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Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint in...
Citations
... These agents exert their activity by blocking inhibitory signaling and enhancing T-cell activity against tumor cells. Moreover, these results have been obtained with tolerable toxicity profile, gaining them approval for numerous different types of cancer and paving the way for designing new trials in rarer ones [5,6]. The first ICPI approved in the treatment of advanced NSCLC is nivolumab, an inhibitor of programmed cell death protein 1 (PD-1) [7]. ...
Purpose
Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC.
Methods
In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography.
Results
An impaired thyroid function was recorded in 23.4% of patients ( n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate ( p = 0.021) and multivariate analyses ( p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels ( p = 0.031).
Conclusions
Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.
... 35,36 The efficacy of immunotherapy in treating MTC is not well documented, but clinical trials are underway to explore this issue. 37 We also found a positive correlation between MPAS signature and NK cells in both wtRET and mutRET cohorts. In mutRET, there was a positive correlation with B cells, macrophages M2, and Tregs, which are associated with immunosuppression in some cancers. ...
Background
About 75% of medullary thyroid cancers (MTCs) are sporadic with 45-70% being driven by a RET mutation. Selpercatinib is an approved treatment for RET -mutated (mut RET ) MTC, however, treatments are needed for wild-type RET MTC (wt RET ). Genomic alterations and transcriptomic signatures of wtRET MTC may reveal new therapeutic insights.
Methods
We did a retrospective analysis of MTC samples submitted for DNA/RNA sequencing and PD-L1 expression using IHC at a CLIA/CAP-certified lab. Tumor microenvironment immune cell fractions were estimated using RNA deconvolution (quanTIseq). Transcriptomic signatures of inflammation and MAP kinase pathway activation scores (MPAS) were calculated. Mann-Whitney U, chi-square, and Fisher exact tests were applied ( p -values adjusted for multiple comparisons).
Results
The 160-patient cohort included 108 mut RET and 52 wtRET MTC samples. wtRET tumors frequently harbored MAPK pathway mutations, including HRAS (42.31%), KRAS (15.7%), NF1 (6.7%), and BRAF (2%) whereas only one MAPK pathway mutation ( NF1 ) was identified among mutRET MTC. Recurrent mutations seen in wt RET MTC included MGA , VHL, APC , STK11 , and NFE2L2 . Increased transcriptional activation of the MAPK pathway was observed in wt RET patients harboring mutations in MAPK genes. While the frequency of PD-L1 expression was similar in wt RET and mut RET (10.2% vs 7.0%, p =0.531), wt RET tumors were more often TMB-high (7.7% vs 0.0%, p =0.011), and wt RET MTC exhibited higher expression of immune checkpoint genes.
Conclusions
We identified molecular alterations and immune-related features that distinguish wt RET from mut RET MTC. While RET mutation drives MTC in the absence of other alterations, we showed that wtRET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with oncology immune-oncology agents for selected patients with wt RET MTC.
... In the treatment of advanced or metastatic thyroid cancer, immunotherapy, particularly immune checkpoint inhibitors, have displayed significant potential. These inhibitors function by obstructing inhibitory receptors present on T cells and, therefore, augment the immune response against cancer cells [169]. Examples of immune checkpoint Table 2 Summary of currently used therapeutic drugs for thyroid cancer. ...
... TKIs were shown to suppress the function of the RET receptor, including in children with MEN2 hereditary syndrome [16,17]. Recent trials evaluated the possibility of treating MTC by combining TKIs with other targeted therapies, mainly due to the adverse events associated with TKIs and the need for more personalized medicine [18]. TKIs, e.g., vandetanib and cabozantinib, have offered novel possibilities for treating patients with advanced MTC but are still hampered due to their mild efficiency and substantial adverse events due to the setting of MKIs. ...
Medullary thyroid carcinoma (MTC) arises from parafollicular cells in the thyroid gland, and although rare, it represents an aggressive type of thyroid cancer. MTC is recognized for its low mutational burden, with point mutations in RET or RAS genes being the most common oncogenic events. MTC can be resistant to cytotoxic chemotherapy, and multitarget kinase inhibitors (MKIs) have been considered a treatment option. They act by inhibiting the activities of specific tyrosine kinase receptors involved in tumor growth and angiogenesis. Several tyrosine kinase inhibitors are approved in the treatment of advanced MTC, including vandetanib and cabozantinib. However, due to the significant number of adverse events, debatable efficiency and resistance, there is a need for novel RET-specific TKIs. Newer RET-specific TKIs are expected to overcome previous limitations and improve patient outcomes. Herein, we aim to review MTC signaling pathways, the most recent options for treatment and the applications for personalized medicine.
