic modalities and recently discovered small molecule inhibitors. The elucidation of molecular mechanisms that contribute to ATC’s metastatic propensity, and the identification of molecular biomarkers for early diagnosis, prognosis, and therapeutic intervention are critical unmet clinical needs-highlighting the importance of novel avenues of intervention. Recently, long non-coding RNAs (lncRNA) have been described as regulators of gene expression and cancer cell phenotypes, exhibiting the importance of identifying non-coding profiles that potentially impact ATC behavior. Publicly available datasets provided by Gene Expression Omnibus (GSE33630, GSE85457) enabled investigation of gene expression profiles of ATC vs. normal thyroid patient tissue. Bioinformatic analyses with the GEO2R program identified the lncRNA, Double Homeobox A Pseudogene 10 (DUXAP10), to be highly upregulated in ATC patient-derived tissue samples when compared to normal thyroid tissue by about 5logFC. Analysis using Gene Expression Profiling Interactive Analysis shows that high DUXAP10 expression is correlated with decreased survival in thyroid cancer patients. To recapitulate this patient data in an in vitro model, we found that the expression of DUXAP10 is also upregulated in the ATC cell line, T238, in comparison to Nthy-ori-3-1, an immortalized “normal” thyroid cell line. To understand the consequences of DUXAP10 overexpression in ATC, we used CRISPRi technology to determine the phenotypic and genotypic effects of DUXAP10 downregulation. CRISPRi knockdown of DUXAP10 significantly reduces the migratory capabilities of T238 by 50%, invasiveness by 37%, clonogenicity by 70%, cell size by 34%, and proliferation by 28%, 45%, and 36% at 24, 48, and 72 hours, respectively. This provides evidence that elevated DUXAP10 expression may increase the probability and negative consequences of metastases. Thus, targeting DUXAP10 expression may have beneficial clinical outcomes. Identification of the molecular innervations of DUXAP10 that orchestrate these pro-metastatic phenotypic changes are currently in progress. Immediate next steps are aimed toward determining if DUXAP10 can be utilized as a potential biomarker for ATC diagnosis and prognosis, as well as elucidating the full range of interactions that DUXAP10 has in shaping the ATC phenotype. Citation Format: Nicole R. DeSouza, Michelle Carnazza, Danielle Quaranto, Tara Jarboe, Kaci Kopec, Sarnath Singh, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Long non-coding RNA DUXAP10 is a putative determinant of anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1406.

Lymph node metastasis‐dependent molecular classification in papillary thyroid carcinoma defines aggressive metastatic outgrowth

Lymph node metastasis‐dependent molecular classification in papillary thyroid carcinoma defines aggressive metastatic outgrowth

Spontaneous Murine Model of Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy with a dismal prognosis. There is an urgent need for more in-depth research on the carcinogenesis and development of ATC, as well as therapeutic methods, since standard treatments are essentially depleted in ATC patients. However, low prevalence has hampered thorough clinical studies and the collection of tissue samples, so little progress has been achieved in creating effective treatments. We used genetic engineering to create a conditionally inducible ATC murine model (mATC) in a C57BL/6 background. The ATC murine model was genotyped by TPO-cre/ERT2; BrafCA/wt; Trp53ex2-10/ex2-10 and induced by intraperitoneal injection with tamoxifen. With the murine model, we investigated the tumor dynamics (tumor size ranged from 12.4 mm2 to 32.5 mm2 after 4 months of induction), survival (the median survival period was 130 days), and metastasis (lung metastases occurred in 91.6% of mice) curves and pathological features (characterized by Cd8, Foxp3, F4/80, Cd206, Ki67, and Caspase-3 immunohistochemical staining). The results indicated that spontaneous mATC possesses highly similar tumor dynamics and immunological microenvironment to human ATC tumors. In conclusion, with high similarity in pathophysiological features and unified genotypes, the mATC model resolved the shortage of clinical ATC tissue and sample heterogeneity to some extent. Therefore, it would facilitate the mechanism and translational studies of ATC and provide an approach to investigate the treatment potential of small molecular drugs and immunotherapy agents for ATC.

Antineoplastic Activity of Pazopanib in Anaplastic Thyroid Cancer in Primary Culture.

Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.

Current picture of anaplastic thyroid cancer patients' care and meetable needs: A survey of 94 Institutions from the EORTC Endocrine and Head and Neck Cancer Groups

