United States

Background: Two-thirds of patients with metastatic differentiated thyroid cancer (DTC) become refractory to radioactive iodine (RAIR). The inhibition of the MAP-kinase pathway that is activated in case of BRAFV600E mutation might increase RAI incorporation into metastatic foci and reverse the RAI refractoriness.MERAIODE is a prospective multicentric open-label phase II trial, using a one-stage Fleming design, evaluating the efficacy and tolerance of trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor) treatment followed by the administration of RAI in metastatic RAIR DTC patients.?Methods: Patients with BRAFV600E mutated RAIR metastatic DTC with RECIST progression within 18 months prior to enrollment and no lesion &gt; 3 cm were included. A baseline rhTSH-stimulated diagnostic whole body scan (dc WBS) was performed prior to treatment initiation. Patients were treated with dabrafenib (150 mg bid) and trametinib (2 mg per day) for 42 days. At day 28, a second rhTSH-stimulated dc WBS was performed. After 35 days, a therapeutic activity of RAI (5.5 GBq) was administered. Primary endpoint was objective response rate (ORR) at 6 months according to RECIST v1.1 (central review).?Patients: Among the 24 patients (mean age 67 years, 15 females) with a BRAFV600E mutated RAI refractory papillary DTC included between March 2018 and January 2020 in 8 French centers from the TUTHYREF netwok, 24 patients were treated and 21 patients were evaluable for the principal outcome at 6 months.?Results: Abnormal RAI uptake was present in only 1 of the 21 patients (5%; 95%CI 0-24%) on a RAI diagnostic whole body scan (dc-WBS) performed prior to treatment initiation, in 11 patients, 11/17 (65%; 95%CI 38-86) on a dc-WBS performed 4 weeks after dabrafenib-trametinib initiation and in 20/21 (95%; 95%CI 76-100) on the post-therapeutic WBS performed after 5.5 GBq of RAI. The RECIST 6-months tumor response (central review) was partial response (PR) in 38% (95%CI 18-61), stable disease (SD) in 52% (95% CI 30-74) and progressive disease (PD) in 10% (95% CI 1-30). The median change in the sum of target lesions was -22% (range: -79 to +46) at 6 months after baseline. The 6-month fluorodesoxyglucose metabolic PET response was PR in 11/17 (65% 95%CI 38-86), SD in 4/17 (23%) (95% CI 7-50) and PD in 2/17 (12%; 95% CI 1-36). Among the 15 patients without Tg antibodies, 7 (47%) patients had a decrease of serum thyroglobulin level on T4 treatment by more than 50%All patients experienced at least one grade 1-2 adverse event, mainly asthenia, nausea, fever, diarrhea and cutaneous eruption. Nine grade 3 toxicities occurred in 6 treated patients. No grade 4-5 adverse event occurred?Conclusion:The association of dabrafenib and trametinib in BRAFV600E mutated patients is effective for restoring RAI uptake and is followed by a tumor control in 90% of patients and by tumor response in 38% with limited adverse events. (PHRC 2015, NCT 03244956)?? 

ENDO 2021

MERAIODE: A Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAFV600E Mutation (NCT 03244956)

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

Background: Two-thirds of patients with metastatic differentiated thyroid cancer (DTC) become refractory to radioactive iodine (RAIR). The inhibition of the MAP-kinase pathway that is activated in case of BRAFV600E mutation might increase RAI incorporation into metastatic foci and reverse the RAI refractoriness.MERAIODE is a prospective multicentric open-label phase II trial, using a one-stage Fleming design, evaluating the efficacy and tolerance of trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor) treatment followed by the administration of RAI in metastatic RAIR DTC patients.?Methods: Patients with BRAFV600E mutated RAIR metastatic DTC with RECIST progression within 18 months prior to enrollment and no lesion > 3 cm were included. A baseline rhTSH-stimulated diagnostic whole body scan (dc WBS) was performed prior to treatment initiation. Patients were treated with dabrafenib (150 mg bid) and trametinib (2 mg per day) for 42 days. At day 28, a second rhTSH-stimulated dc WBS was performed. After 35 days, a therapeutic activity of RAI (5.5 GBq) was administered. Primary endpoint was objective response rate (ORR) at 6 months according to RECIST v1.1 (central review).?Patients: Among the 24 patients (mean age 67 years, 15 females) with a BRAFV600E mutated RAI refractory papillary DTC included between March 2018 and January 2020 in 8 French centers from the TUTHYREF netwok, 24 patients were treated and 21 patients were evaluable for the principal outcome at 6 months.?Results: Abnormal RAI uptake was present in only 1 of the 21 patients (5%; 95%CI 0-24%) on a RAI diagnostic whole body scan (dc-WBS) performed prior to treatment initiation, in 11 patients, 11/17 (65%; 95%CI 38-86) on a dc-WBS performed 4 weeks after dabrafenib-trametinib initiation and in 20/21 (95%; 95%CI 76-100) on the post-therapeutic WBS performed after 5.5 GBq of RAI. The RECIST 6-months tumor response (central review) was partial response (PR) in 38% (95%CI 18-61), stable disease (SD) in 52% (95% CI 30-74) and progressive disease (PD) in 10% (95% CI 1-30). The median change in the sum of target lesions was -22% (range: -79 to +46) at 6 months after baseline. The 6-month fluorodesoxyglucose metabolic PET response was PR in 11/17 (65% 95%CI 38-86), SD in 4/17 (23%) (95% CI 7-50) and PD in 2/17 (12%; 95% CI 1-36). Among the 15 patients without Tg antibodies, 7 (47%) patients had a decrease of serum thyroglobulin level on T4 treatment by more than 50%All patients experienced at least one grade 1-2 adverse event, mainly asthenia, nausea, fever, diarrhea and cutaneous eruption. Nine grade 3 toxicities occurred in 6 treated patients. No grade 4-5 adverse event occurred?Conclusion:The association of dabrafenib and trametinib in BRAFV600E mutated patients is effective for restoring RAI uptake and is followed by a tumor control in 90% of patients and by tumor response in 38% with limited adverse events. (PHRC 2015, NCT 03244956)?? 

