Metastatic Anaplastic Thyroid Carcinoma Research Articles

Impressive response to Pralseltinib in KIAA1468 RET-fusion anaplastic thyroid cancer: a case report and literature review

Anaplastic thyroid carcinoma (ATC) is a severe, aggressive form of cancer with low survival rates. Multimodal therapies are currently employed with limited success and targeting molecular subgroups of ATC, such as those with RET translocation, is an active area of research. In this case report, we present a patient with metastatic ATC harboring a RET translocation, treated with two RET-specific tyrosine kinase inhibitors (TKIs), Pralsetinib and Selpercatinib. Pralsetinib resulted in a significant and rapid reduction in lung metastasis complicated by a pneumothorax effects. The initial efficacy of Pralsetinib in our patient underscores the potential of RET-specific TKIs in the management of RET-altered ATC and highlights the risk of adverse events associated with tumor response in high tumor burden diseases. Meticulous management of side effects remains essential to improve patient outcomes.

Efficacy and safety of anlotinib combined with sintilizumab in locally advanced or metastatic anaplastic thyroid carcinoma.

6103 Background: Anaplastic thyroid carcinoma (ATC) is rare aggressive and fatal malignancy with poor prognosis. Antiangiogenic and multikinase inhibitors and programmed cell death protein-1 (PD-1) antibodies have conferred benefits for ATC. We aimed to assess the efficacy and safety of anlotinib plus sintilizumab in patients with locally advanced or advanced ATC. Methods: In this prospective study, patients with histologically confirmed locally advanced or metastatic ATC, received a combination therapy of anlotinib and sintilizumab. Anlotinib was started at 12 mg once daily for 14 days and combined with sintilizumab at a fixed dose of 200 mg every three weeks. The primary end point was objective response rate (ORR), assessed in patients who received at least one dose of treatment. Tumor samples were characterized by next-generation sequencing in 12 patients and PD-L1 expression levels in 14 patients. Results: Between June 1st, 2022 and August 21st, 2023, 18 patients with locally advanced or metastatic ATC were enrolled and received combination treatment. Best overall response (BOR) within all patients was 5.6% (1/18) complete remission, 38.9% partial remission (7/18), 33.3% stable disease (6/18), and 22.2% progressive disease (4/18). ORR was 44.4% for all patients and 80.0% for 5 patients with BRAF V600E mutation. The only one patient with PD-L1 negative also reached PR. Median follow up time was 14.6 months for all patients and 16.1 months for patients with BRAF V600E mutation. The median progression-free survival was 7.5 months (0.5 to 56.3 months) for all patients and 5.7 months (1.0 to 13.1 months) for patients with BRAF V600E mutation. Duration of treatment was 5.9 months (0.5 to 38.2 months), and 8 of 18 ATC patients are still on therapy. Grade III/IV toxicities were observed in 4 of 18 patients, necessitating dose reduction/discontinuation of anlotinib. The 1-year overall survival (OS) rate was 61.1% and median OS was 12.9 months (0.6 to 56.3 months), with 8 ATC patients being still alive without progression. Conclusions: The combination of anlotinib and sintilizumab demonstrated promising activity and manageable toxicity in patients with locally advanced or metastatic ATC, suggesting its potential as a viable therapeutic option for this patient population. Clinical trial information: ChiCTR2200067045. [Table: see text]

Sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid carcinoma: The phase 2 SETHY, GETNE-T2318 trial.