Anaplastic thyroid carcinoma (ATC) is a rare cancer accounting for 40% of thyroid cancer-specific deaths. In the last 5 years, improved insights into molecular pathways led the Food and Drug Administration to license BRAF/MEK inhibitors (B/Mi) in BRAFV600E-mutant ATC, and pembrolizumab in solid cancer with high tumour mutational burden (TMB-H) (≥10 mutations/megabase) (mut/Mb). In Europe, clinicians face challenges in prescribing novel treatments, as the European Medical Association (EMA) has not licensed B/Mi nor immunotherapy (IO) for ATC so far. Some patients manage to receive these drugs through alternative ways. We investigated the extent of this phenomenon launching an online survey from March 12th to 19th 2021 open to 239 Institutions in the EORTC Endocrine and Head & Neck Cancer Groups. Questions enquired about the number of ATC patients evaluated/year, feasibility of BRAF assessment, accessibility to B/Mi-IO, availability of clinical trials and interest in new studies. Colleagues from 94 Institutions (20 Countries) joined: 30 centres evaluated ≥5 ATC patients/year, with an overall incidence >200 patients/year. 80.8% tested BRAF status, 43.6% by next-generation sequencing. 62.7% and 70% of responders reported limitations in prescribing B/Mi and IO, respectively: either the impossibility of offering them, or drugs accessibility exclusively under certain conditions (e.g. health insurance, clinical trials, compassionate use, off-label). Only 13.8% had clinical trials ongoing while 91.5% of sites claimed ATC-dedicated trials. Disparities in access to novel treatments are diffuse. Access to cutting-edge therapies is an urgent issue in this setting, and clinical trials seem feasible within an appropriate network.

ODP472 Creation of the Anaplastic Care Team (ACT) protocol: Establishing a Benchmark for Timely Access to Care for Anaplastic Thyroid Cancer Patients

Abstract Introduction Novel Coronavirus 19 (COVID19) has been shown to involve multiple organs. Its reported effects on the endocrine system have been via subacute thyroiditis, functional hypopituitarism, and triggering type 1 diabetes with ketosis. We describe a case of COVID19 infection presenting as adrenal insufficiency. Case A 35-year-old female with a history of developmental delay, anxiety, and hypothyroidism presented to the emergency department (ED) from her group home with complaints of abdominal pain and 2-3 episodes of nausea and vomiting per day for one week. She denied any changes in bowel habits, chest pain, shortness of breath. On physical examination, there was mild diffuse abdominal tenderness without any skin hyperpigmentation. In the ED, her vitals showed blood pressure 99/56, heart rate 94, respiratory rate 23, saturating at 100% on room air. Laboratory tests were remarkable for hyponatremia (sodium 123), hypokalemia (potassium 1.9), hypochloremia (chloride 88), hypophosphatemia (phosphorus 2), metabolic acidosis with bicarbonate of 14. Her COVID19 test was positive. She was admitted to the intensive care unit as her blood pressure continued to drop to as low as 76/37. Potassium, phosphorus was replaced, and normal saline infusion was started at 75ml/hr with minimal improvement in blood pressure to 94/53 and sodium to 126 in 24 hours. Urine electrolytes showed sodium &amp;lt;15, making SIADH less likely. On day 3, we suspected adrenal insufficiency due to persistent hypotension. Results showed am cortisol of 1 and ACTH of 10. ACTH stimulation test was unable to be done. She was started on hydrocortisone which improved her blood pressure as well as electrolytes. CT abdomen showed no adrenal abnormality. She was able to be tapered off the steroids in 2 weeks. Conclusion COVID19 associated hypocortisolism presents both as primary and transient secondary adrenal insufficiency (via suppression of the hypothalamic-pituitary-adrenal axis, like in our case). Similar reversible hypocortisolism post-SARS infection was observed in 24 of 61 patients (39.3%) during the 2005 outbreak. Autopsy studies on patients with COVID19 showed adrenal necroptosis of the adrenal cortex. Although critical illness-related cortical insufficiency is not a new concept, the cortisol levels in COVID19 critically ill patients have been shown to be lower than non-COVID19 critically ill patients. Prompt addition of stress dose steroids can be lifesaving in critically ill COVID patients, especially when associated with resistant hypotension. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

162 (PB042) - The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies

Background: Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are the leading causes of endocrine cancer death. Mutations in the MAP kinase (MAPK) pathway are common in PTC and ATC. Recently, the combination of dabrafenib (BRAFi) and trametinib (MEKi) was approved for treatment of BRAF-mutant ATC. However, combined BRAF/ MEK inhibition is rarely curative for ATC patients and has had limited responses in PTC. Here, we identify an induction of Aurora Kinase B (AURKB) in response to MEKi in cells that are resistant to combined BRAF/MEK inhibition.

Integrated analysis of novel macrophage related signature in anaplastic thyroid cancer.

Patients with anaplastic thyroid cancer (ATC) have a very poor prognosis. Immunotherapy is a potential treatment, while the current outcome is limited which may be due to the complicated tumor microenvironment (TME). Tumor associated macrophages (TAMs) is the most abundant cell in the TME of ATC. We aimed to clarify the novel indicators based on TAM in ATC. Transcriptome files were downloaded from the Gene Expression Omnibus (GEO) dataset. Weighted gene co-expression network analysis, cox regression, support vector machine, and random forest were utilized to identify TAM-related prognostic genes. Consensus clustering and principal component analysis were performed for integrated analysis. Moreover, external validation (Fudan University Shanghai Cancer Center cohort) was conducted in 23 ATC samples via immunohistochemistry. ATC patients with an abundance of TAMs had a poorer prognosis. Four TAM related genes (FZD6, RBBP8, PREX1, HSD3B7) were identified and a TAM-related prognostic index (TAMRPI) was constructed with high area under the curve (AUC). Next, high TAMRPI was related to the higher level of TAM infiltration and upregulation of several pathways, such as E2F targets, IL6-JAK-STAT3, and G2M checkpoint. Immune checkpoint TIM-3 and CSF1R were positively associated with TAMRPI, and dysfunction of T cells was increased in high TAMRPI subset. Moreover, in the external validation of protein level, strong expression of TAM related genes was related to poorer prognosis, which was further supported by time-dependent AUC analysis. TAM is negatively correlated to the prognosis of ATC. FZD6, RBBP8, PREX1, and HSD3B7 are potential biomarkers of ATC.

A Pilot Study of Durvalumab (MEDI4736) with Tremelimumab in Combination with Image-Guided Stereotactic Body Radiotherapy in the Treatment of Metastatic Anaplastic Thyroid Cancer.

Background: Metastatic anaplastic thyroid cancer (ATC) has a poor prognosis. This pilot study aims to evaluate tremelimumab plus durvalumab with stereotactic body radiotherapy (SBRT) to improve overall survival (OS). Methods: Eligible patients received up to 4 doses tremelimumab (75 mg) given q4 weeks and up to 1 year of durvalumab (1500 mg) given q4 weeks. SBRT at 9 Gy × 3 fractions was given within the first 2 weeks of the start of treatment. Paired biopsies (pretreatment and between 3 and 10 weeks after the first dose of the drug treatment) were done in the medically qualified patients. Major inclusion criteria are metastatic ATC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no prior immunotherapy, and last anticancer treatment >7 days before starting the study. The primary endpoint was 1 year OS with the combination of durvalumab, tremelimumab, and SBRT in metastatic ATC patients with a target of 1 year OS in ≥2 out of 12 patients. Results: A total of 13 patients signed consent but only 12 patients ultimately participated in this trial. One patient who consented to the protocol became ineligible for this study due to continued decline in performance status. Patient characteristics were as follows: male (n = 6) with a median age of 71 years (range: 49-82), and ECOG = 1. Nine patients had prior neck radiation and nine patients had prior chemotherapy. Next-generation sequencing and PD-L1 staining were done in the nine patients where tissue was available. High microsatellite instability (MSI) corresponding to mismatch repair defect was noted in two patients. There were zero confirmed responses and only one patient had stable disease and was treated with ≥4 cycles of study drugs. The median time that the patients were under treatment was 11 weeks (1-28 weeks). MSI status did not affect treatment response. High MSI patients were on treatment for 8-14 weeks before disease progression. The median OS was 14.5 weeks with only 1 patient alive beyond 1 year. The presence of a BRAF or p53 mutation did not appear to affect treatment outcome. Conclusions: Tremelimumab and durvalumab with SBRT did not improve OS for ATC. Future research is needed to examine other novel immunotherapy combinations with or without radiotherapy in the treatment of ATC. Clinical Trial Registration: NCT03122496.

Lung cavitation in patients with anaplastic thyroid cancer treated with lenvatinib.

Anaplastic thyroid cancer (ATC) is a rare malignancy with a poor prognosis. It accounts for 1-2% of all thyroid cancers. Lenvatinib is an orally administered inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, fibroblast growth factor receptor (FGFR)-1 to -4, platelet-derived growth factor receptor (PDGFR)-α, rearranged during transfection (RET), and KIT. There have been cases of pneumothorax caused by lung cavitation and collapse after administration of lenvatinib in ATC with lung metastasis. In this study, we investigate lung cavitation during treatment with lenvatinib in ATC patients with lung metastasis. All ATC patients with lung metastasis treated at our hospital with lenvatinib between November 2015 and May 2021 were selected from our electronic medical records. The primary objective was to determine the incidence of cavitation of lung metastasis of ATC in patients treated with lenvatinib. The secondary objective was to evaluate prognostic factors in ATC patients with lung metastasis treated with lenvatinib. We identified 26 patients treated with lenvatinib for ATC with lung metastasis. Of these, 12 (46.2%) had cavitation with lung metastasis during lenvatinib treatment. The median overall survival (OS) was 128 days (79-228 days), and the cavitation (+) group had significantly longer OS than the cavitation (-) group [186 days (117-355 days) vs. 89 days (59-179 days), P=0.033]. Kaplan-Meier survival curves indicated a significant difference in OS was observed between the two groups (P=0.0293). Univariate analysis demonstrated lung cavitation was a significant prognostic factor (hazard ratio: 0.38, 95% CI: 0.16-0.93). Lung cavitation occurred in 46.2% of patients treated with lenvatinib for ATC with lung metastasis. Patients who developed lung cavitation had a significantly better prognosis than those who did not.