technical paper

Background: The benefits of post-operative radioactive iodine (RAI) administration have not been demonstrated in patients with low risk differentiated thyroid cancer (DTC). The objective of this randomized phase III trial is to assess in low risk DTC patients the non-inferiority of a follow-up strategy as compared to a systematic adjuvant post-operative RAI administration.?Methods: ESTIMABL2 is a French multicentric randomized phase III trial in patients with low-risk DTC treated with total thyroidectomy with or without prophylactic neck lymph node dissection (pT1am N0 or Nx with a sum of the diameters of tumor lesions ≥ 10mm, pT1b N0 or Nx). Two to five months after surgery, in the absence of suspicious lateral neck lymph node on ultrasonography (US), patients were randomized either to the follow-up group (FU, no RAI administration) or to the ablation group and received post-operative RAI (1.1 GBq following rhTSH stimulation). Yearly controls under levothyroxine treatment consisted in thyroglobulin (Tg) and Tg antibodies (TgAb) determinations and neck-US. The primary objective was to assess at 3 years after randomization the non-inferiority of the proportion of patients without tumor-related event in the FU group as compared to the ablation group. Non-inferiority is demonstrated if the rate of patients without event at 3 years does not differ by more than ΔL=-5%. A tumor-related event was defined by the occurrence of subsequent treatment (RAI administration or surgery) for abnormal RAI uptake on the post-therapeutic WBS or by elevated Tg or TgAb levels and/or abnormal neck US during controls. Tg levels on levothyroxine treatment were considered elevated if > 2ng/mL in the FU group and > 1ng/mL in the ablation group. TgAb were considered elevated if > the upper limit range with an increase above 50% on 2 consecutive determinations performed 6 months apart.?Results: 776 low-risk DTC patients were included between 2013 and 2017 in 35 French centers within the TUTHYREF network; 83% females, mean age: 52 years, papillary TC: 96%, pT1bNx: 43.6%, pT1bN0: 37.5%, pT1amNx: 12.6%, pT1amN0: 6.3%. Among the 729 patients evaluable at 3 years after randomization, tumor-related events occurred in 18/367 patients (4.9% IC95%=[2.9 ; 7.6]) in the FU group and in 15/362 patients (4.1% IC95%=[2.3 ; 6.7]) in the ablation group. Thus, 95.1% of patients in the FU group had no event at 3 years and this percentage is not inferior from the 95.9% of patients observed in the ablation group (difference = -0.8% [95% CI:-3.3%; 1.8%]. The number of subsequent surgery and/or RAI administration was 6 (1.6% IC95%=[0.6 ; 3.5]) in the FU group and 9 (2.5% IC95%=[1.1 ; 4.7]) in the ablation group.?Conclusion: this phase III trial demonstrates the non-inferiority of a follow-up strategy compared to a systematic adjuvant post-operative administration of RAI (1.1GBq following rhTSH) in low risk DTC patients (PHRC 2012; NCT01837745).?? 