TPS6130 Background: Current treatment options for advanced or metastatic differentiated thyroid carcinoma (DTC) with vascular endothelial growth factor inhibitors provide clinical benefit, despite the fact that most patients will acquire treatment resistance, whereas, advanced or metastatic anaplastic thyroid carcinoma (ATC) still lacks effective treatment options. Trophoblast cell surface antigen 2 (TROP-2) is highly expressed at the membrane of DTC and ATC, while it is rarely expressed in normal tissues. Moreover, TROP-2 is associated with tumor aggressiveness and poor prognosis. Targeting TROP-2 with sacituzumab govitecan, an antibody-drug conjugate with a SN-38 payload, showed efficacy in other cancer types such as triple negative or HER positive breast cancer or urothelial cancer and may be an effective treatment for thyroid carcinoma. SETHY is the first clinical trial with antibody-drug conjugates in thyroid cancer. Methods: The SETHY trial is a single-arm, multicohort, prospective, phase 2 trial of sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid cancer being recruited in 10 hospitals in Spain. Patients are ≥ 18 years, ECOG 0-1, should have recovered from any prior toxicity and have an adequate organ function. Patients will be included in two cohorts: DTC after progression (PD) to 1-3 prior systemic therapies (cohort 1) or ATC in 1st-line treatment or after failure of any systemic therapy (Cohort 2). Prior topoisomerase 1 inhibitors are not permitted. All patients will receive sacituzumab govitecan (10 mg/kg intravenously) on Days 1 and 8 of every 21-days cycle, until PD, death, study withdrawal, or unacceptable toxicity. Computed tomography (CT) or magnetic resonance imaging (MRI) scans and blood monitoring of tumor markers are performed every 12 weeks (Q12W) until PD. The primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30 at baseline and Q12W until PD). Archival tumor samples will be collected at screening for retrospective central evaluation of TROP-2 expression levels and ancillary studies. The study uses a Simmon-II design considering a ORR of 5% as null hypothesis and an alternative ORR of 20% (α=0.1 one sided, β=0.2). In total, the study requires a total of 21 patients per cohort; 12 in the 1st stage and, if at least one response is reported, 9 additional in the 2nd stage. The study is approved and open to patient selection in Spain. Clinical trial identification: EU CT: 2023-504898-20-00 / NCT06235216 Clinical trial information: NCT06235216 .

Fine Needle Aspiration and Core Biopsy of Liver Mass as First Time Diagnosis of Sarcomatoid Anaplastic Thyroid Carcinoma, A Rare Malignancy Presenting at an Unexpected Body Site

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a fatal malignancy. We report an unusual case of a patient with ATC whose chief complaint and clinical history were listed as “jaundice and liver mass” without mention of disease in the neck. Methods/Case Report A 66-year-old female presented to the emergency department with worsening “yellow-green skin discoloration” for a few weeks. She also reported worsening dyspnea and recent dysphagia with solid foods, fatigue, abdominal pain and recent hemoptysis. Physical examination revealed conjunctival icterus, jaundice, a tender neck mass, right upper chest wall tenderness and palpable lymphadenopathy in the lower neck. Assessment notes indicated inability to carry out self-care and being bedridden, even though she reported having been active, swimming and cycling, up to one month before her presentation. Computed tomography studies confirmed findings compatible with widespread malignancy with mass lesions in her liver, lungs, adrenals, kidneys, neck, pancreas, gallbladder, and brain. Mild anemia, hemoglobin 10.5g/dL, mild leukocytosis, leukocytes 17,000/mm3, were confirmed. Bilirubin was 15µmol/L, and hepatic enzymes were elevated. An ultrasound-guided liver biopsy was performed and evaluated for cytologic features, histologic features and pattern of immunoreactivity. The combined cytomorphologic and histologic features were those of a pleomorphic sarcomatoid high-grade malignancy with variably spindled to epithelioid morphology and associated necrosis. Immunohistochemical studies performed on sections from the accompanying core biopsy confirmed the malignant cells to be positive with CK-AE1/AE3, CK 7, TTF-1, GATA3, PAX8, SATB2, and BRAF V600E. The malignant cells were nonreactive with CK 20, thyroglobulin, calcitonin, napsin, CDX2, PCEA, and ER. The combined clinical setting, imaging findings, cytomorphology, histomorphology and ancillary testing results together allowed for a specific diagnosis of metastatic anaplastic thyroid carcinoma. The patient was referred for palliative care services and died within a few days of diagnosis. Results (if a Case Study enter NA) NA Conclusion Metastatic disease from a sarcomatoid ATC, as diagnosed in this case, is an important differential diagnosis to keep in mind when an elderly patient presents with multisite metastases from an undefined primary source. Clinical, radiological and laboratory correlations are of paramount importance in correlating with cytomorphology/histomorphology and in helping to determine the best panel of IHC studies to consider.

