Metastatic Medullary Thyroid Carcinoma Research Articles

12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation

Abstract Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None. Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients >= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range <= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T>C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00 Presentation: 6/2/2024

Variable Tracer Avidity and Interlesional Heterogeneity on 18 F-FDG, 68 Ga-DOTATATE, and 68 Ga-DOTA-FAPi-04 PET/CT Imaging in a Single Individual Patient With Progressive Metastatic Medullary Thyroid Carcinoma.

In medullary thyroid carcinoma (MTC), distant metastases have few therapeutic options with low success rates and substantial toxicity in many patients, warranting exploration of alternate systemic treatments with fewer adverse effects. The fibroblast activation protein inhibitor (FAPI)-based PET/CT opens new avenues for several cancers, including MTC. A case of MTC with varying tracer avidity and interlesional heterogeneity on 18 F-FDG, 68 Ga-DOTATATE, and 68 Ga-DOTA-FAPI-04 PET/CT imaging is presented. 68 Ga-DOTA-FAPI-04 PET/CT exhibited superior efficacy in terms of visualization of metastatic soft tissue, lymph nodal, and skeletal lesions, with enhanced target-to-background ratio compared with the other two, facilitating the detection of these lesions, thereby demonstrating the potential for theranostic translation.

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

Clues for Early Diagnosis of MEN2B Syndrome Before Medullary Thyroid Carcinoma.

Early onset medullary thyroid carcinoma, later pheochromocytomas, and nonspecific extra-endocrine features (hypermobility and persistent constipation) are part of the clinical phenotype of Multiple Endocrine Neoplasia type 2B (MEN2B). A de novo pathogenic M918T variant in the rearranged during transfection proto-oncogene is usually identified. Affected children are often seen by multiple clinicians over a long period before consideration of a diagnosis of MEN2B, with metastatic medullary thyroid carcinoma often the precipitator. We describe the clinical presentation and course of 5 children ultimately diagnosed with MEN2B in New South Wales and the Australian Capital Territory, Australia between 1989 and 2021. All cases had intestinal ganglioneuromatosis that could have prompted an earlier diagnosis. Population wide newborn genomic screening for rare diseases is on the horizon. We propose that MEN2B genomic screening should be included in newborn screening programs and that careful exclusion of intestinal ganglioneuromatosis would allow earlier identification leading to improved clinical outcomes.

Phase II trial of regorafenib in metastatic medullary thyroid carcinoma (MTC) and radioactive iodine refractory differentiated thyroid carcinoma (RAIR DTC).

6109 Background: Multi-kinase inhibitors show activity in both MTC & RAIR DTC. However, therapeutic options are limited after disease becomes refractory to one or two lines of standard of care therapies. We report here results of an investigator-initiated phase II clinical trial evaluating regorafenib in this population (NCT02657551). Methods: Patients with MTC (disease progression within 6-12 months, mo, prior to study registration) and RAIR DTC (progression within 12 mo) were enrolled regardless of prior lines of therapy. Regorafenib (each cycle 3 weeks ON/1 week OFF) was started at 80 mg daily, with planned escalation after 1 & 2 weeks to 120 mg daily & 160 mg daily, respectively, in absence of significant treatment-related adverse events (TRAEs). The highest tolerated dose was continued from cycle 2 onwards until progression. The primary endpoints were proportion progression-free at 10 months in MTC & overall response rate (ORR) by RECIST v1.1 in RAIR DTC. Simon two-stage design was utilized; MTC: <2 in 8 progression-free in first stage stops for futility, stage 2: enroll 13, >6/21 provides 81% power for proportion >20%; DTC: <3 in 9 in response in first stage stops for futility; stage 2: enroll 11, >7/20 provides 81% power for ORR >25%. Results: 17 patients (8 MTC, 9 DTC) were enrolled between April 2016 and October 2022. Among MTC, median (range) age was 54.7y (48.1, 62.8), 25% female. Among DTC, median age (range) was 62.8y (44.3, 75.8), 55.6% female. In MTC group, the proportion progression-free at 10 months was 12.5% (95% CI 0.3%, 52.7%) & did not meet the criteria to continue into 2nd stage. ORR in MTC group was 12.5% (95% CI 0.3%, 52.7%). In DTC group, ORR was 11.1% (95% CI 0.3%, 48.2%), & did not meet the criteria to continue into 2nd stage. No patients were receiving treatment at cutoff. Patients with MTC and DTC with objective responses (1 each) had received one (vandetanib) & no prior systemic therapy, respectively. The most common reason for discontinuation was disease progression in MTC (4, 50%) & DTC (5, 55.6%). Grade 3-4 TRAEs were observed in 8/17 (47.1%), most frequent were diarrhea, hypophosphatemia, & hypertension (each grade 3: 2, 11.7%). There were no treatment-related deaths. Median progression-free survival (PFS) in MTC & DTC were 5.3 (95% CI 3.6, 20.1) & 11.0 (95% CI 1.2, 24.0) mo, respectively. Median overall survival (OS) in MTC & DTC were 16.1 (95% CI 5.2, NA) and 20.1 (95% CI 1.6, NA) mo, respectively. Conclusions: Regorafenib clinical trial did not reach its primary endpoints in MTC and DTC. Analyses are planned to investigate impact of prior VEGFR inhibitor exposure, biomarkers and resistance mechanisms. Clinical trial information: NCT02657551 . [Table: see text]

