Advanced Thyroid Cancer Patients Research Articles

Dynamics of The Γδtcr Repertoires During The Dedifferentiation Process and Pilot Implications for Immunotherapy of Thyroid Cancer.

γδ T cells are evolutionarily conserved T lymphocytes that manifest unique antitumor efficacy independent of tumor mutation burden (TMB) and conventional human leukocyte antigen (HLA) recognition. However, the dynamic changes in their T cell receptor (TCR) repertoire during cancer progression and treatment courses remain unclear. Here, a comprehensive characterization of γδTCR repertoires are performed in thyroid cancers with divergent differentiation states through cross-sectional studies. The findings revealed a significant correlation between the differentiation states and TCR repertoire diversity. Notably, highly expanded clones are prominently enriched in γδ T cell compartment of dedifferentiated patients. Moreover, by longitudinal investigations of the γδ T cell response to various antitumor therapies, it is found that the emergence and expansion of the Vδ2neg subset may be potentially associated with favorable clinical outcomes after post-radiotherapeutic immunotherapy. These findings are further validated at single-cell resolution in both advanced thyroid cancer patients and a murine model, underlining the importance of further investigations into the role of γδTCR in cancer immunity and therapeutic strategies.

Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2-88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

Next-Generation-Sequencing on fine needle aspirates in neck recurrence of thyroid cancers.

Tumor molecular genotyping plays a key role in improving the management of advanced thyroid cancers. Molecular tests are classically performed on Formalin-Fixed Paraffin-Embedded (FFPE) carcinoma tissue. However alternative molecular testing strategies are needed when FFPE tumoral tissue is unavailable. The objective of our study was to retrospectively assess the performance of targeted DNA and RNA-based Next Generation Sequencing (NGS) on the fine needle aspirate from thyroid cancer cervical recurrences to determine if this strategy is efficient in clinical practice. A retrospective study of 33 patients who had had DNA and/or RNA-based NGS on ultrasound (US)-guided fine needle aspirates of cervical thyroid cancer recurrences in our Department from July 2019 to September 2022. In total, 34 DNA and 32 RNA-based NGS analyses were performed. Out of the 34 DNA-based NGS performed, 27 (79%) were conclusive allowing the identification of an oncogenic driver for 18 patients (53%). The most common mutation (n = 13) was BRAF c.1799T>A. Out of the 32 RNA-based NGS performed, 26 were interpretable (81%) and no gene fusion was found. The identification of a BRAFV600E mutation was decisive for one patient in our series, who was prescribed dabrafenib and trametinib. NGS performed on fine needle aspirates of neck lymph node metastases enabled the identification of an oncogenic driver alteration in 53% of the cases in our series of advanced thyroid cancer patients and could significantly alter patient management.

Molecular genetic testing in advanced thyroid cancer patients for the purposes of targeted systemic therapy

Molecular genetic testing in advanced thyroid cancer patients for the purposes of targeted systemic therapy

Changes in peripheral blood immune cell population in thyroid cancer patients treated with lenvatinib

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2–3 months intervals 2–4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Using a CT-based scale to evaluate disease extension and the resectability of locally advanced thyroid cancer.

To establish a computed tomography (CT)-based scale to evaluate the resectability of locally advanced thyroid cancer. This twin-centre retrospective study included 95 locally advanced thyroid cancer patients from the 1st centre as the training cohort and 31 patients from the 2nd centre as the testing cohort, who were categorised into the resectable and unresectable groups. Three radiologists scored the CT scans of each patient by evaluating the extension to the recurrent laryngeal nerve (RLN), trachea, oesophagus, artery, vein, soft tissue, and larynx. A 14-score scale (including all comprised structures) and a 12-score scale (excluding larynx) were developed. Receiver-operating characteristic (ROC) analysis was used to evaluate the performance of the scales. Stratified fivefold cross-validation and external verification were used to validate the scale. In the training cohort, compromised RLN (p < 0.001), trachea (p = 0.001), oesophagus (p = 0.002), artery (p < 0.001), vein (p = 0.005), and soft tissue (p < 0.001) were predictors for unresectability, while compromised larynx (p = 0.283) was not. The 12-score scale (AUC = 0.882, 95%CI: 0.812-0.952) was not inferior to the 14-score scale (AUC = 0.891, 95%CI: 0.823-0.960). In subgroup analysis, the AUCs of the 12-score scale were 0.826 for treatment-naïve patients and 0.976 for patients with prior surgery. The 12-score scale was further validated with a fivefold cross-validation analysis, with an overall accuracy of 78.9-89.4%. Finally, external validation using the testing cohort showed an AUC of 0.875. The researchers built a CT-based 12-score scale to evaluate the resectability of locally advanced thyroid cancer. Validation with a larger sample size is required to confirm the efficacy of the scale. This 12-score CT scale would help clinicians evaluate the resectability of locally advanced thyroid cancer. • The researchers built a 12-score CT scale (including recurrent laryngeal nerve, trachea, oesophagus, artery, vein, and soft tissue) to evaluate the resectability of locally advanced thyroid cancer. • This scale has the potential to help clinicians make treatment plans for locally advanced thyroid cancer.

Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in Patients with Advanced Thyroid Cancer

Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (CYP3A4 rs2242480 and rs2687116 and CYP3A5 rs776746) genes and to ATP-binding cassette transporters (ABCB1 rs1045642, rs2032582 and rs2235048 and ABCG2 rs2231142). Our results suggest that the GG genotype for rs2242480 in CYP3A4 and CC genotype in rs776746 for CYP3A5 were both associated with the presence of hypertension. Being heterozygous for SNPs in the ABCB1 gene (rs1045642 and 2235048) implicated a higher grade of weight loss. The ABCG2 rs2231142 statistically correlated with a higher extent of mucositis and xerostomia (CC genotype). Heterozygous and rare homozygous genotypes for rs2242480 in CYP3A4 and for rs776746 for CYP3A5 were found to be statistically linked to a worse outcome. Evaluating the genetic profile before starting lenvatinib treatment may help to predict the occurrence and grade of some side effects, and may contribute to improving patient management.

Adrenal insufficiency in thyroid cancer patients treated with tyrosine kinase inhibitors and detected by ACTH stimulation test

PurposeAdvanced thyroid cancer patients treated with tyrosine kinase inhibitors (TKI) can develop several adverse events (AEs), including adrenal insufficiency (AI).MethodsWe studied 55 patients treated with TKI for radioiodine-refractory or medullary thyroid cancer. The adrenal function was evaluated during follow-up by performing serum basal ACTH, and basal and ACTH-stimulated cortisol.ResultsTwenty-nine/55 (52.7%) patients developed subclinical AI during TKI treatment as demonstrated by a blunted cortisol response to ACTH stimulation. All cases showed normal values of serum sodium, potassium and blood pressure. All patients were immediately treated, and none showed an overt AI. Cases with AI were all negative for adrenal antibodies and did not show any adrenal gland alteration. Other causes of AI were excluded. The onset time of the AI, as measured in the subgroup with a first negative ACTH test, was < 12 months in 5/9 (55.6%), between 12 and 36 months in 2/9 (22.2%) and > 36 months in 2/9 (22.2%) cases. In our series, the only prognostic factor of AI was the elevated, although moderate, basal level of ACTH when the basal and stimulated cortisol were still normal. The glucocorticoid therapy improved fatigue in most patients.ConclusionsSubclinical AI can be developed in > 50% of advanced thyroid cancer patients treated with TKI. This AE can develop in a wide period ranging from < 12 to > 36 months. For this reason, AI must be looked for throughout the follow-up to be early recognized and treated. A periodic ACTH stimulation test, every 6–8 months, can be helpful.

Effect of Pre-Existent Sarcopenia on Oncological Outcome of Advanced Thyroid Cancer Patients Treated with Tyrosine Kinase Inhibitors.

Simple SummaryData regarding the effect of pre-existent sarcopenia on the oncological outcome of advanced thyroid cancer patients treated with tyrosine kinase (TKI) are still lacking. The aim of the study was to investigate the prevalence of pre-treatment sarcopenia in Caucasian patients affected by advanced thyroid carcinoma and the impact of this condition on the response to TKIs treatment. Pre-treatment sarcopenia was found in 20.7% of patients, with an increase of up to 38.5% after 12 months of TKI therapy. Pre-treatment sarcopenia significantly affected treatment outcome, emerging as the parameter that has the greatest impact on Progression Free Survival. Sarcopenia might be used as a prognostic factor of TKI treatment outcome and the prevention of this condition, ideally before starting anticancer treatment, could be the strategy to obtain a better efficacy of therapy.(1) Background: Sarcopenia is associated with poor survival and treatment outcomes in several human cancers. The aim of the study was to investigate the prevalence of sarcopenia in a cohort of 58 Caucasian patients with advanced thyroid cancer before and during TKI treatment. The impact of this condition on the outcome of patients was also evaluated. (2) Methods: Sarcopenia was evaluated using the Skeletal Muscle Index (SMI). (3) Results: Pre-treatment sarcopenia was found in 20.7% of patients and this condition significantly affected treatment outcome, emerging as the parameter that has the greatest impact on Progression Free Survival (PFS) (HR 4.29; 95% CI, 1.21–15.11, p = 0.02). A significant reduction in SMI values was observed 3 (p = 0.002) and 12 months (p < 0.0001) after TKI treatment. At a 12-month follow-up, sarcopenia prevalence increased up to 38.5%. Here, 12-month sarcopenia was predicted by a lower SMI (p = 0.029), BMI (p = 0.02) and weight (p = 0.04) and by the presence of bone metastases (p = 0.02). (4) Conclusions: This is the first study that evaluated sarcopenia prevalence and its change over time in Caucasian patients with advanced thyroid cancer under TKI therapy. Sarcopenia seems to be a prognostic factor of TKI treatment outcome, suggesting the importance of the assessment of the nutritional status and body composition in advanced thyroid cancer patients.

Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors-A Retrospective Multi-Center Registry Analysis.

Simple SummaryLately, a more personalized approach in the management of advanced thyroid cancer patients has improved the outcomes, and several novel molecularly guided therapies, including selective RET inhibitors (sRETis), have demonstrated promising efficacy in clinical trials. RET (rearranged during transfection) variants are the most prevalent oncogenic event in medullary thyroid cancer (MTC). We here found RET oncogene variants in 44/48 prospectively collected MTC tumor samples from patients treated with more unselective kinase inhibitors vandetanib and/or cabozantinib. Our study shows that RET variants were highly prevalent in patients with advanced MTC, and the treatment results in RET-positive cases were similar to those reported in unselected cohorts.Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.

Frequency and outcomes of molecularly guided off-label targeted agent prescriptions in the VA National Precision Oncology Program (NPOP).

e18676 Background: The increasing availability of comprehensive genomic profiling (CGP) and a growing number of targeted agents (TAs) has led to substantial improvements in outcomes among cancer pts with actionable mutations. CGP has led to identification of both on-label (level 1) variants, for which TAs have known efficacy, and off-label variants with lesser strength of supporting data. We sought to evaluate real-world prescription patterns and outcomes of off-label TA prescriptions among pts who underwent CGP. Methods: The NPOP database and VA Corporate Data Warehouse were queried to identify pts who had underwent CGP between February 2019 and December 2021 and were prescribed at least 1 of 73 TAs before January 2022. TAs prescribed for FDA-approved indications not relying on CGP as a companion diagnostic were excluded. OncoKB was used to annotate gene variants and evaluated against prescriptions to select pts who received off-label TAs. The frequency of off-label TA use, and for those treated &gt; 4 weeks, rate of pts treated for 6 months or longer, median treatment duration and overall survival (OS) were computed. Results: Of the 18686 patients who underwent CGP, 2107 (11%) were prescribed any TA, and 191 (1%) were prescribed off-label TAs, with 31 receiving multiple concurrent or sequential off-label TAs. Mean age was 65.5 years, and 88% were male. TAs were most often prescribed for cancers of unknown primary (CUP, 29), NSCLC (24), and colorectal cancer (22). Frequency of off-label prescriptions was highest for pts who completed CGP for thyroid cancer (9%), breast cancer (8%), and CUP (2%). Most common variants involved BRAF (21%), ERBB2 (18%), BRCA1/BRCA2/ATM (9%), and PIK3CA (6%). Among all 164 pts treated &gt; 4 weeks, 40% received TAs for 6 months or longer, including 50%, 47%, and 46% of pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease, respectively. Median therapy duration and OS was 141 [78.5 – 317, IQR] days and 181 [96.5 – 304.5, IQR] days, respectively. Conclusions: Though overall use of off-label TAs following CGP is low, nearly 10% of advanced thyroid and breast cancer patients are prescribed TAs for off-label indications. Forty percent of all pts receiving off-label TAs continue for at least 6 months, with higher rates for pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease. CGP-guided off-label treatment approaches offer unique options for advanced stage cancer with amenable molecular profiles.

The effect of anlotinib on unresectable differentiated thyroid cancer (T4): A retrospective study.

6096 Background: Though the majority of differentiated thyroid cancer (DTC) patients obtained a good prognosis after standardized therapy, approximately 15% of DTC patients will progress to unresectable disease. Part of locally advanced (T4) thyroid cancer patients with progressive invasion into vasculature/windpipe/esophagus lost the surgery opportunity because of difficult in achieving R0/R1 resection. The study aimed to evaluate the efficacy and safety of anlotinib in T4 PTC. Methods: Retrospectively included T4 papillary thyroid cancer (PTC) patients from West China Hospital of Sichuan University between Sep. 2020 and Feb. 2022. The patients were prescribed with Anlotinib (12 mg orally daily, two weeks on/one week off) at least two courses. The tumor response was defined by RECIST v. 1.1. The primary endpoint was objective response rate (ORR). Results: The study included 22 T4 PTC patients, including 8 patients with lung metastasis. The median age of patients was 59.2 years, 8/22 patients were male. The median follow-up was 5.5 months (2-13 months). Totally, the ORR was 68.2% (CR: 9.1%; PR: 59.1%), disease control rate (DCR) was 95.5% (SD: 27.3%), one patient progressed (PD). 8 patients with lung metastasis, the ORR was 75% (6/8). The average tumor shrinkage rate was 42.1%. And two female patients (T4aN1M1 and T4bN1M0 respectively) obtained CR. Additionally, one juvenile patient (14 y) also response to Anlotinib treatment with 55.2% tumor shrinkage, and no obvious AE was observed in this patient. Most adverse events (AEs) were grade 1 or 2. Common AEs of all grades were hypertension (68.2%), hypertriglyceridemia (36.4%), proteinuria (31.8%), and tended to discontinue when treatment ceased. Conclusions: Anlotinib demonstrated antitumor activity in the treatment of unresectable T4 PTC; Juvenile PTC patients also response to Anlotinib treatment; Anlotinib treatment was tolerable in T4 PTC patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in advanced thyroid cancer (TC) patients; single-center experience