SAT576 Change Is Not Always For The Best! A Transformation of Papillary Into Metastatic Anaplastic Thyroid Carcinoma

Abstract Disclosure: J. Syeda: None. R. Zafar: None. K. Rajamani: None. INTRODUCTION: Anaplastic thyroid carcinoma (ATC) can occur de-novo or from preexisting well-differentiated thyroid carcinoma (1). The presence or absence of certain driver mutations can help predict the likelihood of this transformation process. We present a case of an elderly female with an initial diagnosis of well-differentiated papillary thyroid cancer (PTC) with a transformation into metastatic anaplastic thyroid carcinoma (ATC). CASE PRESENTATION: An 81-year-old female patient was initially seen 8 years ago with a 35-year history of goiter. At the initial presentation, she felt well and did not have any symptoms. Physical examination revealed an enlarged thyroid gland with left lobe nodularity. A thyroid ultrasound showed a multinodular thyroid gland including a 2x1.7x1.2 cm solid nodule with macro calcifications in the right lobe, 2.8x2.6x2.5 cm solid nodule, and 1.6x1.3x1.6 cm heterogeneous solid nodule with calcifications and irregular margins in the left lobe. She had a fine needle aspiration of these three nodules. The right nodule was non-diagnostic and both left nodules were positive for PTC. She underwent a total thyroidectomy and central lymph node dissection. Radioactive iodine treatment with 163mCi was administered after surgery. One and a half years after surgery, her thyroglobulin levels started trending upward. This led to a further workup including a PET/CT scan, which showed a hyper metabolic 6 mm left supraclavicular lymph node. Needle biopsy of this lymph node disclosed metastatic PTC. The pathologic diagnosis following surgical resection was positive for metastatic poorly differentiated thyroid carcinoma. A subsequent PET/CT scan and a thyroid ultrasound showed an abnormal uptake of the left neck lymph node and additional metastatic nodes in the left neck respectively. A core needle biopsy of these lesions was positive for ATC. Foundation One CDx testing was positive for BRAF V600E, TP53, and TERT promoter mutations. Cellblock from the initial thyroidectomy was reevaluated by pathology and confirmed no evidence of ATC. Foundation One CDx testing of the thyroidectomy specimen was positive for BRAF V600E and TERT promoter mutations. Surveillance imaging shows mediastinal adenopathy, left pleural thickening, and bone and liver metastases. DISCUSSION: Anaplastic transformation is not uncommon (1). This case supports the evidence that TERT promoter mutations may not trigger anaplastic transformation but may predispose to the aggressive PTC phenotype prone to conversion to ATC when one of the ATC-related “second hit” genetic events occurs (2). This case suggests that the “second hit” event is a TP53 mutation. The detection of a TP53 mutation in PTC with an aggressive phenotype may help predict anaplastic transformation. REFERENCES: 1-Endocrine Pathology. 2021 Mar; 32(3):347-356. 2- Semin Cancer Biol. 2020 Apr; 61: 23-29. Presentation: Saturday, June 17, 2023

Efficacy and safety of anlotinib-based chemotherapy for locally advanced or metastatic anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies with no effective treatment. In this study, we investigated the efficacy and safety of anlotinib-based chemotherapy as first-line therapy for ATC. Locally advanced or metastatic (LA/M) ATC patients who never received antitumor treatment of any sort were eligible for this study. The patients received 2-6 cycles anlotinib12mg on days 1-14 per 21 days. Chemotherapy regimens consisted of paclitaxel, capecitabine, or paclitaxel plus carboplatin/capecitabine. The end points including Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Disease Specification Survival (DCS) were analyzed. A total of 25 patients were enrolled. 1 patient achieved a Complete Response (CR) and 14 patients achieved Partial Response (PR). The best ORR was 60.0%, and the DCR was 88.0%. The median PFS was 25.1 weeks, and the median DCS was 96.0 weeks. Approximately 56% (14 patients) had at least one Adverse Event (AE) of any grade. Most AEs were well tolerated. The most common AEs was palmar-plantar erythrodysesthesia syndrome (28.0%). Anlotinib-based chemotherapy as first-line therapy is a safe and effective intervention for the treatment of LA/M ATC patients.