... Another pathway expressed in MTC patients that could be used as a therapeutic approach is CTLA-4, and some studies using ipilimumab have been conducted, associating with PD-1/PD-L1 pathway blockade, since they are different pathways and might have synergic effects (75). A phase-II study of patients with radioactive iodine-refractory, aggressive thyroid cancer conducted an exploratory cohort of MTC patients included seven patients with MTC enrolled between October 2017 and May 2019, treated with ipilimumab plus nivolumab. ...
... Based on their potential clinical efficacy and acceptable tolerance, ICIs are currently under active evaluation in patients with neuroendocrine tumors (NETs) of different origin, based on either single or combined therapeutic protocols [9][10][11][12][13][14]. In PitNETs, the experience is yet limited to case reports or small case series reported since 2018 [15][16][17][18][19][20][21][22][23], including aggressive and metastatic tumors-which will be respectively designed as ag-PitNETs and met-PitNETs. ...
Background: Aggressive and metastatic PitNETs are challenging conditions. Immune checkpoint inhibitors (ICIs) are currently considered in cases resistant to temozolomide (TMZ). However, clinical experience is essentially limited to case reports, with variable outcomes. Material and Methods: The effects of ICIs on 12 aggressive/metastatic PitNETs from the literature were reviewed and analyzed according to tumor characteristics, with the additional description of a silent-Pit1 metastatic tumor responding to pembrolizumab. Results: Most cases were metastatic (10/13: 6 corticotroph, 3 lactotroph, 1 silent Pit1); 3 were aggressive (2 corticotroph, 1 lactotroph). ICIS was used either as monotherapy or in combination. At last follow-up on ICI, a complete response (CR) was present in 3 cases and a partial response (PR) in 2 cases (4/5 metastatic). One sustained stable disease (SD) was reported. Progressive disease (PD) was observed in 7 cases, 3 of them after initial SD (n = 1) or PR (n = 3), with 2 reported deaths. PDL1 expression was studied in 10 cases and was high (>95%) in 2 Pit1-derived metastatic PitNETs (1 CR and 1 remarkable PR) but absent/low (<1%) in the remaining cases (including 1 CP and 2 PR). Elevated tumor mutation burden could be informative in corticotroph PitNETs, especially in mismatch repair-deficient tumors. Conclusion: Significant benefits from ICIs were documented in about half of TMZ-resistant PitNETS. High PDL1 expression was associated with remarkable responses but may be dispensable. Based on their acceptable tolerance and awaiting recognized predictors of response, ICIs may be considered a valuable option for such patients.
... Although survival rates have been improving over time, tailored therapies are needed, especially for patients with rapidly progressing diseases. The role of immunotherapy in NENs is gaining interest [8,9], and encouraging clinical results have been reported in small cell lung cancer (SCLC) [10], Merkel cell carcinoma [11], pheochromocytoma/paraganglioma [12], lung carcinoid [13], and medullary thyroid carcinoma (MTC) [14]. T cell immunotherapy using CAR-T cells is showing encouraging results in cancer treatment. ...
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic approaches are required. Immunotherapy, based on chimeric antigen receptor T cells (CAR-T), is showing impressive results in several cancer treatments. The aim of this narrative review is to analyze the available data about the use of CAR-T in NENs, including studies in both preclinical and clinical settings. We performed an extensive search for relevant data sources, comprising full-published articles, abstracts from international meetings, and worldwide registered clinical trials. Preclinical studies performed on both cell lines and animal models indicate a significant therapeutic effect of CAR-T cells in NENs. Ongoing and future clinical trials will clarify the possible role of these drugs in patients with highly aggressive NENs.
... As a new era in cancer treatment (Ngamcherdtrakul et al., 2021;Johnson et al., 2022), immune checkpoint inhibitors (ICIs) has achieved positive efficacy in many tumors such as non-small cell lung cancer (NSCLC) (Kazandjian et al., 2016), melanoma (Bhatnagar et al., 2017), head and neck squamous cell carcinoma (Larkins et al., 2017). Similarly, it has broad prospects in the clinical treatment of THCA (Varricchi et al., 2019;Di Molfetta et al., 2021). While ICIs can significantly improve survival in several cancers, they may also induce a series of immune-related adverse events (irAEs) with endocrine disorders being the most common (Wright et al., 2021). ...