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in advanced thyroid cancer (TC) patients; single-center experience

Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors

MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAFV600E promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAFV600E-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAFV600E mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAFV600E-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.

Nutrition in Advanced Thyroid Cancer Patients.

In the last decade, multikinase inhibitors (MKIs) have changed the paradigm of treatment of advanced and progressive thyroid cancer. Compared with the traditional treatment with chemotherapy and radiotherapy, these new drugs have shown a good efficacy in controlling the neoplastic disease, and also a different toxicity profile compared to traditional chemotherapy, milder but still present and involving mainly the nutritional profile. Weight loss, nausea, anorexia, stomatitis, diarrhea may be associated with malnutrition and cancer-related cachexia. The latter is characteristic of the advanced cancer stage and may be present before starting MKIs, or may develop afterwards. Adverse events with nutritional impact may cause a significant impairment of quality of life, often requiring dose reduction and sometimes drug discontinuation, but with a lower efficacy on the neoplastic disease. The aim of this paper was to discuss the role of nutritional therapy in advanced thyroid cancer and the importance of prevention, early recognition and careful management of malnutrition and cachexia during systemic therapy with MKIs.

Nephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: An update.

Over the past decade, the prognosis of advanced thyroid cancer (TC) patients has dramatically improved thanks to the introduction of tyrosine kinase inhibitors (TKIs). Despite their effectiveness, these drugs are burdened with several side effects that can negatively affect quality of life and compromise therapy continuation. Among renal adverse events (RAEs), proteinuria is the most frequently reported in clinical trials and real-life experiences, especially during treatment with lenvatinib or cabozantinib. This peculiar toxicity is commonly associated with targeted therapies with anti-angiogenic activity, even if the mechanisms underlying its onset and progression are not entirely clear. RAEs should be early recognized and properly managed to avoid renal function worsening and life-threatening consequences. Aiming at providing a comprehensive summary that can help clinicians to identify and manage TKIs-related RAEs in TC patients, we reviewed the current evidence about this topic, from pathogenesis and potential risk factors to diagnosis and treatment.

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo.

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.

Sarcopenia may Influence the Prognosis in Advanced Thyroid Cancer Patients Treated With Molecular Targeted Therapy.

Reportedly, sarcopenia and nutritional status are associated with prognosis in cancer patients. However, data regarding the relationship of these factors with advanced thyroid cancer patients receiving molecular targeted therapy remains scarce. Therefore, we investigated the relationship between nutritional assessment, as well as sarcopenia, and prognosis in patients with advanced thyroid cancer undergoing molecular targeted therapy. In this retrospective study, sarcopenia and several markers of nutritional status were assessed in advanced thyroid cancer patients at the Kanazawa University Hospital, before the introduction of molecular targeted therapy. Advanced thyroid cancer patients with sarcopenia presented a worse prognosis than those without sarcopenia. Additionally, sarcopenia strongly correlated with several markers of nutritional status, such as albumin, prognostic nutrition index, and Glasgow prognostic score. Sarcopenia could be a prognostic factor in patients with advanced thyroid cancer receiving molecular targeted therapy.

MON-537 Primary Adrenal Insufficiency During Tyrosine Kinase Inhibitors Treatment in Advanced Thyroid Cancer Patients

Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI). Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts. Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation. Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (<12 months) or late (>36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.

HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer.

Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 µM on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out HDAC1 and HDAC2 genes in SW579 cells, we observed that the histone acetylation level and cell cycle arrest were enhanced without any impact on cell growth. Furthermore, HDAC1 and HDAC2 double knockout (KO) cells showed dramatic cell apoptosis activation compared to HDAC1 and HDAC2 individual KO cells. This suggests expressional and biofunctional compensation between HDAC1 and HDAC2 on SW579 cells. This study provides strong evidence that panobinostat can potentially be used in the clinic of advanced thyroid cancer patients.