Search

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues. [ABSTRACT FROM AUTHOR]

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment (p = 0.427) and prior treatments with surgery (p = 0.864) and radiation (p = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9–22.1]) compared with DT alone (9.0 months [CI, 4.5–13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0–15.0]) compared with DT alone (4.0 months [CI, 0.7–7.3]), p = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5–110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation. [ABSTRACT FROM AUTHOR]

Importance: Approximately 43 720 new cases of thyroid carcinoma are expected to be diagnosed in 2023 in the US. Five-year relative survival is approximately 98.5%. This review summarizes current evidence regarding pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer. Observations: Papillary thyroid cancer accounts for approximately 84% of all thyroid cancers. Papillary, follicular (≈4%), and oncocytic (≈2%) forms arise from thyroid follicular cells and are termed well-differentiated thyroid cancer. Aggressive forms of follicular cell-derived thyroid cancer are poorly differentiated thyroid cancer (≈5%) and anaplastic thyroid cancer (≈1%). Medullary thyroid cancer (≈4%) arises from parafollicular C cells. Most cases of well-differentiated thyroid cancer are asymptomatic and detected during physical examination or incidentally found on diagnostic imaging studies. For microcarcinomas (≤1 cm), observation without surgical resection can be considered. For tumors larger than 1 cm with or without lymph node metastases, surgery with or without radioactive iodine is curative in most cases. Surgical resection is the preferred approach for patients with recurrent locoregional disease. For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma. Conclusions: Approximately 44 000 new cases of thyroid cancer are diagnosed each year in the US, with a 5-year relative survival of 98.5%. Surgery is curative in most cases of well-differentiated thyroid cancer. Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease. This narrative review summarizes current evidence regarding the pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer. [ABSTRACT FROM AUTHOR]

B Dear Editor: b Advanced thyroid cancers may invade recurrent laryngeal nerve (RLN) through direct tumor extension or lymph node metastasis, resulting in vocal fold paralysis (VFP) which impacts patient's quality of life, affects the resectability when operating on the contralateral (functional) side due to the significant risk for bilateral VFP during surgery and the potential need for tracheotomy, and significantly impacts the surgical strategy.[1],[2] Many patients will be understandably hesitant to undergo surgery that involves permanent tracheotomy.[3] Both unilateral or bilateral VFP have a negative impact on a patient's quality of life and general health.[4],[5] While preoperative VFP is highly suggestive of RLN invasion, normal voice or laryngeal exam does not exclude RLN invasion at surgery. I BRAF SP V600E sp i mutations were detected in all seven patients (100%), I TERT i promoter mutations were detected in four patients (57.1%), I PIK3CA i mutations in two patients (28.6%), and I TP53 i mutations in two patients (28.6%), Supplementary Table S1. Overall, the median number of cycles of all neoadjuvant therapy received per patient regardless of therapy type was 4 cycles/patient. [Extracted from the article]

Background: A history of thyroid and nonthyroid malignancies has traditionally been an exclusion criterion in patients with anaplastic thyroid cancer (ATC) seeking to enroll in clinical trials. In this study, we examined the impact of prior malignancies on overall survival (OS) in patients diagnosed with ATC. Methods: In our retrospective cohort study, we identified 451 patients with ATC treated at MD Anderson between 2000 and 2019. Clinical and pathological information was obtained through chart review. Survival analyses were conducted using the Kaplan–Meier method and multivariable Cox proportional hazard models. Results: A history of clinically documented differentiated thyroid cancer (DTC) was reported in 14% of patients with ATC (n = 62), most commonly papillary thyroid cancer (81%, n = 50). The median time from diagnosis of prior DTC to ATC diagnosis was 3.5 years (range: 6 months to 35 years). Concomitant DTC was found on pathology in a higher proportion of patients (52%, n = 234). A history of nonthyroid cancer was reported in 23% of patients (n = 102), where 19% (n = 87) had one, 2% (n = 10) had two, and 1% (n = 5) had three prior cancers. The median time from diagnosis of prior nonthyroid cancer to ATC diagnosis was 8 years (range: 3 months to 53 years). The most common prior nonthyroid cancers were nonmelanoma skin (28.4%), prostate (19.6%), and breast cancers (16.7%). In a subgroup analysis performed in patients with available tumor mutation information (n = 183), the frequency of detected tumor driver mutations (BRAF, RAS, TP53) was not significantly different between patients with ATC with and without a history of nonthyroid cancer. On multivariate analysis after adjusting for age and overall stage, prior DTC, concomitant DTC, and prior nonthyroid cancers, all had no significant impact on OS. Conclusions: The presence of prior malignancy does not significantly impact OS in patients with ATC. Revision of eligibility criteria for enrollment of patients with ATC into clinical trials is warranted. [ABSTRACT FROM AUTHOR]