Clinical and molecular features and survival in thyroid cancer with brain metastases.

2023 Background: Brain metastases (BM) in advanced thyroid cancer are rare; however, they may be underreported as staging brain imaging is not routine. Prognostic features and molecular alterations for this group are poorly described. We characterized the clinical and molecular features of thyroid cancer with BM and evaluated differences in survival. Methods: In this single-center retrospective analysis, patients with metastatic radioactive iodine refractory well-differentiated, poorly-differentiated, or medullary thyroid carcinoma seen at the Princess Margaret Cancer Center from 2007-2022 were included. Electronic medical records were reviewed to collect clinicopathologic and treatment data. All patients had tumor next-generation sequencing (NGS) by a targeted gene panel. Overall survival (OS) from initial medical oncology consultation was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazards models. Results: Of 248 patients with advanced thyroid cancer, 41(17%) were diagnosed with BM. The median interval from thyroid cancer diagnosis to BM development was 6.49 years (y) (IQR 3.51- 14.35 y). The median age at the time of BM diagnosis was 63.6 y and 23 (56%) were male. Most (76%) were asymptomatic at the diagnosis of BM and 80% had an ECOG of 0-1. Among patients with well-differentiated histology, 27 (18%) developed BM, while 7 (12%) with poorly-differentiated and 7 (19%) with medullary thyroid cancer developed BM. The most common molecular alterations included BRAFV600E (n=19), TERT (n=11), RAS (n=9), RET (n=8), and FANCA (n=3). Patients were treated with surgery (n=5), stereotactic radiation (n=21), whole brain radiation therapy (n=12), or a combination of both (n=2). OS was similar in patients with BM compared to those without (6.05 vs 6.45 y). There were no differences in histology or molecular alterations between patients that developed BM compared to those who did not. The median survival from the time of BM was 3.23 y. Patients with BM with ≥4 lesions had worse survival (0.52 vs 5.09 y, p=0.01). There were no differences in survival based on histology, symptoms, treatment or molecular alterations among those with BM. Conclusions: This is one of the largest reported thyroid BM cohorts and the first with complete NGS. The prevalence of BM in our cohort was higher than previously described, often diagnosed incidentally. Screening for BM in advanced thyroid cancer may detect higher rates, offering prognostic insights. While the number of BM was predictive of survival, molecular alterations did not predict BM development or survival and larger studies are needed.

Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

Evaluation of calcitonin measurement in fine needle aspirates in the diagnosis of primary and metastatic medullary thyroid carcinoma

