scholarly journals What's New in Molecular Targeted Therapies for Thyroid Cancer?

2021 ◽  
Vol 37 (2) ◽  
pp. 1-9
Author(s):  
Seonyoung Min ◽  
Hyunseok Kang
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapies ◽  
Radioactive Iodine ◽  
Checkpoint Inhibitors ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Thyroid Cancers ◽  
Ret Mutation ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Thyroid cancer refers to various cancers arising from thyroid gland. Differentiated thyroid cancers (DTCs) include papillary, follicular, and Hurthle cell carcinomas and represent cancers retain normal thyroid functions such as iodine uptake. Radioactive iodine (RAI) is generally used for upfront treatment of metastatic DTCs, but RAI refractory DTCs remain to be clinical challenges. Sorafenib and lenvatinib were approved for the treatment of RAI refractory DTCs and more recently, genomics-based targeted therapies have been developed for NTRK and RET gene fusion-positive DTCs. Poorly differentiated and anaplastic thyroid cancers (ATCs) are extremely challenging diseases with aggressive courses. BRAF/MEK inhibition has been proven to be highly effective in BRAF V600E mutation-positive ATCs and immune checkpoint inhibitors have shown promising activities. Medullary thyroid cancers, which arise from parafollicular cells of thyroid, represent a unique subset of thyroid cancer and mainly driven by RET mutation. In addition to vandetanib and cabozantinib, highly specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated impressive activity and are in clinical use.

scholarly journals Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

2016 ◽  
Vol 23 (4) ◽  
pp. R185-R205 ◽  
Author(s):  
David Viola ◽  
Laura Valerio ◽  
Eleonora Molinaro ◽  
Laura Agate ◽  
Valeria Bottici ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Survival Rates ◽  
Current Status ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Advanced Thyroid Cancer ◽  
Well Differentiated ◽  
Differentiated Thyroid Cancers

AbstractThyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15–20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

scholarly journals Foundation One Genomic Interrogation of Thyroid Cancers in Patients With Metastatic Disease Requiring Systemic Therapy

2020 ◽  
Vol 105 (7) ◽  
pp. e2346-e2357 ◽  
Author(s):  
Nicole M Iñiguez-Ariza ◽  
Sina Jasim ◽  
Mabel M Ryder ◽  
Ashish V Chintakuntlawar ◽  
John C Morris ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Outcome Measures ◽  
Systemic Therapy ◽  
Radioactive Iodine ◽  
Patient Characteristics ◽  
Genomic Alterations ◽  
Epithelial Tumor ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

scholarly journals Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

2021 ◽  
Vol 22 (6) ◽  
pp. 3117
Author(s):  
Loredana Lorusso ◽  
Virginia Cappagli ◽  
Laura Valerio ◽  
Carlotta Giani ◽  
David Viola ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Approved Drugs ◽  
New Generation ◽  
Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

scholarly journals Differentiated Thyroid Cancer: Management of Patients with Radioiodine Nonresponsive Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Naifa Lamki Busaidy ◽  
Maria E. Cabanillas
Keyword(s):  
Thyroid Cancer ◽  
Radioactive Iodine ◽  
Differentiated Thyroid Carcinoma ◽  
Thyroid Cancers ◽  
Cancer Management ◽  
Oncogenic Mutations ◽  
Differentiated Thyroid Cancers ◽  
Disease Free ◽  
Metastatic Thyroid Cancer

Differentiated thyroid carcinoma (papillary and follicular) has a favorable prognosis with an 85% 10-year survival. The patients that recur often require surgery and further radioactive iodine to render them disease-free. Five percent of thyroid cancer patients, however, will eventually succumb to their disease. Metastatic thyroid cancer is treated with radioactive iodine if the metastases are radioiodine avid. Cytotoxic chemotherapies for advanced or metastatic noniodine avid thyroid cancers show no prolonged responses and in general have fallen out of favor. Novel targeted therapies have recently been discovered that have given rise to clinical trials for thyroid cancer. Newer aberrations in molecular pathways and oncogenic mutations in thyroid cancer together with the role of angiogenesis in tumor growth have been central to these discoveries. This paper will focus on the management and treatment of metastatic differentiated thyroid cancers that do not take up radioactive iodine.

scholarly journals Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2775
Author(s):  
Assunta Melaccio ◽  
Lucia Ilaria Sgaramella ◽  
Alessandro Pasculli ◽  
Giovanna Di Meo ◽  
Angela Gurrado ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Current Status ◽  
Thyroid Cancers ◽  
Angiogenic Switch ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Disease Understanding

Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target.

scholarly journals Radioactive Iodine Resistant Papillary Thyroid Cancer “Redifferentiated” With Dabrafenib

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A898-A898
Author(s):  
Christine Zayouna ◽  
Hajerah Sonnabend ◽  
Ambika Amblee
Keyword(s):  
Lymph Nodes ◽  
Molecular Mechanisms ◽  
Radioactive Iodine ◽  
Kinase Inhibitors ◽  
Structural Response ◽  
Pulmonary Nodules ◽  
Braf V600e ◽  
Whole Body ◽  
Thyroid Cancers ◽  
Differentiated Thyroid Cancers

