Follicular-derived Thyroid Cancer Research Articles

Oncogenic mutations in the TP53 and PI-3 kinase/AKT pathway are independent predictors of survival for advanced thyroid cancer: Analysis from the Molecular Screening and Therapeutics (MoST) program

BackgroundThyroid cancers with mutations in the phosphatidylinositol-3 kinase/AKT pathway have a poorer prognosis. However, knowledge about the relationship between histology, mutation profile, and outcomes is still developing. This study assessed the prognostic value of genomic profiles for patients with advanced thyroid cancer who experienced progression on conventional treatment. MethodsPatients recruited to a national clinical oncology program for treatment-refractory locally advanced, recurrent or metastatic cancers were analyzed. Patients' archival tumor samples underwent comprehensive genomic profiling. Specific oncogenic mutations and the presence of cancer related pathways were correlated with overall survival. ResultsFrom 2018 to 2021, 4,955 patients were recruited, with 44 (0.9%) having a diagnosis of thyroid cancer with 4 medullary and the remaining follicular derived: 17 differentiated, 13 poorly differentiated, and 10 anaplastic thyroid cancers. Of the 40 follicular-derived thyroid cancer samples, 17 (42.5%) carried TP53 mutations, followed by 11 with BRAF V600E (27.5%), 9 with NRAS (22.5%), 9 with mutations in the phosphatidylinositol-3 kinase/AKT pathway (22.5%), and 7 with TERT promoter mutations (17.5%). Both TP53 and phosphatidylinositol-3 kinase/AKT pathway alterations were associated with reduced overall survival (hazard ratio, 5.19; 95% confidence interval, 1.59–16.70, P = .02 and hazard ratio, 10.12; 95% confidence interval, 1.61–63.76, P = .01). Cox regression showed histologic type anaplastic thyroid cancer (hazard ratio, 12.93, P = .004), poorly differentiated thyroid cancer (hazard ratio, 5.19, P = .039), and TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations (hazard ratio, 4.73, P = .017) were independently associated with overall survival. ConclusionTP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations correlated with overall survival independently of histotype in patients with advanced thyroid cancer. Comprehensive genomic profiling has potential to inform prognosis, as well as identifying treatment targets for patients with advanced thyroid cancer.

Cobimetinib plus atezolizumab for RAS and NF1/2-mutated poorly differentiated thyroid carcinoma.

6106 Background: Poorly differentiated thyroid carcinomas (PDTC) are a subset of thyroid cancers characterized by high-grade pathologic features. They hold an intermediate position on the spectrum of follicular-derived thyroid cancers. Due to their more aggressive clinical behavior, PDTCs typically exhibit shorter responses to the usual kinase inhibitors (KIs) used in advanced differentiated thyroid cancers and develop resistance earlier on. In fact, median progression free survival (PFS) with single-agent lenvatinib in patients with PDTC in the SELECT trial (n=28) was 14.8 months. Although there are increasing data to support the use of immunotherapy plus KI combinations in anaplastic thyroid cancer, evidence demonstrating the efficacy of this strategy in PDTC is sparse. We aimed to study the safety and efficacy of atezolizumab combined with KIs in PDTC. Methods: We enrolledpatientswith PDTC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients with RAS or NF- mutated tumors were treated with atezolizumab plus the MEK inhibitor (MEKi) cobimetinib. Primary outcome was median overall survival (mOS). Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Eight patients with RAS/NF-mutated PDTC were enrolled. Median age at treatment start was 68.5 years. All patients had distant metastatic disease at time of enrollment. Prior to study entrance, 7/8 patients (88%) had surgical resection of the primary tumor, 6/8 (75%) radioactive iodine, 2/8 (25%) external beam radiation to the neck, and 3/8 (38%) bridging cytotoxic chemotherapy. All patients were naïve to KIs. Six (75%) patients had RAS mutations (1 HRAS, 3 KRAS, 2 NRAS) and 3 (38%) had NF mutations (2 NF1, 1 NF2). One patient’s tumor harbored both KRAS and NF2 mutations at baseline. PD-L1 score was positive in 3/4 evaluable specimens. Median duration of follow-up was 65 months. Best response to therapy was stable disease in 6/8 (75%), partial response in 1/8 (12.5%) and progressive disease in 1/8 (12.5%). mOS was 23 months (95% CI, 12.8 – 33.2) and median PFS was 7 months (95% CI, 2.4 – 11.6). 4/8 patients received radioactive iodine (RAI) while on systemic therapy. Median dose of RAI was 149 millicuries (range, 108 – 153). mOS was significantly longer in patients who received RAI (32 vs 16 months; p= 0.034). The combination of cobimetinib + atezolizumab was overall well tolerated, with an expected adverse event profile. Conclusions: In patients with metastatic PDTC driven by RAS or NFmutations, combination of the anti-PD-L1 atezolizumab with MEKi cobimetinib showed some clinical efficacy, although PFS was shorter than with single-agent lenvatinib. However, SELECT trial did not delineate responses by driver mutations. This combination could thus be considered in selected patients at high risk of complications with antiangiogenic KIs. Clinical trial information: NCT03181100 .

Emerging therapeutic options for follicular-derived thyroid cancer in the era of immunotherapy.

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

NF-κB signaling activation and roles in thyroid cancers: implication of MAP3K14/NIK

Among follicular-derived thyroid cancers (TC), those with aggressive behavior and resistance to current treatments display poor prognosis. NF-κB signaling pathways are involved in tumor progression of various cancers. Here, we finely characterize the NF-κB pathways and their involvement in TC. By using immunoblot and gel shift assays, we demonstrated that both classical and alternative NF-κB pathways are activated in ten TC-derived cell lines, leading to activated RelA/p50 and RelB/p50 NF-κB dimers. By analyzing the RNAseq data of the large papillary thyroid carcinoma (PTC) cohort from The Cancer Genome Atlas (TCGA) project, we identified a tumor progression-related NF-κB signature in BRAFV600E mutated-PTCs. That corroborated with the role of RelA and RelB in cell migration and invasion processes that we demonstrated specifically in BRAFV600E mutated-cell lines, together with their role in the control of expression of genes implicated in invasiveness (MMP1, PLAU, LCN2 and LGALS3). We also identified NF-κB-inducing kinase (NIK) as a novel actor of the constitutive activation of the NF-κB pathways in TC-derived cell lines. Finally, its implication in invasiveness and its overexpression in PTC samples make NIK a potential therapeutic target for advanced TC treatment.

Progress in Treating Advanced Thyroid Cancers in the Era of Targeted Therapy.

Background: Thyroid cancer is a common malignancy whose detection has increased significantly in past decades. Most of the increased incidence is due to detection of early well-differentiated thyroid cancer, but the incidence of more advanced thyroid cancers has increased as well. Recent methodological advancements have allowed for a deep understanding of the molecular underpinnings of the various types of thyroid cancer. Summary: Thyroid cancers harbor a high frequency of potential druggable molecular alterations, including the highest frequency of oncogenic driver kinase fusions seen across all solid tumors. Analyses of poorly differentiated and anaplastic thyroid carcinoma confirmed that these tumors develop from more well-differentiated follicular-derived thyroid cancers through acquired additional mutations. The recognition of driver genomic alterations in thyroid cancers not only predicts tumor phenotype but also now can inform treatment approaches. Conclusions: Major progress in understanding the oncogenic molecular underpinnings across the array of thyroid cancers has led to considerable gains in gene-specific systemic therapies for many cancers. This article focuses on the molecular characteristics of aggressive follicular-derived thyroid cancers and medullary thyroid cancer and highlights advancements in treating thyroid cancer in the era of targeted therapy.

Molecular Genetics of Follicular-Derived Thyroid Cancer.

Simple SummaryThyroid tumors that derive from follicular cells are not a homogeneous entity, showing variable morphological appearance and different degrees of differentiation. Molecular markers are useful for both diagnostic purposes and prognostic stratification of patients. In presurgical setting, molecular testing of indeterminate thyroid nodules on aspirates provides useful diagnostic information; the molecular analysis on tumor tissues can also reveal the presence of genetic alterations related to patients’ prognosis. In recent years, the molecular characterization of these tumors has acquired even more importance thanks to the introduction of targeted drugs. This review summarizes the current literature on the molecular landscape of follicular-derived thyroid tumors.Thyroid cancer is the most common type of endocrine-related malignancy, whose incidence rates have increased dramatically in the last few decades. Neoplasms of follicular origin generally have excellent prognosis, with the exception of less differentiated tumors. Follicular-derived thyroid cancer can manifest as a variety of morphologically distinct entities, characterized by various degrees of differentiation and invasiveness. Histological evaluation is thus crucial for the definition of patients’ prognosis. However, within each histological subtype, tumor behavior can be highly variable, and, in this respect, molecular characterization can provide insightful information to refine the risk stratification of tumors. In addition to the importance of its prognostic role, molecular testing can be used to support the differential diagnosis of thyroid nodules in the absence of marked cyto-morphological aberrations. Finally, with the advent of targeted drugs, the presence of molecular alterations will guide the therapeutic strategies for patients with advanced tumors who do not respond to standard treatment. This review aims to describe the genetic landscape of follicular-derived thyroid tumors also highlighting differences across histological subtypes.

MON-LB101 Pharmacokinetics of Liothyronine during Thyroid Hormone Therapy Withdrawal

Background Liothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer patients during the preparation for nuclear medicine procedures, and there is renewed interest in its use in combination with LT4 in patients who do not respond to the standard treatment. This therapy is commonly done on fixed doses potentially resulting in supraphysiologic levels of T3. A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes able to maintain serum T3 levels within normal range, but data on the PK of LT3 are conflicting. Here we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, not receiving LT4. Methods We performed an open label PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived thyroid cancer (Clinicaltrials.gov ID NCT01441154). LT3 was substituted for LT4 at 1:3 mcg/mcg dosage ratio thrice daily for at least thirty days. PK of single dose LT3 and terminal elimination were assessed over eleven days and first dose PK was offered following the nuclear medicine procedures. Results Fourteen patients (7 males, 7 females) age 48.5±16.0 years completed the study. The LT3 daily dose was 53.7±12.3 (0.74±0.1 mcg/Kg). PK studies performed with the morning dose (18.8±4.4 mcg), indicate a Cmax of 320±60 ng/dl, significantly above the upper limit (90-215). Tmax was 1.8±0.5 hours and two distinct phases of linear elimination with a fast distribution phase and slow elimination phases with half-lives of 1.2 hours and 29.9 hours were identified, supporting a two-compartment model. PK modeling for a 50 mcg LT3 total dose predicted that while the mean T3 levels would not significantly differ among single, twice, or thrice daily administration regimens, the variance would differ dramatically, 213.5±126 vs. 214.5±61 vs. 214.5±35 ng/dl, single, twice and thrice daily administration, respectively. We next performed a PK modeling for LT3/LT4 combination therapy, twice daily administration. The results indicate that low dose LT3 (up to 0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the normal range. Conclusions The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapy directed to maintain stable T3 serum levels. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

A Review of Driver Genetic Alterations in Thyroid Cancers

Thyroid cancer is a frequent endocrine-related malignancy with continuously increasing incidence, and recently the development in understanding its molecular pathogenesis is mainly through the explanation of the original role of several key signaling pathways and related molecular distributors. Central to these mechanisms are the genetic and epigenetic alterations in these pathways such as mutation and DNA rearrangements. However, it does not mean that all the somatic abnormalities in a cancer genome are involved in cancer development and just driver mutations are concerned in tumor initiation. By way of illustrations, MAPK pathway motivated by BRAF V600E and RAS and RET / PTC rearrangements are suggesting driver genetic alterations in follicular derived thyroid cancers considered in the current review.

Erratum for "Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial".

Erratum for "Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial".

Indications for radioiodine administration in follicular-derived thyroid cancer

Indications for radioiodine administration after thyroid cancer surgery have shifted in recent years toward personalized management, adapted to the individual risk of tumor progression. The most recent guidelines and studies favor de-escalation in indications for administration, dosage and means of preparation with exogenous recombinant TSH stimulation as treatment of choice.Radioiodine administration has 3 possible objectives: •ablation of normal thyroid tissue remnants in patients with low risk of progression, using low radioiodine activity levels, with the advantage of completing disease staging on whole-body scintigraphy performed after administration of the radioiodine capsule, and of facilitating follow-up by thyroglobulin assay;•adjuvant treatment for suspected microscopic metastases in patients with intermediate or high risk of progression, using higher activity levels, with the theoretic aim of limiting recurrence and mortality;•curative treatment in high-risk patients with proven metastases, using exclusively high activity levels, with a view to improving specific survivalIn future, indications for ablation and/or activity prescription may be governed by an algorithm incorporating individual baseline progression risk (essentially founded of pTNM staging) and postoperative data such as thyroglobulin level and neck ultrasound results.

Rexinoid therapy for poorly differentiated thyroid cancer: A pilot clinical phase II trial and correlation to retinoid and peroxisome-proliferator activated receptor gamma receptors expression.

TPS269 Background: Thyroid cancer causes over 1,600 deaths annually, mostly from poorly differentiated tumors that are radioiodine resistant. Cytotoxic chemotherapy has limited efficacy so alternative therapies are warranted. Retinoids are vitamin A derivatives that bind to retinoic acid and retinoid × receptors (RARs and RXRs), each with α, β, and γ isotypes. Retinoid receptors are present in thyroid tissue and the RXRγ isotype has been shown to be higher in thyroid cancer than matched normal tissue. RXRs can form a heterodimer partnership with PPARγ to enhance transcriptional activity upon DNA binding. Bexarotene is a selective RXR agonist approved for the treatment of cutaneous T-cell lymphoma. Preclinical in vitro and in vivo studies show that bexarotene reduces growth in RXRg expressing cells and xenograft tumor size, and this effect is enhanced when PPARγ is present. Additionally, bexarotene has been shown to increase radioiodine uptake in some patients with previously radioiodine-resistant thyroid cancer. Methods: Adult patients with radioiodine-resistant follicular-derived thyroid cancer and RECIST criteria disease progression and/or PET positive lesions will be enrolled. Eligible patients will receive open-label bexarotene at a dose of 300 mg/m2/day. Concomitant omega-3 fatty acids will be started two weeks before bexarotene. We propose a two-part, standard phase II trial where we will study 19 patients and if we see one response we will enroll 12 more for a total of 26 patients. With an anticipated 10-30% drop out this will allow for 14 initial patients and if a responder is found 23 patients total. Study drug will be given for one year and the primary end points are tumor response by RECIST criteria and correlation with primary thyroid cancer tissue expression of RXR and PPARy receptors. The secondary endpoint is radioiodine uptake at 6 months and 1 year. At weeks 8, 18, 24, 30, 38, 46, and 52 TSH, Free T4, total T4, total T3, thyroglobulin and thyroglobulin antibodies will be obtained. Neck ultrasound, PET-CT scan, and rhTSH-stimulated radioactive iodine whole body scan will be obtained on weeks 24 and 52. No significant financial relationships to disclose.

Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis

BackgroundCarcinoma of the thyroid gland is an uncommon cancer, but the most frequent malignancy of the endocrine system. Most thyroid cancers are derived from the follicular cell. Follicular carcinoma (FTC) is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Opioid Growth Factor (OGF; chemical term - [Met5]-enkephalin) and its receptor, OGFr, form an inhibitory axis regulating cell proliferation. Both the peptide and receptor have been detected in a wide variety of cancers, and OGF is currently used clinically as a biotherapy for some non-thyroid neoplasias. This study addressed the question of whether the OGF-OGFr axis is present and functional in human thyroid follicular cell - derived cancer.MethodsUtilizing human ATC (KAT-18), PTC (KTC-1), and FTC (WRO 82-1) cell lines, immunohistochemistry was employed to ascertain the presence and location of OGF and OGFr. The growth characteristics in the presence of OGF or the opioid antagonist naltrexone (NTX), and the specificity of opioid peptides for proliferation of ATC, were established in KAT-18 cells. Dependence on peptide and receptor were investigated using neutralization studies with antibodies and siRNA experiments, respectively. The mechanism of peptide action on DNA synthesis and cell survival was ascertained. The ubiquity of the OGF-OGFr axis in thyroid follicular cell-derived cancer was assessed in KTC-1 (PTC) and WRO 82-1 (FTC) tumor cells.ResultsOGF and OGFr were present in KAT-18 cells. Concentrations of 10-6 M OGF inhibited cell replication up to 30%, whereas NTX increased cell growth up to 35% relative to cultures treated with sterile water. OGF treatment reduced cell number by as much as 38% in KAT-18 ATC in a dose-dependent and receptor-mediated manner. OGF antibodies neutralized the inhibitory effects of OGF, and siRNA knockdown of OGFr negated growth inhibition by OGF. Cell survival was not altered by OGF, but DNA synthesis as recorded by BrdU incorporation was depressed by 28% in OGF-treated cultures compared to those exposed to sterile water. The OGF-OGFr axis was detected and functional in PTC (KTC-1) and FTC (WRO 82-1) cell lines.ConclusionThese data suggest that OGF and OGFr are present in follicular-derived thyroid cancers, and that OGF serves in a tonically active inhibitory manner to maintain homeostasis of cell proliferation. These results may provide a biotherapeutic strategy in the treatment of these cancers.