Serum CT represents the tumoral marker of medullary thyroid carcinoma (MTC), and is a main diagnostic tool and follow-up after treatment. Nevertheless, calcitonin levels can be elevated in a number of other situations and does not always distinguish MTC from other clinical circumstances, particularly when elevation remains moderate. Fine needle aspiration biopsy is a widely used examination for the investigation of thyroid nodules and lymph nodes, but its sensitivity for the diagnosis of MTC remains low ranging from 45% to 63%. Calcitonin measurement in fine needle aspiration wash out fluid has been reported as reliable, and is recommended by the experts of American Thyroid Association (ATA) in their 2015 consensus for the management of MTC even if its diagnostic is not standardized yet. Material and methods: Twenty patients with 45 lesions (thyroid nodule and lymph node) were included in this study; calcitonin was performed in each of them, the puncture needles were washed with 1ml of saline solution to obtain to measure Calcitonin in fine needle aspiration washout fluid. Results: After surgery 32 MTC were diagnosed on histology. Receiver operating curve (ROC curve) indicated CT in fine needle aspiration >22.99pg/ml as more accurate cut off value with a sensitivity and specificity of 96.87% and 100%. Calcitonin ratio was evaluated too, the cut off value being>0.64 with a sensitivity of 62.5% and specificity of 100%. Conclusion: Calcitonin in fine needle aspiration wash out fluid constitutes an excellent diagnostic tool of MTC with the use of 22.99pg/ml threshold.

Ectopic ACTH-dependant Cushing's syndrome in MEN2A and metastatic medullary thyroid carcinoma: Challenges beyond Diagnosis

Ectopic ACTH-dependant Cushing's syndrome in MEN2A and metastatic medullary thyroid carcinoma: Challenges beyond Diagnosis

RET 898-901Del mutant, a variant of unknown significance, has a durable response to Pralsetinib in a Medullary Thyroid Carcinoma patient

Background Patients with distant metastatic Medullary Thyroid Carcinoma (MTC) have an estimated 40% ten-year survival rate. Gain of function mutations in the REarranged during Transfection or RET gene in MTC can result in an aggressive phenotype resistant to traditional therapy. In this case report, we describe the treatment of an MTC patient with a unique RET kinase deletion mutation. Case presentation Since diagnosis, 21 years ago, this patient has had chronically elevated calcitonin levels (>40,000 pg/mL) that was unable to be controlled by conventual therapy and clinical trials. As result of uncontrolled MTC, metastatic disease was found in the spine, liver, and lungs. Circulating tumor DNA (ctDNA) analysis identified a RET 898-901Del mutation, reported as a variant of unknown significance. The treating physician identified that the deletion was in the activation loop of RET kinase and considered that the mutation was constitutively activating RET kinase. The patient was prescribed Pralsetinib, a small molecule inhibitor targeting the ATP binding site of RET. Pralsetinib treatment achieved a durable response and was able to significantly decrease serum calcitonin levels (<200 pg/mL) and tumor size. Conclusion This RET deletion mutation is a pathogenic mutation with comparable enzymatic activity to the more common RET M918T mutation. The case report highlights the versatility of structural biologic approaches to guide therapeutic decisions.

Patterns of Treatment Failure After Selective Rearranged During Transfection (RET) Inhibitors in Patients With Metastatic Medullary Thyroid Carcinoma.

Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs. MTC patients who were initiated on RETi between 2018 and 2022 were included. Baseline characteristics, RET mutational status, RETi response, available tumor tissue and molecular profiles sampled pre- and post-RETi were analyzed. Among 46 MTC patients on RETi during the study period, 26 patients had discontinued at data cut-off because of progression (n = 16), death (n = 4), and toxicity (n = 6). The most frequent RET mutations at baseline were p.M918T (n = 29), and p.C634X (n = 6). Pre- and post-RETi molecular profiles were available in 14 patients. There was no primary resistance on pre-RETi samples. Post-RETi profiles revealed a bypass mechanism of resistance in 75% of the cases including RAS genes mutations (50%), FGFR2 and ALK fusions and and MYC p.P44L. RET solvent from and hinge region mutations was the only resistance mechanisms in 25% of the cases. Tumor samples from initial thyroidectomy, pre- and post-RETi, from six patients, showed an increase of the mean Ki 67-index of 7%, 17% and 40% respectively (P = 0.037) and a more aggressive poorly differentiated histology in three patients. Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.