Abstract Background: Differentiated thyroid cancers (DTC) make up 95% of all thyroid cancers. Radioactive iodine therapy (RAI Rx) is an integral part of DTC management. However, 5-15% of DTC and 50% of metastatic DTC become resistant to RAI Rx and carries a 10-year survival of only 10%. One of the newer therapeutic options target “redifferentiation” of the tumor using RAI sensitizers, notably with short-term use of tyrosine kinase inhibitors (TKI). Clinical Case: A 62-year-old women with a 3-year history of Papillary TC s/p surgery (Sx) and 175 mCi RAI presented to establish care and was found to have bulky palpable disease in her left lateral neck. Imaging showed bilateral enlarged lymph nodes in the neck and multiple bilateral pulmonary nodules. Her stimulated thyroglobulin (TG) level was 5341 (1.59 - 50.03 ng/dL) with negative TG antibodies. Bone scan showed no evidence of bone mets. She underwent repeat neck dissection (49 positive lymph nodes) and was BRAF V600E positive. Post-Sx her non-stimulated (NS) TG was 340 ng/dL (0.00 - 41.00 ng/mL) and she received 200mCi RAI Rx with post-Rx whole body scan (WBS) showed uptake only in the thyroid bed. Imaging 6 months later showed stable lung nodules but increase in lymphadenopathy in the neck and her NS-TG was 181 ng/dL. She received 250 mCi of RAI Rx, 10 months after the first dose. Post Rx WBS again showed uptake only in the neck. Her non-stim TG, 9 months later was still high at 130 ng/dL. Given the discordant imaging and TG findings, functional imaging was done which showed multiple avid lesions in bone and lymph nodes confirming the diagnosis of radioiodine-refractory (RAI-R) DTC. Given BRAF V600E positive status, she received Dabrafenib 150 mg PO BID for 6 weeks followed by RAI 300 mCi. Post-RAI WBS showed extensive uptake in base of skull, sternum, cervical spine and right supraclavicular area. Six months post Dabrafenib and RAI, her NS-TG had come down from 130 to 25.7 ng/dL and imaging showed stable structural disease. Her TG levels and imaging have remained stable over the last 18 months indicating both biochemical and structural response to Dabrafenib. Conclusion: The goal of TKIs in redifferentiation of RAI-R DTC is to target specific molecular mechanisms to render the tissue sensitive to RAI. There are several published trials using TKIs for redifferentiation based on the mutation present. Dabrafenib alone and in combination with other TKI’s (Vemurafenib, Trametinib) followed by RAI has shown some response in 60-70% of treated patients with RAI-R tumors. In a study with 10 RAI-R patients with BRAF V600E mutations, dabrafenib used as a radiosensitizer showed RAI uptake in 60%. Three months post Rx, 2 of 6 had a reduction in disease burden while the other 4 had stable disease. Redifferentiation Rx can be successful in slowing disease progression and could be an option in the treatment of RAI-R DTC before initiation of long term TKI Rx.

NIMG-04. PREDICTING THE BRAF MUTATIONAL STATUS IN PATIENTS WITH MELANOMA BRAIN METASTASES USING RADIOMICS - A BICENTRIC STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi127-vi128
Author(s):  
Anna-Katharina Meissner ◽  
Robin Gutsche ◽  
Norbert Galldiks ◽  
Martin Kocher ◽  
Stephanie T Juenger ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Test Data ◽  
Targeted Therapies ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Support Vector ◽  
Mutational Status ◽  
Melanoma Brain Metastases ◽  
Group 2 ◽  
Group 1

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

scholarly journals Correlation between F18-FDG PET/CT Imaging and BRAF V600E Genetic Mutation for the Early Assessment of Treatment Response in Papillary Thyroid Cancers

2020 ◽  
Vol 10 (2) ◽  
pp. 52
Author(s):  
Andra Piciu ◽  
Maria-Iulia Larg ◽  
Doina Piciu
Keyword(s):  
Thyroid Cancer ◽  
Prognostic Factors ◽  
Papillary Thyroid Cancer ◽  
Genetic Mutation ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Early Assessment ◽  
Pet Ct ◽  
Ct Evaluation

In thyroid neoplastic pathology, the BRAF V600E mutation is shown to be involved in the oncogenesis of papillary thyroid cancer and its subtypes. The purpose of this study is to evaluate the correlation between the mutation of the BRAF V600E oncogene and the pathological standardized uptake values (SUV) at the F18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) evaluation, for a group of 20 patients with radically treated (total thyroidectomy and radioiodine therapy) papillary thyroid cancer, with subclinical persistent disease, at 6 months after the initial treatment. We analyzed the correlations between the values of SUV and the presence of the BRAF mutation as well with other prognostic factors such as stage, age, specific tumor markers (thyroglobulin and anti-thyroglobulin), extrathyroid extension, the presence of metastatic lymph nodes or distant metastasis. The value of SUV in the case of BRAF+ (positive) patients was higher than in the negative ones, but without statistical significance, thus, the values of the SUV cannot be a predictable factor for the presence of the genetic mutation. There was a statistically significant correlation in BRAF+ subgroup between the SUV values and the positive resection limit following surgery, showing a higher SUV value in the PET/CT evaluation. No correlation was observed between the aforementioned prognostic factors involved in papillary thyroid cancer and the BRAF V600E mutation.

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