To measure the potential clinical impact of neoadjuvant treatment response, change in thyroid neck surgical morbidity score was assessed using CT neck with contrast (1.25 mm cuts) at baseline and preoperatively at the completion of neoadjuvant therapy. The first patient was treated with the study drug LOXO-292 (provided by Loxo Oncology) after an investigational drug application approval by the FDA, which has been previously published.[3] The remaining three patients were treated outside of a clinical trial. B Dear Editor: b Selective RET inhibitors, including selpercatinib and pralsetinib, were recently approved by the U.S. Food and Drug Administration (FDA) and have demonstrated efficacy and acceptable safety profiles for I RET i -altered thyroid cancers.[1],[2] The potential to limit surgical morbidity for medullary thyroid cancer (MTC) with neoadjuvant therapy has not been studied, with only a single case report to date.[[3], [5]] We present a consecutive case series of four patients with I RET i -mutated MTC treated with neoadjuvant selpercatinib followed by surgical resection. All patients with locoregionally advanced I RET i -mutated MTC who underwent neoadjuvant treatment with an RET-specific inhibitor before surgery were reviewed. [Extracted from the article]

Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients. [ABSTRACT FROM AUTHOR]

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC. MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models. RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAF V600E and RAS , which were mutually exclusive. The BRAF V600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS -mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAF V600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAF V600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21). CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care. Largest study, to our knowledge, published to date to examine the impact of tumor mutations on survival outcomes in ATC, demonstrating that driver mutation status is a key determinant of survival outcomes. Data support routine assessment of tumor mutation profiles in ATC. [ABSTRACT FROM AUTHOR]

Context: Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust preclinical thyroid cancer models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models may resemble patient tumors by recapitulating key genetic alterations and gene expression patterns, making them excellent preclinical models for drug response evaluation.Objective: We developed distinct ATC PDX models concurrently with cell lines and characterized them in vitro and in vivo.Methods: Fresh thyroid tumor from patients with a preoperative diagnosis of ATC was surgically collected and divided for concurrent cell line and PDX model development. Cell lines were created by generating single cells through enzymatic digestion. PDX models were developed following direct subcutaneous implantation of fresh tumor on the flank of immune compromised/athymic mice.Results: Six ATC PDX models and 4 cell lines were developed with distinct genetic profiles. Mutational characterization showed one BRAF/TP53/CDKN2A, one BRAF/CDKN2A, one BRAF/TP53, one TP53 only, one TERT-promoter/HRAS, and one TERT-promoter/KRAS/TP53/NF2/NFE2L2 mutated phenotype. Hematoxylin-eosin staining comparing the PDX models to the original patient surgical specimens show remarkable resemblance, while immunohistochemistry stains for important biomarkers were in full concordance (cytokeratin, TTF-1, PAX8, BRAF). Short tandem repeats DNA fingerprinting analysis of all PDX models and cell lines showed strong concordance with the original tumor. PDX successful establishment rate was 32%.Conclusion: We have developed and characterized 6 novel ATC PDX models with 4 matching cell lines. Each PDX model harbors a distinct genetic profile, making them excellent tools for preclinical therapeutic trials. [ABSTRACT FROM AUTHOR]

Background: Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development. Material and Methods: Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents. Results: Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53. Conclusions: HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer that requires a rapid diagnosis and treatment to achieve disease control. Gene mutation profiling of circulating cell-free DNA (cfDNA) in peripheral blood may help to facilitate early diagnosis and treatment selection. The relatively rapid turnaround time compared with conventional tumor mutation testing is a major advantage. The objectives of this study were to examine the concordance of ATC-related mutations detected in cfDNA with those detected in the corresponding tumor tissue, and to determine the prognostic significance of cfDNA mutations in ATC patients. Methods: The ATC patients who were diagnosed and treated at The University of Texas MD Anderson Cancer Center between January 2015 and February 2018 and who had cfDNA testing were included in this study. cfDNA was collected by blood draw and was analyzed by next-generation sequencing (NGS) using the Guardant360-73 gene platform. Results: A total of 87 patients were included in the study. The most frequently mutated genes detected in cfDNA were TP53, BRAF, and PIK3CA. In 28 treatment naive ATC patients, the concordance rate of detected mutations in TP53, BRAFV600E, and PIK3CA between cfDNA and matched tissue NGS was 82.1%, 92.9%, and 92.9%, respectively. Patients with a PIK3CA mutation detected on cfDNA had worse overall survival (OS) (p = 0.03). This association was observed across various treatment modalities, including surgery, cytotoxic chemotherapy, radiation, and BRAF inhibitor (BRAFi) therapy. With regard to treatment, BRAFi therapy significantly improved ATC OS (p = 0.003). Conclusions: cfDNA is a valuable tool to evaluate a tumor's molecular profile in ATC patients. We identified high concordance rates between the gene mutations identified via cfDNA analysis and those identified from the NGS of the corresponding tumor tissue sequencing. Identified mutations in cfDNA can potentially provide timely information to guide treatment selection and evaluate the prognosis in patients with ATC. [ABSTRACT FROM AUTHOR]

Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: The BRAFV600E mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAFV600E-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAFV600E-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Patients: Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAFV600E mutation at progression. Results: Patients 1 and 3 acquired a KRASG12V mutation in the progressive tumor, patient 2 acquired a NRASQ61K mutation in a progressive lymph node, and patient 4 acquired NRASG13D mutation on liquid biopsy performed at the time of radiographic disease progression. Conclusion: Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers. [ABSTRACT FROM AUTHOR]

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAFV600E-mutated ATC. Methods: Case series of six consecutive patients with BRAFV600E-mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAFV600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAFV600E-mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration. [ABSTRACT FROM AUTHOR]

Purpose: Anaplastic thyroid cancer (ATC) is a deadly form of thyroid cancer. BRAF V600E is the only actionable mutation for which there is a Food and Drug Administration–approved drug combination. Rapid detection of BRAF V600E and initiation of therapy is critical. We explored the ability of droplet digital polymerase chain reaction (ddPCR) to identify this mutation in circulating cell-free DNA (cfDNA) in plasma. Materials and Methods: The ddPCR assay was evaluated for its sensitivity, specificity for detection of BRAF V600E cfDNA, and concordance with tumor tissue. The assay also was used to evaluate its potential role as a biomarker of response. Results: Forty-four patients with ATC who were tested for the BRAF mutation by tumor tissue DNA sequencing or immunohistochemistry were included. Sixteen BRAF V600E–positive patients had treatment samples to evaluate cfDNA levels as a biomarker of response in correlation with restaging scans. Concordance of ddPCR with tumor tissue was 93%, with a sensitivity of 85% and specificity of 100%. Area under the curve by Wilcoxon rank sum test was 0.9 (95% CI, 0.80 to 0.99; P <.001). As a biomarker of response to treatment, 94% of ddPCR samples were concordant with tumor shrinkage in restaging scans, and 47% were concordant with tumor growth (Fisher's exact test P =.0061). In addition, cfDNA levels by ddPCR were predictive of treatment response in 71% of samples. Conclusion: cfDNA detection by ddPCR is highly sensitive, specific, and concordant with mutation status on ATC tumors. ddPCR also can be used for monitoring cfDNA levels in conjunction with imaging scans in patients with ATC. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis. Patients who have disease confined to the thyroid and who are able to undergo complete surgery and chemoradiation stand the best chance for survival. Unfortunately, nearly 50% of patients have distant metastases at diagnosis, and most present with locally advanced, unresectable tumors. Nevertheless, BRAF -mutated ATC patients represent a subset of cases who can benefit from a combination therapy with BRAF and MEK inhibitors. Here, a patient is presented with end-stage, locally advanced, unresectable ATC who was treated with this combination. Immunotherapy with pembrolizumab was added at the first sign of progression after which he achieved a partial response to therapy, enabling a complete surgical resection followed by postoperative chemoradiation to be undertaken. This novel neoadjuvant approach to BRAF -mutated ATC should be studied in further in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial. Methods: This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAFV600E mutant tumors) were started on lenvatinib, and six with BRAFV600E-mutated tumors received a combination of dabrafenib plus trametinib. Best response evaluated by RECIST v1.1, progression-free survival, and overall survival were determined. Adverse events were evaluated for safety. Results: The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable. Conclusions: Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAFV600E mutants) may provide clinical benefit in ATC patients who are unable to participate in clinical trials, and toxicities are manageable. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is one of the most lethal forms of cancer with a high mortality rate. Current guidelines support surgery for resectable ATC followed by external beam radiation therapy (EBRT) with or without chemotherapy. Treatment for those who are unresectable is palliative. Our goal was to examine first-line therapies as well as the role of genomic profiling in an effort better understand how to approach ATC. Methods: This is a retrospective study of ATC patients who were seen at our institution from January 2013 to October 2015. Median overall survival (OS) and time to treatment failure (TTF) were calculated by the Kaplan-Meier method. Results: Fifty-four patients were included. Median age at diagnosis was 63 years and 29/54 (54%) were women. The majority had stage IVC disease at diagnosis (50%), followed by IVB (32%), and IVA (18%). Approximately 93% had somatic gene testing. Initial treatment was surgery in 23 patients, EBRT with or without radiosensitizing chemotherapy in 29 patients, and systemic chemotherapy in 2 patients. Nineteen patients had all three treatment modalities. For the entire cohort, median OS was 11.9 months with 39% survival at 1 year and median TTF was 3.8 months. The majority of patients (74%) developed new distant metastasis or progression of existing metastatic disease. Patients who received trimodal therapy consisting of surgery, EBRT, and chemotherapy had a median OS of 22.1 months versus 6.5 months in those who received dual therapy with EBRT and chemotherapy ( p = 0.0008). The TTF was the same in the two groups (7.0 and 6.5 months, respectively). Men were three times more likely to die from ATC than women ( p = 0.0024). No differences in OS or TTF were noted based on tumor size (5 cm cutoff), age (60 years cutoff), or presence of any mutation. There was a trend toward shorter TTF in patients with somatic mutations in TP53. Conclusion: Patients with ATC amenable to aggressive tri-modal therapy demonstrate improved survival. The short TTF, due primarily to distant metastatic disease, highlights the potential opportunity for improved outcomes with earlier initiation of systemic therapy including adjuvant or neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma is one of the most aggressive and deadly cancers in humans and accounts for one to two cases per million persons annually. The rarity of this malignancy and the rapidity by which it grows has been a major barrier to progress in finding effective therapies. Thus, the treatment that is the current standard of care for these patients is largely palliative, and few are cured; however, novel therapies and approaches are being studied in patients with anaplastic thyroid carcinoma and are delineated herein. [ABSTRACT FROM AUTHOR]

