D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms.

PURPOSE: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case. MATERIALS AND METHODS: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells. RET C634R and wild-type cells served as positive and negative controls, respectively. RESULTS: The patient showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months. Comprehensive next-generation sequencing of a progressing lesion during selpercatinib showed no additional RET mutation but an acquired complete genetic loss of CDKN2A, CDKN2B, and MTAP genes. Subsequent treatment with cabozantinib and 5-FU-dacarbazine had poor efficacy. In vitro, RET Δ898-901 showed higher ligand-independent RET autophosphorylation compared with RET C634R and similar proliferation rates in cell models. Subcutaneous injection of Δ898-901 NIH 3T3 cells in nude mice produced tumors of around 500 mm3 in 2 weeks, similarly to RET C634R cells. Selpercatinib inhibited cell growth of Ba/F3 RET Δ898-901 and RET C634R with a similar half maximal inhibitory concentration (IC50) of approximately 3 nM. Vandetanib was five-fold less effective at inhibiting cell growth promoted by RET Δ898-901 mutant (IC50, 564 nM) compared with RET C634R one (IC50, 91 nM). Cabozantinib efficiently inhibited Ba/F3 RET C634 proliferation (IC50, 25.9 nM), but was scarcely active in Ba/F3 RET 898-901 (IC50 > 1,350 nM). CONCLUSION: D898_E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms.

[Increasing the efficiency of a mobile EPI strategy using injectable polio vaccine in Africa]. / Augmentation de l'efficience d'un PEV en stratégie mobile utilisant le vaccin polio injectable en Afrique.

Introduction: In 1980, partners initiated a mobile simplified EPI (Expanded programme on immunization) strategy for immunizing, with mobile teams, rural and urban populations in Western Africa. This strategy delivered EPI vaccines in two sessions: 1) 3-8 month-old children: BCG-Diphteria Tetanus Pertussis + reinforced killed Polio vaccine; 2) 9-15 month-old children: Diphteria Tetanus Pertussis + reinforced killed Polio vaccine, Measles-Yellow Fever. This strategy was compared to WHO-UNICEF extended EPI strategy, but results were never published in the context of a planned rapid polio eradication with oral polio vaccine. Methods: For comparison with standard WHO-UNICEF extended EPI strategy, using oral polio vaccine in four sessions, all the costs generated by these two strategies in 1988 have been collected in two adjacent zones in Burkina Faso, Western Africa: 203,642 inhabitants for WHO-UNICEF extended EPI strategy (Yako); 109,483 inhabitants for mobile simplified EPI strategy (Gourci). An EPI coverage survey at the end of this year has been done in these two adjacent zones with efficiency (costs per fully immunized child) computed. Results: In Africa, the simplified mobile EPI strategy using reinforced killed polio vaccine was found two times more efficient (12.71 US$ per fully immunized child) than WHO-UNICEF extended EPI strategy using oral polio vaccine (29.67 US$ per fully immunized child), even if DTP-reinforced killed polio vaccine (0.52 US$ per dose) was more expensive than DTP and oral polio vaccine (0.14 US$ for the combined dose). The missed opportunities uncaught up would have doubled coverage in the WHO-UNICEF extended EPI strategy, versus only a 10% increase with the mobile simplified EPI strategy. The main reason for uncaught up missed opportunities in WHO extended EPI strategy was the absence of requested vaccine delivered by a health agent when attending population at meeting point, due to insufficient cold box volume carried on his moped for transport of vaccine. Discussion: After 30 years, since 1990, of poliomyelitis eradication in Africa using oral polio vaccine and with non-added costs in this study of polio mass campaigns, these results should be published to review EPI strategy.

ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: a prospective randomized trial.

BACKGROUND: Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. TRIAL DESIGN AND METHODS: Prospective randomized open multicenter phase III trial including patients with 11-40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/- 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. DISCUSSION (POTENTIAL IMPLICATIONS): If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. TRIAL REGISTRATION: NCT03570021. June 26,2018.

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer.

PURPOSE: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. PATIENTS AND METHODS: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. RESULTS: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients. CONCLUSIONS: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Deiodinases in thyroid tumorigenesis.

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.

Type 2 deiodinase is expressed in anaplastic thyroid carcinoma and its inhibition causes cell senescence.

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial-mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.

Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors.

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

Prognostic value of 12-month response to therapy in pediatric patients with differentiated thyroid cancer.