Estimabl2: Is There a Need for Radioiodine Ablation in Low Risk Differentiated Thyroid Cancer (DTC) Patients ? : Results From the French Randomized Phase III Prospective Trial on 776 Patients (NCT 01837745)

Thyroid Immune-Related Adverse Events Following Checkpoint Inhibitor Treatment

Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of the cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases. Using RNASeq analysis of uterine tissue from this mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered significant upregulation of inflammatory proteases such as Neutrophil Elastase (NE). NE is secreted by myeloid cells such as polymorphonuclear cells (PMNs) and has been reported to promote invasion, migration, and proliferation in various cancers. We found this to be true in LAM as well, as depleting myeloid cells with an antibody directed against PMNs, or inhibiting NE with the NE inhibitor, sivelestat, markedly decreased TSC2-null uterine tumor growth. NE is released when PMNs undergo Neutrophil Extracellular Trap release, or NETosis. NETosis has been shown to have a pro-tumorigenic role in various cancers and we are investigating the effects of NETosis in LAM. We have also generated a novel uterine-specific TSC2-null mouse in the background of no NE to determine whether uterine tumor burden and lung metastases are reduced in NE-null mice and if these mice have PMNs capable of undergoing NETosis in the absence of NE. Overall, our results suggest that NE release from PMNs is critical for LAM tumor development and may be a novel target for its treatment.?? 

Pro-Tumorigenic Role of Neutrophil Elastase in Lymphangioleiomyomatosis (LAM)

Deleterious Cross-Talk between Thyroid and Estrogen Hormones Contributes to Endocrine Therapy Resistance and Poor Survival in Steroid Receptor Positive Breast Cancer Patients

Metastatic estrogen receptor α (ERα) positive breast cancer is presently incurable and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ERα to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. We exploited our finding that estrogen-ERα activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERα to induce lethal hyperactivation of the anticipatory UPR (a-UPR), triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERαD538G and ERαY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. In mouse xenografts bearing large breast tumors, oral and injected ErSO induced complete regression (>115,000 fold mean regression) in about 45% of mice (18/39). Although durable response without treatment for 4-6 months was common, tumors that did recur remained fully sensitive to ErSO re-treatment. Consistent with the essential nature of the a-UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. On average, ErSO-treated tumors were >180-fold smaller than vehicle-treated tumors. Moreover, use of ErSO is not limited to breast cancer. With its unique mechanism of action through the a-UPR, ErSO eradicated orthotoptic ERα positive ovarian tumors that do not require estrogen for growth. These xenograft studies used human cancer cells in immune compromised mice and therefore did not exploit the known ability of inducers of necrotic cell death to activate immune cells and induce immunogenic cell death. Notably, medium from breast cancer cells killed by ErSO contained high levels of the established immune cell activators, HMGB1 and ATP, robustly activated mouse and human macrophages and increased macrophage migration. ErSO’s potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy.?? 

ERa-Dependent Lethal Hyperactivation of the Anticipatory Unfolded Protein Response Induces Complete Regression Without Recurrence of Advanced Breast Cancer

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.?Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.?Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.?Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.?? 

Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia

Obesity is associated with increased severity of viral illnesses, but its impact on outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is yet to be elucidated. We sought to determine the association of obesity and other clinical factors with outcomes among patients hospitalized for severe coronavirus disease (COVID-19). This study included patients hospitalized between March 1, 2020 and September 17, 2020 in a 5-hospital health care system in Northeast United States, who had a positive RT-PCR assay of nasopharyngeal swabs for SARS-CoV-2 performed during hospitalization. Body mass index (BMI) was calculated using admission weight and height, and the WHO classification was used to define obesity. Both bivariate and multivariate logistic regression analyses were performed to determine the association of obesity and other clinical parameters with mortality (defined as in-hospital death or transition to hospice care) and intensive care use (defined by transfer to intensive care unit [ICU]). Multivariate model was adjusted for demographics and 8 pertinent comorbidities. Among 3246 patients hospitalized with COVID-19, median age was 65 years (interquartile range, 51-78), 49.9% were female, 30.5% overweight, and 43.2% had obesity (20.8%, 12.1%, and 10.4% with class I, II, and III obesity, respectively). A total of 542 (16.7%) patients died or received hospice care, and 811 (25.0%) required ICU care. In unadjusted analyses, patients with obesity had lower mortality compared with normal weight adults (13.0% vs. 23.1%) but a higher risk of ICU care (26.5% vs. 22.5%) and longer duration of ICU stays (9.5±10.6 vs. 6.6±8.5 [days]; all p-values <0.05). Obesity was associated with a higher incidence of hypoxic respiratory failure requiring invasive (17.8% vs. 9.3%) and noninvasive (22.7% vs. 14.0%) ventilatory support. In multivariate analysis, older age, male sex, and diabetes were significantly associated with both mortality and ICU care. In contrast, obesity was not associated with a significantly higher mortality (adjusted odds ratio [OR] 1.14; 95% CI, 0.91-1.43) but was associated with a higher risk of ICU care (OR 1.27; 95% CI 1.07-1.51 for all obesity and OR 2.07; 95% CI 1.51-2.82 for class III obesity compared with normal weight). The association of underweight with mortality (OR 1.56; 95% CI 0.93 - 2.60) and ICU care (OR 1.20; 95% CI, 0.71-1.99) was not statistically significant. This retrospective study of hospitalized patients suggests that obesity is associated with intensive care use and longer duration of ICU stay but not with mortality due to COVID-19. These findings underscore the vulnerability of individuals with obesity during the current pandemic.?? 