• Half of patients with unresected ATC treated with definitive dose IMRT had LRC. • Classic radio-resistant and rapid Type A failures predominated. • Isolated extraneous dose failures were rare, supporting the volume delineation strategies described. • Novel strategies to improve LRC are needed for this patient population. The aim of this study is to characterize the patterns of loco-regional progression (LRP) and outcomes after definitive-dose intensity modulated radiation therapy (IMRT) for anaplastic thyroid cancer (ATC) with macroscopic neck disease at the time of IMRT. Disease/treatment characteristics and outcomes for patients with unresected or incompletely resected ATC who received IMRT (≥45 Gy) were retrospectively reviewed. For those with LRP after IMRT, progressive/recurrent gross tumor volumes (rGTV) were contoured on diagnostic CTs and co-registered with initial planning CTs using deformable image registration. rGTVs were classified based on established spatial/dosimetric criteria. Forty patients treated between 2010–2020 formed the cohort. Median IMRT dose was 66 Gy (45–70 Gy); altered fractionation (AF) was used in 24 (60 %). All received concurrent chemotherapy. In addition to areas of gross disease, target volumes (TVs) commonly included: central compartment/upper mediastinum (levels VI/VII), neck levels II-V in an involved, and levels III-IV in an uninvolved lateral neck. Median overall survival was 7.1 m. Median progression free survival was 7.4 m for patients with locoregional disease and 1.8 m for patients with distant metastasis at the time of IMRT. Twenty-one patients (53 %) developed LRP at median of 10.9 m; freedom from LRP at 3 m and 12 m was 71 % (95 %CI 58–87 %) and 47 % (95 %CI 32–68 %). Forty-one individual rGTVs were identified and most occurred within the high dose (HD) TVs: Type A/central HD (n = 29, 71 %) and B/peripheral HD (n = 3, 7 %). Despite an intensive treatment schedule, including AF and concurrent chemotherapy, classic radio-resistant and rapid Type A failures predominated; isolated extraneous dose failures were rare. While these findings support the IMRT and TV delineation strategies described herein, they highlight the importance of identifying novel strategies to further improve LRC for patients with unresectable disease without targetable mutations for contemporary neo-adjuvant strategies. [ABSTRACT FROM AUTHOR]