PURPOSE: In pediatric patients with differentiated thyroid cancer (DTC) we assessed the prognostic value of the 12-month response to therapy after initial treatment with surgery and radioactive iodine (RAI). METHODS: We retrospectively evaluated 94 pediatric patients with DTC, treated with surgery and RAI who were initially classified as low, intermediate or high risk of relapse of disease according to the American Thyroid Association (ATA) guidelines. Twelve months after RAI administration the response to therapy was assessed by serum thyroglobulin (Tg) measurement and neck ultrasound and patients were classified as having excellent response (ER) or no-ER. RESULTS: At the 12 months evaluation, 62 (66%) patients had ER and 32 (34%) no-ER. During a mean follow-up time of 86 months (range 9-517), 19 events occurred (20% cumulative event rate). Events occurred more frequently in younger patients (p < 0.05), in those at ATA intermediate/high risk (p < 0.01) and with a pre-RAI therapy Tg level > 10 ng/mL (p < 0.001), and in those with no-ER (p < 0.001). At multivariate analysis, the evidence of no-ER was the only independent predictor of events. CONCLUSION: In pediatric patients with DTC, the response to therapy evaluated 12 months after initial treatment has an independent prognostic impact and is able to predict mid-term outcome. Patients with no-ER at 12 months after RAI therapy should be closely followed-up.

Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = -0.45, p = 0.0002, 95% confidence interval [CI] -0.63 to -0.23; Ala/Thr r = -0.39, p = 0.0012, CI -0.60 to -0.67; and Ala/Ala r = -0.30, p = 0.2347; CI -0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

Breast cancer risk among thyroid cancer survivors and the role of I-131 treatment.

BACKGROUND: Female thyroid cancer survivors are more likely to have a higher risk of breast cancer compared to the general population, and the underlying causes are yet to be understood. The potential role of I-131 treatment on this association remains controversial. METHODS: We pooled individual data of women who were treated for differentiated thyroid cancer from 1934 to 2005 in France, Italy and Sweden. Standardized incidence ratios (SIRs) for breast cancer were estimated by comparison with age, sex and calendar-year expected values of the general population in each country. We estimated breast cancer risk in relation to I-131 treatment using time-dependent Poisson models. RESULTS: Of 8475 women (mean age at diagnosis: 45 years, range 2-90 years), 335 were diagnosed with breast cancer [SIR = 1.52, 95% confidence interval (CI): 1.36-1.69] during a median follow-up time of 12.7 years since diagnosis. Overall, breast cancer risk did not differ between women treated or not with I-131 (relative risk=1.07, 95% CI 0.84-1.35). However, breast cancer risk increased with increasing cumulative I-131 activity, without significant departure from linearity (excess relative risk per 100 mCi=17%, 95% CI: 2% to 38%). The higher risk associated with a cumulative I-131 activity of ≥100 mCi and ≥400 mCi was translated into 4 (95% CI -4 to 13) and 42 (95% CI -8 to 93) excess breast cancer cases per 10,000 person-years, respectively. CONCLUSIONS: An elevated risk was observed for the highest cumulative administered activity (>=400 mCi), and a significant dose-dependent association was observed among thyroid cancer survivors who were treated with I-131. However, overall, I-131 treatment might only explain partly the increase in breast cancer risk among female thyroid cancer survivors.

Tackling Thyroid Cancer in Europe-The Challenges and Opportunities.

Thyroid cancer (TC) is the most common malignancy of the endocrine system that affects the thyroid gland. It is usually treatable and, in most cases, curable. The central issues are how to improve knowledge on TC, to accurately identify cases at an early stage that can benefit from effective intervention, optimise therapy, and reduce the risk of overdiagnosis and unnecessary treatment. Questions remain about management, about treating all patients in referral centres, and about which treatment should be proposed to any individual patient and how this can be optimised. The European Alliance for Personalised Medicine (EAPM) hosted an expert panel discussion to elucidate some of the challenges, and to identify possible steps towards effective responses at the EU and member state level, particularly in the context of the opportunities in the European Union's evolving initiatives-notably its Beating Cancer Plan, its Cancer Mission, and its research funding programmes. Recommendations emerging from the panel focus on improved infrastructure and funding, and on promoting multi-stakeholder collaboration between national and European initiatives to complement, support, and mutually reinforce efforts to improve patient care.

Prognostic of recurrence and survival in poorly differentiated thyroid cancer.

The prognosis of poorly differentiated thyroid carcinomas (PDTC) defined by the Turin criteria is variable. The aim of this study on 51 PDTC patients was to determine clinical, histological and molecular prognostic factors associated with recurrence in patients with localized disease at initial treatment and with overall survival in patients with distant metastases. Of 40 patients for whom next-generation sequencing (NGS) by ThyroSeq v3 was able to be performed on historical samples, we identified high-risk molecular signature (TERT, TP53 mutations) in 24 (60%) cases, intermediate risk signature in 9 (22.5%) cases and low-risk signature in 7 (17.5%) cases. Potentially actionable mutations were identified in 10% of cases. After a median follow-up of 57.5 months, recurrence occurred in 11 (39%) of the 28 patients with localized disease. The American Thyroid Association (ATA) high risk of relapse, high mitotic count, high molecular risk signature and CD163 expression were associated with recurrence (P = 0.009, 0.01, 0.049, 0.03 respectively). After a median follow-up of 49.5 months, thyroid cancer-related death occurred in 53% of the patients with distant metastases. There was no significant prognostic factor associated with death in univariate analysis. However, none of the patients with intermediate ATA risk of recurrence and none of the patients with low-risk molecular signature died from the disease. In addition, high molecular-risk signature was associated with the presence of synchronous or metachronous distant metastasis (P = 0.007) and with poor overall survival (P = 0.01). In conclusion, ATA risk of relapse and high mitotic count was associated with higher rate of recurrence in localized PDTC. High molecular-risk signature was associated with the presence of distant metastasis and poor overall survival. Further studies are needed to determine if molecular testing adds to ATA risk stratification or response to therapy in predicting outcomes.

Emerging drugs for the treatment of radioactive iodine refractory papillary thyroid cancer.

INTRODUCTION: The most frequent radioactive (RAI) refractory thyroid cancers are papillary thyroid carcinoma, followed by poorly differentiated thyroid carcinoma. They are rare and lethal. In recent years, significant therapeutic progress has been achieved. AREAS COVERED: This paper offers insights on refractoriness to RAI treatment and the optimization of treatment initiation and treatment choice. Clinical trials performed with anti-angiogenic kinase inhibitors and with targeted inhibitors in patients with BRAF, RAS mutation or RET, TRK or ALK fusion are discussed. EXPERT OPINION: These treatments provide high response rates. Anti-angiogenic kinase inhibitors improve median progression-free-survival; however, their benefit in terms of overall survival has been shown in only few subsets of patients. Treatment sequencing is challenging; in the absence of targetable abnormality, lenvatinib should be used as first-line treatment. Options for second-line treatment include lenvatinib (if not given at first line), cabozantinib or the addition of an anti-checkpoint antibody. In patients with a targetable abnormality, specific inhibitors, might be used as first-line treatment and lenvatinib as second line or vice-versa. Further studies are needed, based on documented genomic and immunologic characteristics of the tumor to assess the potential role of combination and redifferentiation therapy.

Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial.

BACKGROUND: Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) is an aggressive form of thyroid cancer. Lenvatinib is a multikinase inhibitor approved for treatment of RAI-R DTC. The impact of tumor response and tumor burden on overall survival (OS) after lenvatinib treatment in patients with RAI-R DTC was assessed. METHODS: Data from patients treated with lenvatinib (N = 261) in SELECT were retrospectively analyzed. Patients were divided into lenvatinib responder or nonresponder subgroups and into low (≤40 mm) or high (>40 mm) tumor burden subgroups based on baseline sums of diameters of target lesions using Response Evaluation Criteria in Solid Tumors, version 1.1 (cutoff values were determined by receiver-operating characteristic analyses). Associations of tumor response and tumor burden with OS were assessed. RESULTS: Median OS was prolonged in lenvatinib responders versus nonresponders (52.2 vs 19.0 months; hazard ratio [HR], 0.32; 95% CI, 0.23-0.46). Patients with a lower tumor burden who received lenvatinib had prolonged OS versus those with a higher tumor burden (median OS, not reached vs 29.1 months, respectively; HR, 0.42; 95% CI, 0.28-0.63). Baseline tumor burden was associated with OS by multivariate analysis (HR, 0.56; 95% CI, 0.35-0.89; P = .0138). CONCLUSIONS: Patients with a lower tumor burden receiving lenvatinib had prolonged OS compared with those with a higher tumor burden receiving lenvatinib. Baseline tumor burden may be a prognostic factor for OS in patients with RAI-R DTC treated with lenvatinib.

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).