Background: Factors such as variations in thyroid carcinoma (THCA) gene characteristics could influence the clinical outcome. Ferroptosis and immunity have been verified to play an essential role in various cancers, and could affect the cancer patients’ prognosis. However, their relationship to the progression and prognosis of many types of THCA remains unclear.
Methods: First, we extracted prognosis-related immune-related genes and ferroptosis-related genes from 2 databases for co-expression analysis to obtain prognosis-related differentially expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and screened BID and CDKN2A for building a prognostic model. Subsequently, multiple validation methods were used to test the model’s performance and compare its performance with other 4 external models. Then, we explored the mechanism of immunity and ferroptosis in the occurrence, development and prognosis of THCA from the perspectives of anti-tumor immunity, CDKN2A-related competitive endogenous RNA regulatory, copy number variations and high frequency gene mutation. Finally, we evaluated this model’s clinical practice value.
Results: BID and CDKN2A were identified as prognostic risk and protective factors, respectively. External data and qRT-PCR experiment also validated their differential expression. The model’s excellent performance has been repeatedly verified and outperformed other models. Risk scores were significantly associated with most immune cells/functions. Risk score/2 PR-DE-IRFeGs expression was strongly associated with BRAF/NRAS/HRAS mutation. Single copy number deletion of CDKN2A is associated with upregulation of CDKN2A expression and worse prognosis. The predicted regulatory network consisting of CYTOR, hsa-miRNA-873-5p and CDKN2A was shown to significantly affect prognosis. The model and corresponding nomogram have been shown to have excellent clinical practice value.
Conclusion: The model can effectively predict the THCA patients’ prognosis and guide clinical treatment. Ferroptosis and immunity may be involved in the THCA’s progression through antitumor immunity and BRAF/NRAS/HRAS mutation. CYTOR-hsa-miRNA-873-5p-CDKN2A regulatory networks and single copy number deletion of CDKN2A may also affect THCA′ progression and prognosis.
... Blocking these inhibitory pathways enhances effector T cells and inhibits regulatory suppressor cells [124]. Their blockade is a promising immunotherapeutic method that is used in other cancer types, but in medullary thyroid carcinoma, the studies supporting this method are insufficient [125]. In a recently conducted study, 200 patients who received surgery before systemic treatment were tested. ...
Medullary thyroid carcinoma (MTC) is a neoplasm originating from parafollicular C cells. MTC is a rare disease, but its prognosis is less favorable than that of well-differentiated thyroid cancers. To improve the prognosis of patients with MTC, early diagnosis and prompt therapeutic management are crucial. In the following paper, recent advances in laboratory and imaging diagnostics and also pharmacological and surgical therapies of MTC are discussed. Currently, a thriving direction of development for laboratory diagnostics is immunohistochemistry. The primary imaging modality in the diagnosis of MTC is the ultrasound, but opportunities for development are seen primarily in nuclear medicine techniques. Surgical management is the primary method of treating MTCs. There are numerous publications concerning the stratification of particular lymph node compartments for removal. With the introduction of more effective methods of intraoperative parathyroid identification, the complication rate of surgical treatment may be reduced. The currently used pharmacotherapy is characterized by high toxicity. Moreover, the main limitation of current pharmacotherapy is the development of drug resistance. Currently, there is ongoing research on the use of tyrosine kinase inhibitors (TKIs), highly specific RET inhibitors, radiotherapy and immunotherapy. These new therapies may improve the prognosis of patients with MTCs.
... In this study, CTLA-expression, PD-1/PD-L1 co-expression, and TIM-3 expression were associated with worse recurrence-free survival, and moderate to strong CTLA-4, PD-1, or PD-L1 expression along with consistent TIM-3 expression was noted in MTC of patients who developed advanced disease. Currently, data on ICI therapy in thyroid cancer, including MTC, is extremely sparse [83,84]. In one report, a patient with advanced, metastatic MTC demonstrated substantial improvement in calcitonin doubling time and tumor burden following yeast-CEA vaccine, followed by surgery and then ICI therapy with avelumab under a phase I trial [85]. ...
Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.
