Immunotherapy in anaplastic thyroid cancer: Case series.

Unresectable anaplastic thyroid cancer (ATC) has a poor prognosis. Chemotherapy and radiotherapy have limited effects on it. Here, we present four cases who underwent immunotherapy for ATC. The patients were aged between 58 and 70 years. Two male patients with pulmonary metastases received pembrolizumab and lenvatinib. However, they died of septic shock and respiratory failure in 2.7 and 1 months, respectively, after the initiation of combination therapy. Another male patient with stage IVB disease was treated with spartalizumab. The tumor remained stable after surgical debulking but slightly progressed after 23 months. He survived for 45.5 months after spartalizumab initiation. A female patient with BRAF-mutant ATC and lung metastases was treated with a combination of pembrolizumab and lenvatinib, which was complicated with grade 4 transaminitis. The patient subsequently received dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) treatment, which was continued for 10.2 months with a best response of partial remission. She died 18 months after the initial diagnosis (11.4 months after treatment with dabrafenib and trametinib). In conclusion, the treatment responses of immunotherapy, either alone or in combination with other therapies, were highly variable in patients with ATC and should be carefully monitored along with the side effects.

The role of immune checkpoint inhibitors in anaplastic thyroid cancer (Case Series).

Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid neoplasm. However, it is one of the most aggressive forms of malignancy accounting for approximately 50% of mortality associated with all thyroid cancers. Here we report two cases of ATC treated with immune checkpoint inhibitors. Next generation sequencing identified BRAFV600E mutation in one of the patients who also derived benefit from BRAF targeted therapy. We here discuss these cases highlighting the importance of expert pathological review, utilizing molecular testing to identify the underlying genetic targets for personalized therapy, and the potential role of PD-1 inhibitors for the treatment of ATC.

Molecular therapeutics for anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) represents one of the most lethal human cancers and although this tumor type is rare, ATC accounts for the majority of deaths from thyroid cancer. Due to the rarity of ATC, a comprehensive genomic characterization of this tumor type has been challenging, and thus the development of new therapies has been lacking. To date, there is only one mutation-driven targeted therapy for BRAF-mutant ATC. Recent genomic studies have used next generation sequencing to define the genetic landscape of ATC in order to identify new therapeutic targets. Together, these studies have confirmed the role of oncogenic mutations of MAPK pathway as key drivers of differentiated thyroid cancer (BRAF, RAS), and that additional genetic alterations in the PI3K pathway, TP53, and the TERT promoter are necessary for anaplastic transformation. Recent novel findings have linked the high mutational burden associated with ATC with mutations in the Mismatch Repair (MMR) pathway and overactivity of the AID/APOBEC family of cytidine deaminases. Additional novel mutations include cell cycle genes, SWI/SNF chromatin remodeling complex, and histone modification genes. Mutations in RAC1 were also identified in ATC, which have important implications for BRAF-directed therapies. In this review, we summarize these novel findings and the new genetic landscape of ATC. We further discuss the development of therapies targeting these pathways that are being tested in clinical and preclinical studies.

1,25­Dihydroxyvitamin D3 enhances the susceptibility of anaplastic thyroid cancer cells to adriamycin­induced apoptosis by increasing the generation of reactive oxygen species.

Anaplastic thyroid cancer (ATC) is a very aggressive malignancy that is resistant to various types of chemotherapy in humans. Most patients with late­stage ATC cannot undergo surgery and receive chemotherapy drugs. The present study investigated the influence of 1,25­dihydroxyvitamin D3 (1,25(OH)2D3) pretreatment on adriamycin (ADM) chemotherapy efficacy in the 8305c and 8505c ATC cell lines. The apoptotic effects of ADM on ATC cells pretreated with 1,25(OH)2D3 were evaluated. Cell viability was identified by using the Cell Counting Kit­8 assay. Apoptosis was assessed by flow cytometry and staining with Hoechst 33342. The expression of the apoptotic protein cleaved caspase­3 was tested with a colorimetric assay kit and by western blotting. Reactive oxygen species (ROS) generation was assessed with the antioxidant N­acetyl­L­cysteine (NAC) and the assay H2­DCFDA. In addition, ROS production could be reversed by NAC treatment. The present study demonstrated that 1,25(OH)2D3 enhanced ADM­induced apoptosis in 8305c and 8505c cell lines. Furthermore, 1,25(OH)2D3 improved the ADM­induced ROS production and expression of cleaved caspase­3. NAC treatment inhibited the expression of cleaved caspase­3 in ATC cells, and reduced apoptosis in cells that were pretreated with 1,25(OH)2D3 and ADM. These results demonstrated that 1,25(OH)2D3 may enhance ADM­induced apoptosis by increasing ROS generation in ATC cells.

Therapeutic advances in anaplastic thyroid cancer: a current perspective.

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.

Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine-refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt-mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546-53. ©2018 AACR.

Hipercalcemia paraneoplásica de carcinoma anaplásico da tireoide / Paraneoplastic hypercalcemia of anaplastic thyroid carcinoma: case report

A hipercalcemia deve ser considerada no diagnóstico diferencial de alterações neuropsiquiátricas agudas. Em 90% dos casos, a etiologia corresponde a hiperparatireoidismo primário ou neoplasias. Valores séricos superiores a 14mg/dL e sintomáticos são frequentemente tradutores de causa maligna. O carcinoma anaplásico da tireoide consiste em um tumor indiferenciado, com progressão rápida e prognóstico reservado, que evolui, em alguns casos, a partir de lesões tireóideas preexistentes, benignas ou malignas (desdiferenciação). Embora a apresentação clínica mais frequente destes tumores consista no desenvolvimento de massa cervical, eles podem ser diagnosticados no esclarecimento etiológico de metástases ou síndromes paraneoplásicos. A hipercalcemia, associada à neoplasia, pode ocorrer em contexto de metástases ósseas, com libertação de citocinas, ou por mecanismo humoral, mediada pela proteína relacionada ao hormônio hormônio paratireóideo (PTHrP). Os autores descrevem o caso de uma mulher de 85 anos, com antecedentes de bócio multinodular benigno, internada para esclarecimento etiológico de hipercalcemia grave, com manifestações neuropsiquiátricas, diagnosticando-se, após avaliação, carcinoma anaplásico da tireoide. O caso foi abordado em reunião multidisciplinar, optando-se por limitação terapêutica a cuidados paliativos. A doente faleceu 3 meses após o diagnóstico.(AU)

Hypercalcaemia should be considered in the differential diagnosis of acute neuropsychiatric disorders. In 90% of the cases, the etiology corresponds to primary hyperparathyroidism or neoplasms. Serum values above 14mg/dL and symptomatic are often indicative of a malignant cause. The anaplastic thyroid carcinoma consists of an undifferentiated tumor, with rapid progression and poor prognosis, which in some cases progresses from pre-existing benign or malignant thyroid diseases (dedifferentiation). Although the most frequent clinical presentation of these tumors consists of the development of a cervical mass, they can be diagnosed in the etiological clarification of metastases or paraneoplastic syndromes. Neoplasm-associated hypercalcaemia may occur in the context of bone metastasis, with release of cytokines, or through a humoral mechanism, mediated by the parathyroid hormone (PTHrP)-related protein. The authors describe the case of an 85-year-old woman with a history of multinodular benign goiter, hospitalized for etiological elucidation of severe hypercalcaemia with neuropsychiatric manifestations, with a final diagnosis of anaplastic thyroid carcinoma, after the diagnostic evaluation. The case was approached in a multidisciplinary meeting, and the therapeutic limitation to palliative care was chosen. The patient died 3 months after the diagnosis.(AU)