Abstract #1399687: Precision Oncology in the Management of Medullary Thyroid Cancer in an Adolescent with MEN2B, 1-year Follow-up

Medullary thyroid carcinoma (MTC) is a rare but aggressive thyroid tumor, with 25% of hereditary and 75% of sporadic forms. RET mutations are found in 98% of hereditary MTC and in 55% of sporadic MTC. Targeted therapies are a management option for patients with progressive or symptomatic disease with locoregional or metastatic MTC. We present the case of an adolescent with type 2B multiple endocrine neoplasia (MEN-2B) syndrome with an optimal response to pralsetinib. A 14-year-old adolescent, she was admitted for maxillofacial surgery in September 2019 due to a thyroid nodule and cervical nodes whose FNA reported: MTC; she underwent total thyroidectomy extended to prethyroid muscles + bilateral radical dissection. The pathology reported: multicentric MTC: in LTL tumor of 3.0 x 1.5cm, with invasion of tumor capsule and extraglandular 4mm to the adiposomuscular plane, lymphatic and venous permeation, tumor in isthmus of 1cm and RTL of 0.6cm; Bilateral periglandular and cervical lymph node metastasis (23/58) EC-IVA. Endocrinological evaluation showed a marfanoid phenotype, thick lips, tongue neuromas, diastema, and a history of chronic constipation with segmental colonic dilatation on abdominal radiography. No history of HTA. No similar family history. PET-CT-18FDG: mediastinal lymph nodes suggestive of metastasis. She received cervical-mediastinal radiotherapy: 6000 cGy in April 2020. Follow-up was interrupted due to a pandemic, she was readmitted with mediastinal disease progression according to PET-CT in June 2021. She had access to a genetic NGS tumor study that showed the RET M918T mutation. In December 2021, she started Pralsetinib 200 mg/day, achieving a biochemical and structural response in follow-up sustained to date, without developing major adverse events. The NCCN Guidelines advise performing the RET study at the time of initial diagnosis. Targeted therapies have helped supplant cytotoxic chemotherapy, which has low efficacy against disease progression, but there is still the problem of toxic side effects and frequent development of tumor resistance when using the current treatment regimen. In this case, with the MEN-2B criteria established, the RET M918T mutation detected. and presenting with disease progression (elevated calcitonin and CEA, associated with mediastinal disease progression), she agreed to an expanded program of anti-RET therapy with Pralsetinib, demonstrating safety and efficacy after 1 year of use.

The Role of a Neoadjuvant RET Inhibitor in Medullary Thyroid Cancer

The Role of a Neoadjuvant <i>RET</i> Inhibitor in Medullary Thyroid Cancer

Peptide Receptor Radionuclide Therapy in Patients With Advanced Progressive Medullary Thyroid Cancer: Efficacy, Safety, and Survival Predictors.

Progressive metastatic medullary thyroid carcinoma (MTC) is often characterized by rapid disease progression and poor prognosis, with only few therapeutic options available. Peptide receptor radionuclide therapy (PRRT) has demonstrated remarkable success in the management of gastroenteropancreatic neuroendocrine tumors and has also been suggested to treat MTC. However, evidence on its effectiveness and long-term outcome for this indication is still limited. The objective of this study was to assess the safety and efficacy of PRRT in patients with advanced, progressive MTC and to determine survival. Potential predictors of survival were also evaluated. From September 2003 to June 2019, 28 patients (15 men and 13 women; mean age, 49 ± 14 years) with progressive, somatostatin receptor-positive advanced MTC received PRRT with 177Lu- or 90Y-labeled somatostatin analogs at Zentralklinik Bad Berka, Germany. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 5.0. Treatment response was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, as well as molecular imaging criteria (European Organisation for Research and Treatment of Cancer). Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. Seventy-seven cycles of PRRT were administered (mean cumulative administered activity, 16.0 ± 7.8 GBq). No acute or long-term grade 3/4 toxicity was recorded with a follow-up of 3 to 140 months, except for 1 patient (4%) who suffered from grade 3 anemia (possibly related to disease progression). According to the RECIST criteria, the disease control rate after 3 to 4 months of PRRT was 56% (partial remission, 12%; stable disease, 44%). The disease control rate (72%) was higher by molecular response evaluation. Median OS and PFS were 63.7 and 10.1 months, respectively. The annual OS rates were 84% at 1 year, 65% at 3 years, 57% at 5 years, and 18% at 10 years. The annual PFS rates were 42% at 1 year, 21% at 2 years, and 13% at 5 years. Patients with bone metastases had poorer OS and PFS than those without metastases (median OS, 58.7 vs 92.3 months [P = 0.035; hazard ratio, 2.7; 95% confidence interval, 0.92-7.84]; median PFS, 8.5 vs 12.8 months [P = 0.592; hazard ratio, 1.2; 95% confidence interval, 0.56-2.76]). Peptide receptor radionuclide therapy was well tolerated and effective in patients with advanced, aggressive MTC. Bone metastasis was an independent adverse prognostic factor for OS.