Role of surgery to the primary tumor in metastatic anaplastic thyroid carcinoma: pooled analysis and SEER-based study

PurposeAnaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival.MethodsUsing individualized patient data derived from our systematic review of literature and our single center study (n = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study (n = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC.ResultsPooled cohort study showed surgery (p < 0.001), RT ≥ 30 Gy (p < 0.001), ChT (p < 0.001) and multimodal treatment (p = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162–3.433], p = 0.012) and RT ≥ 30 Gy (1.877 [1.232–2.843], p = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment (n = 445) total thyroidectomy (p = 0.031), administration of ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332–0.862, p = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy (p = 0.031), ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS (p < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332–0.862, p = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p = 0.002).ConclusionsSurgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease.

An Evaluation of Clinical Efficacy of Immune Checkpoint Inhibitors for Patients with Anaplastic Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy that is associated with poor prognosis. Current treatment options include surgery, radiation, cytotoxic chemotherapy, and multikinase inhibitor therapy. The role of immunotherapy in ATC is an area of active interest and recent evidence suggests that it may be a potentially effective treatment option. Methods: We report a case series of 13 patients with locally advanced or metastatic unresectable ATC who received immune checkpoint inhibitor therapy (pembrolizumab or nivolumab) at a single institution. Results: The patients' median age was 70 years, 54% (7/13) were male, and 85% (11/13) had stage IVC disease with lungs and lymph nodes being the most common sites of metastases. Ten patients had tumor tissue available for programmed death-ligand 1 (PD-L1) expression testing, all of which were positive for PD-L1, and seven of these patients also had a BRAFV600E mutation. The median progression-free survival was 1.9 months and median overall survival (OS) was 4.4 months. The objective response rate was 16% (2/13). Two patients had partial response (PR), and three patients had durable stable disease. Among patients with a clinical benefit, after a median follow-up of 13.5 months, median OS had not been reached (range 4+ to 29+ months). Responses were ongoing in four subjects. The one-year survival rate was 38% (5/13). Six patients (46%) experienced an immune-related adverse event, and 15% (2/13) experienced a grade 3 or higher adverse event, including one patient with grade 5 immune checkpoint-related thyroiditis. Conclusions: Immune checkpoint blockade was well tolerated with a toxicity profile consistent with published literature on PD-1/PD-L1-targeting therapies. For ATC patients, immune checkpoint inhibition may represent an effective treatment option with robust sustained responses seen in a subset of patients.

Revisiting Combination Chemotherapy as a Single Modality Palliative Therapy for Advanced Anaplastic Thyroid Carcinoma-a Single Institution Experience.

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with dismal outcome especially in metastatic setting. Consensus for ideal treatment of advanced and metastatic ATC remains elusive. This study aimed to analyze the impact of palliative chemotherapy versus supportive care on overall survival in patients with metastatic anaplastic thyroid carcinoma. Patients diagnosed with ATC between the period January 2018 and December 2019 were prospectively followed. The patients opting for palliative chemotherapy received 3 weekly Paclitaxel (175 mg/m2) and Carboplatin (AUC-5). Out of the 31 patients diagnosed with ATC, clinicopathological profile of 29 patients was analyzed (2 patients who underwent upfront surgical resection with curative intent were excluded), out of which 20 patients were included in the survival analysis. The median age of presentation was 55.8 years with male:female ratio 1.9:1. Seventeen out of the total 29 patients presented with anaplastic transformation in long-standing goiter. Nineteen out of 20 (95%) patients presented with distant metastasis with lungs being the most common site. Nodal metastasis was present in all patients. Invasion of the strap muscles (90%) and trachea (80%) was the most common peri-thyroidal tissue invasion followed by invasion of the esophagus (40%), internal jugular vein (30%), and carotid artery (5%). Twelve out of the 20 patients opted for palliative chemotherapy. Overall, median survival from the time of diagnosis was 2.6 months, with median survival in patients receiving chemotherapy 3.1 months and those opting for supportive care 1.6 months (p=0.004). Out of all the factors analyzed, male sex (HR 6.521, 95% CI 1.143-37.206, p value 0.03) and vascular invasion (HR 0.066, 95% CI 0.009-0.499, p value 0.008) were poor prognostic indicators. Palliative chemotherapy showed increased survival benefit in patients with metastatic ATC. Male sex and vascular invasion were found to be significant factors associated with poor outcomes on Cox regression analysis.

Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab.Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14–24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1–90%).Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%.Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

Anaplastic Thyroid Cancer Presenting With Brain Metastasis: 17-year Progression Free Survival

Anaplastic Thyroid Cancer is the most aggressive thyroid cancer with a median survival of just five months. Long term survival has been reported in locally aggressive cases but has yet to be reported in metastatic disease. This is a report of a 34-year-old male who presented with symptoms of dizziness, confusion, intermittent headaches, and erratic behavior for two weeks found to have metastatic anaplastic thyroid cancer. CT of the head revealed a 1 cm ring enhancing lesion and he was taken to the operating room for a left parietal craniotomy with mass removal. Initial pathology suggested papillary thyroid origin. His neck exam revealed a palpable 3 cm mass in the right thyroid lobe and he subsequently underwent total thyroidectomy. Final pathology revealed anaplastic carcinoma identical to the brain lesion. Post-operatively, he underwent 15 cycles of whole brain radiation therapy. Two additional brain lesions were identified after thyroidectomy and a third was identified after whole brain radiation. He underwent stereotactic radiosurgery of these three lesions less than two months after thyroidectomy. The patient went on to receive modified mantle field irradiation to the neck, thyroid bed, and the upper mediastinum and chemotherapy with doxorubicin for 6-8 weeks and temozolomide for 2 years. Radioactive iodine treatment was not administered. The patient has currently survived 17 years and his persistent, but stable, brain lesions are being followed with serial imaging. He remains clinically and neurologically asymptomatic. This is the first case presenting with long-term survival in a patient with metastatic anaplastic thyroid carcinoma.

A Case of Occult Anaplastic Thyroid Cancer Presenting as Huge Renal Mass

Anaplastic thyroid cancers (ATC) are a rapid growing and highly lethal form of thyroid cancer. Distant metastases of ATC are detected in about half of patients. Clinically, it is very rare to metastasize to the kidney. The most common initial symptoms of ATC are a palpable neck mass and accompanying compression symptoms of the upper aerodigestive tract. A 68-year-old patient was referred with a huge renal mass, which was detected during the evaluation of abdominal pain. Left total nephrectomy was performed. Histologically, the kidney tumor was a metastatic anaplastic thyroid carcinoma. To our knowledge, it is the first case of occult ATC presenting as a huge renal mass.

Rechallenge with dabrafenib plus trametinib in anaplastic thyroid cancer: A case report and review of literature

Introduction: Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated rare tumor. Median overall survival is usually between 8 and10 months, with a 1-year survival rate of 20%. Conventional anthracycline based chemotherapy regimens demonstrate low response rates with short duration. Novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape of ATC have been investigated. Case presentation: We herein report the rechallenge of a 52-year-old ATC patient with BRAF V600E mutation with dabrafenib plus trametinib. She presented with recurrent and progressive disease despite surgery, radiation therapy, 3 different chemotherapy regimens, and combination of dabrafenib-trametinib in different settings. She was rechallenged with dabrafenib-trametinib, and had a good response. Conclusion: To our knowledge, this is the first ATC case who responded to dabrafenib-trametinib rechallenge, reported in the literature. We want to emphasize that combination of dabrafenib and trametinib might be a good choice for resistant locoregional and metastatic ATC patients with BRAF V600E mutation, particularly in whom rapid clinical response is urgently needed. Moreover, rechallenge with this combination should be kept in mind in selected cases.

Multimodal treatment based on thyroidectomy improves survival in patients with metastatic anaplastic thyroid carcinoma: a SEER analysis from 1998 to 2015.

The aim of this retrospective study was to evaluate multimodal treatments consisting of surgery, radiotherapy (RT) and chemotherapy (CT) in metastatic anaplastic thyroid carcinoma (ATC) patients using the Surveillance, Epidemiology, and End Results (SEER) database. Patients with a histopathologic diagnosis of ATC between 1998 and 2015 were included. The endpoint of this study was overall survival (OS). The prognostic significance in terms of OS was analyzed by univariate and multivariate analyses. A total of 433 metastatic ATC patients were identified. The median OS was two months, with a 1-year OS rate of 6.9%. In the multivariate analysis, the factors significantly correlated with OS were age [<68 vs. ≥68 years old, P=0.032, hazard ratio (HR) =1.252], tumor size (<7 vs. ≥7 cm, P=0.004, HR =1.418; <7 cm vs. unknown, P=0.005, HR =1.424), surgery at the primary site (none/unknown vs. less than thyroidectomy, P<0.001, HR =0.623; none/unknown vs. thyroidectomy, P=0.001, HR =0.616), use of RT (P<0.001, HR =0.562) and use of CT (P<0.001, HR =0.621). In the subgroup analysis, the combination of thyroidectomy, RT and CT demonstrated the best OS outcome when compared with other therapeutic modalities. Surgery, RT and CT were all strong prognostic factors for improved OS in metastatic ATC patients. In addition, treatment approaches consisting of thyroidectomy were beneficial compared with nonsurgical treatment. However, given the limited benefit of only a few months in the clinic, we suggest that thyroidectomy in combination with RT and CT should be delivered in selected patients with caution for better management of metastatic ATC.

MON-446 Anaplastic Thyroid Cancer Presenting with Brain Metastasis: 17-Year Progression Free Survival

Background: Anaplastic Thyroid Cancer is the most aggressive thyroid cancer with a median survival of just five months. Long term survival has been reported in locally aggressive cases, but has yet to be reported in metastatic disease. Case Information: A 34-year-old male presented with symptoms of dizziness, confusion, intermittent headaches, and erratic behavior for two weeks. CT of the head revealed a 1 cm ring enhancing lesion in the left parietal lobe with surrounding vasogenic edema. He was taken to the operating room for a left parietal craniotomy and a vascular, solid mass was removed. Initial pathology suggested papillary thyroid origin due to positive staining for thyroid transcription factor (TTF) and thyroglobulin (Tg). On exam, he had a palpable 3 cm mass in the right thyroid lobe with no associated adenopathy. He underwent thyroidectomy to optimize post-operative radioactive iodine treatment. Intraoperative frozen section revealed anaplastic thyroid cancer and final pathology revealed anaplastic carcinoma identical to the brain lesion. The tumor pathology showed extension through the thyroid capsule with lymphovascular invasion and one of two positive lymph nodes. Post-operatively, he underwent 15 cycles of whole brain radiation therapy for a total of 35 Gy. Two additional brain lesions were identified after thyroidectomy and a third was identified after whole brain radiation. He underwent stereotactic radiosurgery of these three lesions less than two months after thyroidectomy. The patient went on to receive modified mantle field irradiation (46 cycles, total 55.2 Gy) to the neck, thyroid bed, and the upper mediastinum. Additionally, he received chemotherapy with doxorubicin 6-8 weeks and temozolomide for 2 years. Thyroid uptake studies showed minimal residual iodine-avid disease and, in the setting of chemotherapy-induced cytopenias, radioactive iodine treatment was not administered. The patient has currently survived 17 years post-treatment. His persistent, but stable, brain lesions are being followed with serial imaging. He remains clinically and neurologically asymptomatic. Conclusions: This is the first case presenting with long-term survival in a patient with metastatic anaplastic thyroid carcinoma. A multidisciplinary course with early aggressive surgical removal, adjuvant treatment with chemotherapy and radiation, and long term imaging follow up may be an acceptable treatment plan for stable patients.

Metastatic Anaplastic Thyroid Carcinoma in Complete Remission: Morphological, Molecular, and Clinical Work-Up of a Rare Case

Anaplastic thyroid carcinoma (ATC) exhibits an exceedingly poor prognosis, and the current treatment options are, for most cases, palliative by nature. Few reports of long-time survivors exist, although in these patients, tumors often were limited to the thyroid and/or regional lymph nodes. We describe a 64-year-old male who developed a rapidly growing mass in the left thyroid lobe. A fine-needle aspiration biopsy (FNAB) was consistent with ATC, and the patient underwent preoperative combined chemo- and radiotherapy followed by a hemithyroidectomy. The ensuing histopathological investigation was consistent with ATC adjoined by an oxyphilic well-differentiated lesion, likely a Hürthle cell carcinoma. Tumor margins were negative, and no extrathyroidal extension was noted. Focused next-generation sequencing analysis of the primary tumor tissue identified a TP53 gene mutation but could not identify any potential druggable targets. Additional Sanger sequencing detected a C228T TERT promoter mutation. The tumor was found to be microsatellite stable and displayed PDL1 expression in 80% of tumor cells. Following a CT scan 1 month postoperatively, metastatic deposits were suspected in the lung as well as in the left adrenal gland, of which FNAB verified the latter. Remarkably, upon radiological follow-up, the disease had gone into apparent complete remission. The patient is alive and well with no signs of residual disease after 12 months of follow-up. We here summarize the clinical, histological, and molecular data of this highly interesting patient case and review the literature for possible common denominators with other patients with disseminated ATC.

Reintroducing the Sodium-Iodide Symporter to Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC), the most aggressive form of thyroid cancer, is unresponsive to radioiodine therapy. The current study aimed to extend the diagnostic and therapeutic application of radioiodine beyond the treatment of differentiated thyroid cancer by targeting the functional sodium-iodide symporter (NIS) to ATC. The study employed nanoparticle vectors (polyplexes) based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG) and coupled to the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand in order to target a NIS-expressing plasmid (LPEI-PEG-GE11/NIS) to EGFR overexpressing human thyroid carcinoma cell lines. Using ATC xenograft mouse models, transfection efficiency by 123I scintigraphy and potential for systemic radioiodine therapy after systemic polyplex application were evaluated. In vitro iodide uptake studies in SW1736 and Hth74 ATC cells, and, for comparison, in more differentiated follicular (FTC-133) and papillary (BCPAP) thyroid carcinoma cells demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS that correlated well with EGFR expression levels. After systemic polyplex injection, in vivo 123I gamma camera imaging revealed significant tumor-specific accumulation of radioiodine in an SW1736 and an Hth74 xenograft mouse model. Radioiodine accumulation was found to be higher in SW1736 tumors, reflecting in vitro results, EGFR expression levels, and results from ex vivo analysis of NIS staining. Administration of 131I in LPEI-PEG-GE11/NIS-treated SW1736 xenograft mice resulted in significantly reduced tumor growth associated with prolonged survival compared to control animals. The data open the exciting prospect of NIS-mediated radionuclide imaging and therapy of ATC after non-viral reintroduction of the NIS gene. The high tumor specificity after systemic application makes the strategy an attractive alternative for the treatment of highly metastatic ATC.

Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

Abstract 1724: Genomic mechanisms of exquisite sensitivity and acquired resistance to everolimus in a patient with anaplastic thyroid carcinoma

Abstract Understanding genetic mechanisms of sensitivity and resistance to targeted anticancer therapies may improve patient selection and rational treatment designs. One approach to increase this understanding involves the study of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder on a study of the allosteric mTOR inhibitor everolimus in thyroid cancer: a 57-yr-old woman with refractory metastatic anaplastic thyroid carcinoma (ATC), a highly aggressive neoplasm with no adequate therapies and a median survival of 5 months. After beginning treatment with everolimus, the patient experienced a near complete response that lasted for 18 months, followed by progressive disease, which was then re-biopsied. To date, mechanisms of clinical resistance to mTOR inhibition have not been described. We performed whole exome sequencing (WES) of both pre-treatment and drug resistant tumor tissue to look for the underlying mechanisms of exquisite sensitivity and acquired resistance to everolimus. WES of the pre-treatment tumor revealed a somatic nonsense mutation in TSC2, a tumor suppressor gene whose inactivation is known to activate the mTOR pathway and result in sensitivity to mTOR inhibition in some cancers. WES of the drug resistant tumor additionally revealed a mutation in mTOR (mTOR-F2108L) not detected in the pre-treatment tumor. Structural modeling demonstrated that this mutation occurs in the FKBP12-rapamycin binding domain of mTOR and is predicted to prevent binding of the drug to the protein. Overexpressing mTOR-F2108L in HEK-293T cells resulted in significant resistance to rapamycin compared to cells expressing wild type (wt) mTOR. In cells expressing the mutant mTOR, rapamycin did not decrease phosphorylation of S6K1, a downstream target of mTOR, compared with cells expressing wt mTOR. Notably, cells expressing mTOR-F2108L remained sensitive to the direct TOR inhibitor torin, suggesting a therapeutic approach to overcome resistance in this patient. In summary, we add ATC to the growing list of cancers found to be exquisitely sensitive to everolimus when activating mTOR pathway mutations are present. Moreover, we present the first reported, to our knowledge, mechanism of acquired resistance to everolimus identified in patients. The fact that this occurs via a binding domain mutation that blocks allosteric mTOR inhibition suggests that followup therapy with direct TOR inhibitors may still have benefit in some patients who develop resistance to everolimus. The use of precision medicine approaches in ATC to screen for alterations in the mTOR pathway may help identify subsets of patients who would benefit from targeted therapies directed against mTOR. Moreover, the use of serial biopsies to profile patients who develop resistance to everolimus could dictate optimal followup treatment in ATC and other cancers. Citation Format: Nikhil Wagle, Brian C. Grabiner, Eliezer M. Van Allen, Ali Amin-Mansour, Scott C. Carter, Nathanael Gray, Justine A. Barletta, Scott J. Swanson, Daniel Ruan, David J. Kwiatkowski, Glenn J. Hanna, Robert I. Haddad, David Sabatini, Pasi A. Janne, Levi A. Garraway, Jochen H. Lorch. Genomic mechanisms of exquisite sensitivity and acquired resistance to everolimus in a patient with anaplastic thyroid carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1724. doi:10.1158/1538-7445.AM2014-1724