Obesity Is Associated With Intensive Care Use and Duration of ICU Stay but Not Mortality Among 3246 Patients Hospitalized With COVID-19

BACKGROUND: In Spring 2020 the severe acute respiratory syndrome coronavirus 2 pandemic disease (Covid-19) badly affected Northern Italy. We have described for the first time the occurrence of thyrotoxicosis due to atypical subacute thyroiditis in 15% of patients hospitalised for Covid-19 pneumonia, compared with only 1% among patients hospitalised in the same wards during Spring 2019, thus before the Covid-19 pandemic. The whole group of Covid-19 patients also had median serum TSH concentrations significantly lower compared with the control group. The atypical thyroiditis induced by Covid-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome. Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients.?METHODS: Longitudinal follow-up study of survived Covid-19 patients without previous known history of thyroid disorders and/or medications, assessing serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC) and thyroid ultrasound (US) every 3 months. Patients showing baseline (at hospitalisation for Covid-19) thyroid dysfunction and/or focal hypoechoic areas suggestive for subacute thyroiditis at US performed 3 months post-infection, also underwent thyroid 99mTc or I123uptake.?RESULTS: To date, 53 patients have been included in the follow-up study. At 3 months post-infection, all of them presented with increased median (IQR) serum TSH concentrations compared with baseline: 1.3 (0.9-2.0) mIU/L versus 0.9 (0.5-1.8) mIU/L (p=0.0001). Similarly, serum concentrations of free-thyroxine, free-triiodothyronine, CRP and FBC had normalised compared with baseline. All patients had negative autoantibodies to TSH receptor; autoantibodies to thyroglobulin and to thyroid peroxidase were positive in 6/53 (11%) and 5/53 (9%) of patients, respectively. The thyroid US showed the presence of focal hypoechoic areas of thyroiditis in 16/51 (32%) patients, with thyroid uptake normal in 6/16 (37%), focally reduced in 8/16 (50%) and diffusely reduced in 2/16 (12%).?CONCLUSIONS: At 3 months after Covid-19 disease all patients had a normalised thyroid function, however imaging findings suggestive for subacute thyroiditis were still present in about one third of cases. The thyroid dysfunction induced by Covid-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months.?? 

Early Follow-up of Atypical Thyroiditis Induced by SARS-CoV-2

Background:There is some data available in adults which suggests that Type 1 diabetes may be associated with higher risk with Covid-19 (1). Limited data has been available in pediatric Type 1 diabetes with Covid-19 Methods: We used TriNetX, with a large COVID-19 database, collecting real-time electronic medical records data. We compared children (0-18 years) who were diagnosed with Covid-19 with and without Type 1 diabetes. This database collected information from 54 health care organizations Results: Mortality rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Mortality rate in children with Covid-19 without Type 1 diabetes was 0.102% (257/251517). Relative risk of mortality for children with Covid-19 and Type 1 diabetes was 6.05 with a p value of < 0.0001. Endotracheal intubation rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Endotracheal intubation rate in children with Covid-19 without Type 1 diabetes was 0.071% (178/251517). Relative risk of endotracheal intubation for children with Covid-19 and Type 1 diabetes was 8.73 with a p value of < 0.0001. Pneumonia rate in children with Covid-19 and Type 1 diabetes was 0.804% (13/1618). Pneumonia rate in children with Covid-19 without Type 1 diabetes was 0.562% (1414/251517). Relative risk of pneumonia for children with Covid-19 and Type 1 diabetes was 1.43 with a p value of < 0.1959. Septic shock rate in children with Covid-19 and Type 1 diabetes was 1.05% (17/1618). Septic shock rate in children with Covid-19 without Type 1 diabetes was 0.293% (737/251517). Relative risk of septic shock for children with Covid-19 and Type 1 diabetes was 3.59 with a p value of < 0.00001. Conclusion: Mortality rate, endotracheal and septic shock were increased in children with Type 1 diabetes and Covid-19 versus children with Covid-19 and no Type 1 diabetes. Further studies with larger sample size are needed to study complication rate of Covid-19 and Type 1 diabetes. References 1) Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol 2020 Oct;8(10):813-822. doi: 10.1016/S2213-8587(20)30272-2. Epub 2020 Aug 13.?? 

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MERAIODE: A Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAFV600E Mutation (NCT 03244956)

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Estimabl2: Is There a Need for Radioiodine Ablation in Low Risk Differentiated Thyroid Cancer (DTC) Patients ? : Results From the French Randomized Phase III Prospective Trial on 776 Patients (NCT 01837745)

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