Metastatic medullary thyroid carcinoma (MTC): disease course, treatment modalities and factors predisposing for drug resistance.

MTC has varying clinical course. In cases with metastatic disease (meta-MTC) further therapeutic modalities (locoregional and/or Tyrosine-Kinase-Inhibitors, TKIs) are needed. Clinical features, disease progression, response to therapy and possible factors predisposing to TKIs response-resistance in meta-MTCs were investigated. Out of 338 MTC patients 54 had meta-MTC and were followed for 0.7-46 years (median 10.5); therapeutic interventions and response to therapy were recorded retrospectively. Of 54 meta-MTC patients, 34/54 were men, 44/54 sporadic (age-at-diagnosis 47 ± 17.4 years, range: 5-78). Distant metastases at diagnosis were present in 12/54 (≥2 loci in 8/12), 7/12 received TKIs; During follow-up metastases occurred in 42/54 (within 0.6-25 years from diagnosis, median 5 yrs). Locoregional therapies were administered to 44/54 (81.5%) and TKIs to 40/54 (74.1%). Vandetanib was administered in 30 patients (24 as first-line therapy). The median progression-free-survival, PFS) was 48 months (range 4-120), partial response (PR): 26.7%, stable disease (SD): 23.3%, progressive disease (PD): 50.0%, cancer-specific survival: 44.8%, (16 in ongoing-therapy). More favorable disease course was recorded in familial-MTC compared to sporadic (p = 0.02) and in those patients with serious-adverse-events (SAEs) under treatment (p = 0.027). Those with biochemical progression under vandetanib, later showed more frequently structural progression (p = 0.007). Ten patients received cabozantinib (8/10 as second-line therapy, median PFS:11 months (3-36 months), 8/10 died). Three RET-mutant patients received selpercatinib; all showed PR. Within the total follow-up period, the response to therapy was: PR: 8/54 (14.8%), SD: 15/54 (27.8%), PD: 31/54 (57.4%), cancer-specific survival 46.3%. Mortality was higher in older patients (≥60 years) compared to younger ones (<60 yrs) (83.3 vs 45.2%, p = 0.021). Outcome was better in familial-MTC vs sporadic (PR: 50 vs 6.8%, SD: 20 vs 29.5%, PD: 30 vs 59.1%, p = 0.007). Meta-MTCs treatment results in disease stabilization in 42.6% during a median 10.5 year follow-up. Combination of locoregional and systemic therapies may result in more favorable PFS. Family history, younger age, SAEs may predict better response; biochemical escape under TKI needs to be followed-up closely as it may indicate disease progression.

Vandetanib.

Vandetanib is an anti-cancer drug called an antineoplastic kinase inhibitor. The FDA authorized vandetanib on April6, 2011 for the treatment of nonresectable, locally progressed, or metastatic medullary thyroid carcinoma in adults. Because Vandetanib can make the Q-T interval last longer, it shouldn't be given to people with serious heart problems like congenital long QT syndrome or heart failure that hasn't been fixed yet. This chapter provides an overview of Vandetanib's physical and molecular properties, mode of action, pharmacokinetics, and common applications. In furthermore, a detailed summary of the reported techniques of Vandetanib measurement will be provided to assist analysts in selecting the most practical approach for its estimation in routine analysis. This chapter will also explain the synthesis methods developed in the preparation of vandetanib as well as pharmacology of its. In addition, this section summarizes the analytical and characterization techniques utilized to characterize vandetanib row material.

ODP450 A Case of Metastatic Medullary Thyroid Cancer Presenting with Pathologic Hip Fracture