Abstract 1278: Phase 1 study of CS-7017, an oral PPAR-γ agonist, in combination with paclitaxel in advanced anaplastic thyroid cancer

Abstract Background: Stage IVC (metastatic) anaplastic thyroid cancer (ATC) has a median overall survival (OS) of only 1.9 months. Single agent paclitaxel has modest activity in ATC. In pre-clinical studies, CS-7017 inhibited ATC proliferation through a novel mechanism–activation of PPAR-γ, followed by sequential upregulation of RhoB, then p21. Moreover, CS-7017 augmented the proapoptotic effects of paclitaxel. Based on these results, a multicenter study was conducted to determine if CS-7017+paclitaxel might prove safe and effective in advanced ATC. Design: A Phase 1 study was conducted to determine the Phase 2 dose. In Phase 1, patients received CS-7017 orally BID for one week (run-in phase), followed by a 3 h iv infusion of paclitaxel (175 mg/m2) every 3 weeks in combination with BID CS-7017. CS-7017 doses were escalated (0.15, 0.3, or 0.5 mg). Tissue biopsies were obtained at baseline and at one and three weeks for immunohistochemistry of PPAR-γ responsive proteins; serum CS-7017 PK studies were also performed. Results: Nineteen patients were enrolled, but 4 were not dosed (3 due to progression, 1 ineligible). Seven participated in CS-7017 dose levels 1a/1b (0.15 mg BID), six in dose level 2 (0.3 mg BID), and two in dose level 3 (run-in phase only–0.5 mg BID). Demographics: Of the 15 treated patients, 10 (67%) were women. Median age was 59 years (range: 43-82) Efficacy: Of 15 patients receiving drug, one had a confirmed partial response (PR) lasting from Day 69 to Day 175, and eight had stable disease (SD) as their best response. Median Time to Progression in 7 patients at Dose Level 1 was 49 days, but 70 days in Dose Level 2 (43% prolongation); corresponding median survival was 99 (0.15 mg BID) vs. 140 days (0.3 mg BID, 42% increase). Median peak CS-7017 blood level was 8.6 ng/mL (range: 5.1 to 13.7) for Level 1 and 22.0 ng/mL (17.0 to 31.5) for Dose Level 2. Adverse Events: Ten patients had AEs ≥ Grade 3, with two (anemia and localized edema) related to CS-7017. Thirteen events of fluid retention/edema were reported in 8 patients, with only 2 events of CTCAE grade ≥ 3. Eight patients had ≥ one SAE, with one (anemia) due to CS-7017. One SAE (anaphylactic reaction) was related to paclitaxel. No dose limiting toxicity was observed. Immunohistochemistry: Biopsies were available on 7 patients. PPAR-γ, RXR-α, RhoB were present in all; Angiopoietin-like 4 was induced by CS-7017. Conclusions: Combination therapy with CS-7017 and paclitaxel was tolerated and has biologic activity in patients with metastatic anaplastic thyroid carcinoma, with initial exploratory data suggesting a dose-dependent improvement in time to progression and survival in response to escalating CS-7017 dosage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2011-1278