Abstract Introduction Medullary thyroid cancer accounts for less than 5% of thyroid malignancies. Distant metastatic disease typically presents in lymph nodes, lung, liver and bone. We present a patient who initially presented with a pathologic hip fracture with bone biopsy revealing medullary thyroid carcinoma. Case Description A 44-year-old male with no past medical history presented to the emergency department for right hip pain following a mechanical fall. Imaging showed a right femoral neck pathologic fracture as well as lytic lesions within the right femoral neck and right ilium. Family history was significant for pancreatic cancer and breast cancer. The patient underwent bone biopsy of the right femur followed by total hip arthroplasty. Bone biopsy revealed metastatic medullary thyroid carcinoma. Thyroid ultrasound showed a 1.2 centimeter right solid hypoechoic nodule along with extensive cervical lymphadenopathy. Further imaging revealed metastatic disease throughout the thoracic spine, mediastinal lymphadenopathy, and a left 2.2 centimeter adrenal lesion with peripheral enhancement and possible necrosis. Carcinoembryonic antigen (CEA) level was 551 ng/mL (normal &amp;lt;4.7), calcitonin was 2,498 pg/mL (normal &amp;lt;10), and calcium levels were normal. Plasma free metanephrines were normal and plasma normetanephrines were less than two times the upper limit of normal. Genetic testing on the bone biopsy specimen revealed a RET p. C618S variant. Germline RET testing was collected. The patient was discharged with close follow-up with oncology to initiate systemic therapy and follow-up with endocrinology for the adrenal mass. Discussion Majority of cases of medullary thyroid carcinoma are sporadic. Patients typically present with a thyroid nodule with many having cervical lymph node involvement at diagnosis and 5-10% having distant metastatic disease. Our patient's initial presentation was unique in that he presented with a pathologic fracture. Bone metastases can be seen in about 30% of cases of metastatic medullary thyroid carcinoma. Calcitonin levels greater than 500 pg/mL require additional imaging to exclude metastatic disease. If RET mutational status is unknown, patients should be screened for primary hyperparathyroidism and pheochromocytoma. Screening for pheochromocytoma is critical in preoperative management of these patients. Treatment for patients with metastatic disease involves surgery, external beam radiotherapy, and kinase inhibitors. Presentation: No date and time listed

LBODP099 A Young Patient With Undifferentiated And Advanced Medullary Thyroid Carcinoma With Negative RET - CASE REPORT

Abstract A Young Patient With Undifferentiated And Advanced Medullary Thyroid Carcinoma With Negative RET – CASE REPORT INTRODUCTION: Medullary Thyroid Carcinoma (MTC) is a rare and aggressive form of thyroid cancer that arises from C cells, representing 5% of all thyroid malignancy. The biochemical characteristic of MTC is the elevation of serum calcitonin (CTN), which aids in the initial diagnosis and surveillance of this disease. Another important, but less specific marker in the follow-up is the carcinoembryogenic antigen (CEA). Although, it is observed in the Undifferentiated MTC that there is a disproportion between the expected values of CEA and CTN. Case Report A previously healthy 16 years old female patient was hospitalized for the investigation of cervical discomfort, involuntary weight loss and progressive back pain for 9 months. She had a BMI of 14.9kg/cm2, a palpable thyroid nodule measuring approximately 2. 0cm and painful cervical lymph node enlargement. Laboratory tests showed CTN 79.1pg/mL, CEA 4999.42ng/mL added with an independent PTH hypercalcemia. Thyroid US showed a solid nodule with lobulated contours, heterogeneous echotexture, predominantly hypoechogenic, with its longest axis parallel to the skin, measuring approximately 2.4×0.9×0.9 cm, located in the lower middle third of the right thyroid lobe (TI -RADS 4) added to multiple lymph nodes inthe anterior cervical area (in agreement with the neck CT). Regarding the staging Chest CT showed a metastasis suggestive nodulation; Cranial CT, bone scan and total spine MRI showed evidence of several infiltrative nodular formations with heterogeneous enhancement affecting the skullcap, sacrum, iliac bones and multiple vertebral bodies. Sacral bone biopsy was performed giving us the diagnose of a metastatic Medullary Thyroid Carcinoma (MTC). A FineNeedle Aspiration (FNA) of the thyroid nodule and cervical lymph node showed calcitonin levels of 31.1pg/mL added with positive immunohistochemistry for chromogranin,synaptophysin, CD56 and Calcitonin in a focal manner, confirming the hypothesis of Undifferentiated CMT. Genetic testing was performed by next-generation sequencing of the genes ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53 (including promoter), VHL, which results were negative for all pathogenic variants, probably pathogenic or VUS therefore being considered a sporadic MTC. Patient was referred for cervical radiotherapy and started Vandetanib. Conclusion Serum CTN is the main diagnostic and surveillance marker of MTC. CEA is another marker that must be taken into account. We report the case of a young patient diagnosed with metastatic RET negative MTC with disproportionate values of CTN and CEA, which suggests its undifferentiated feature, revealing the importance of joint assessment of these two markers. Presentation: No date and time listed

RF07 | PSUN366 An Uncommon Path Leading to Diagnosis of Multiple Endocrine Neoplasia 2A

Abstract Introduction MEN2 is a rare Autosomal Dominant disorder resulting from mutations in the RET proto-oncogene. MEN2 is classified into two distinct syndromes: MEN2A and MEN2B. MEN2A is a syndrome that presents with Medullary Thyroid Carcinoma (MTC) in 90% of adult gene carriers, unilateral or bilateral pheochormocytoma in 50%, and multigland parathyroid tumors in 20-30% of affected individuals. Other rare variants of MEN2 include Familial Medullary Thyroid Carcinoma (FMTC), MEN2A with cutaneous lichen amyloidosis, and MEN2A or FMTC with Hirschprung's disease. We present a patient with incidentally noted elevated calcitonin levels, later diagnosed with MEN2A. Clinical Case 37-year-old Caucasian male was referred to our clinic for elevated calcitonin levels noted on lab work done as part of evaluation and management for weight loss prior to initiating GLP-1 agonists. He was diagnosed with hypothyroidism and multinodular goiter and started on Synthroid. His only symptoms were weight gain, tiredness, soft stools and facial flushing He denied any family history of endocrine disorders. Physical exam was unremarkable. Pertinent labs included serum calcitonin 93 pg/mL (&amp;lt;10 pg/mL), serum CEAg 5.2 ng/mL (0-3 ng/mL), and work up for pheochromocytoma and hyperparathyroidism was negative. USG thyroid showed a left lobe thyroid nodule measuring 7×5×7 mm with macrocalcifications, a right lobe thyroid nodule measuring 8×5×10mm, and an abnormal left lateral level III LN. He underwent left thyroid lobectomy with level VI neck dissection (total thyroidectomy aborted due to hypoxia), and subsequently completion thyroidectomy with right central neck dissection. Pathology showed metastatic MTC with pathologic staging pT1aN1a. Genetic testing showed RET c. 1826G&amp;gt;A (p. C609Y) which is ATA – MOD risk. Patients’ father was also genetically screened and diagnosed with MEN2A and noted to have elevated calcitonin levels. He also subsequently underwent total thyroidectomy, which revealed medullary thyroid microcarcinoma. Conclusion A number of studies support that measurement of serum calcitonin is the most sensitive screening test for detecting occult MTC in individuals with thyroid nodules. Yet, the use of serum calcitonin in the routine evaluation of thyroid nodules is controversial due to absence of uniform calcitonin thresholds, high false positive values and unavailability of pentagastrin stimulation testing. Moreover, there are no recommendations based on the current data to check calcitonin levels prior to initiating GLP-1 agonists but their use is not recommended in patients with personal or family history of MTC/MEN2. Based on the above case, measurement of calcitonin levels should be a part of the work up in patients who present with thyroid nodules and are receiving GLP-1 agonists. Attention should also be paid to the importance of genetic counseling in first-degree relatives of patients with MEN2A. This allows for timely diagnosis and reduces morbidity and mortality. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Feasibility and therapeutic potential of the 68Ga/177Lu-DOTATATE theranostic pair in patients with metastatic medullary thyroid carcinoma

BackgroundThis study assessed: 1) the clinical efficacy of imaging with 68Ga-DOTATATE PET/CT (SSTR (somatostatin receptor)-PET) to detect medullary thyroid carcinoma (MTC); and 2) the therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in MTC patients. Materials and methodsPatients with histologically proven MTC and suspected recurrence following thyroidectomy, based on raised serum calcitonin levels, underwent SSTR-PET. In addition, to evaluate the clinical efficacy and safety of PRRT, the patients with intense uptake on SSTR-PET or 99mTc-octreotide scintigraphy underwent PRRT. The Common Terminology Criteria for Adverse Events (version 4.03) was used to grade adverse events after PRRT. Treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ResultsTwenty MTC patients (10 male, 10 female) with a median age of 48.5 years underwent SSTR-PET. SSTR-PET was positive in 17/20 patients (85%). Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score ≥ 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52–29.48). There were no cases of significant toxicity. ConclusionRadiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with 177Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC.