Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAFV600E Mutant Anaplastic Thyroid Cancer: A Single-Center Retrospective Cohort Study.

Background: The aim of this study was to describe the oncologic outcomes of patients with BRAFV600E-mutated anaplastic thyroid cancer (ATC) who had neoadjuvant BRAF-directed therapy with subsequent surgery. For context, we also reviewed patients who received BRAF-directed therapy after surgery, and those who did not have surgery after BRAF-directed therapy. Methods: This was a single-center retrospective cohort study conducted at a tertiary care cancer center in Texas from 2017 to 2021. Fifty-seven consecutive patients with BRAFV600E-mutated ATC and at least 1 month of BRAF-directed therapy were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Results: All patients had stage IVB (35%) or IVC (65%) ATC. Approximately 70% of patients treated with BRAF-directed therapy ultimately had surgical resection of residual disease. Patients who had neoadjuvant BRAF-directed therapy followed by surgery (n = 32) had 12-month OS of 93.6% [confidence interval (CI) 84.9-100] and PFS of 84.4% [CI 71.8-96.7]. Patients who had surgery before BRAF-directed therapy (n = 12) had 12-month OS of 74.1% [CI 48.7-99.5] and PFS of 50% [CI 21.7-78.3]. Finally, patients who did not receive surgery after BRAF-directed therapy (n = 13) had 12-month OS of 38.5% [CI 12.1-64.9] and PFS of 15.4% [CI 0-35.0]. Neoadjuvant BRAF-directed therapy reduced tumor size, extent of surgery, and surgical morbidity score. Subgroup analysis suggested that any residual ATC in the surgical specimen was associated with significantly worse 12-month OS and PFS (OS = 83.3% [CI 62.6-100], PFS = 61.5% [CI 35.1-88]) compared with patients with pathologic ATC complete response (OS = 100%, PFS = 100%). Conclusions: We observed that neoadjuvant BRAF-directed therapy reduced extent of surgery and surgical morbidity. While acknowledging potential selection bias, the 12-month OS rate appeared higher in patients who had BRAF-directed therapy followed by surgery as compared with BRAF-directed therapy without surgery; yet, it was not significantly different from surgery followed by BRAF-directed therapy. PFS appeared higher in patients treated with neoadjuvant BRAF-directed therapy relative to patients in the other groups. These promising results of neoadjuvant BRAF-directed therapy followed by surgery for BRAF-mutated ATC should be confirmed in prospective clinical trials.

Prior Thyroid and Nonthyroid Cancer History Do Not Significantly Alter Overall Survival in Patients Diagnosed with Anaplastic Thyroid Cancer.

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.

Clinical outcomes of combined cervical and transthoracic surgical approaches in patients with advanced thyroid cancer.

BACKGROUND: Advanced thyroid disease involving the mediastinum may be managed surgically with a combined transcervical and transthoracic approach. Contemporary analysis of this infrequently encountered cohort will aid the multidisciplinary team in personalizing treatment approaches. METHODS: Retrospective review of patients undergoing combined transcervical and transthoracic surgery for thyroid cancer at a single high-volume institution from 1994 to 2015. RESULTS: Thirty-eight patients with median age 59 years (range 28-76) underwent surgery without perioperative mortality. Most patients had primary disease. A majority had distant metastases outside the mediastinum but had locoregionally curable disease. Common complications were temporary (39%) and permanent (18%) hypoparathyroidism, and wound infection (13%). One-year overall survival was 84%; 1-year locoregional disease-free survival was 64%. Median time to locoregional recurrence was 36 months. Only esophageal invasion was associated with worse oncologic outcomes. CONCLUSIONS: Combined transcervical and transthoracic surgery for advanced thyroid cancer can be performed without mortality and with acceptable morbidity.

Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma.

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 BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E 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 BRAFV600E. 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 BRAFV600E-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.

Imaging of Cervical Lymph Nodes in Thyroid Cancer: Ultrasound and Computed Tomography.

Sonographic evaluation of cervical lymph nodes in patients with thyroid malignancy is important both for preoperative staging and for post-treatment surveillance, and contrast-enhanced computed tomography plays a complementary role. Knowledge of anatomy and surgical approaches, combined with an understanding of the various imaging features that distinguish malignant from benign lymph nodes, allows for accurate staging, thereby enabling complete surgical initial resection.

Management of Anaplastic and Recurrent Differentiated Thyroid Cancer: Indications for Surgical Resection, Molecular Testing, and Systemic Therapy.

Differentiated and anaplastic thyroid cancer are tumors derived from follicular thyroid cancers and are clinically and genetically distinct. Treatment of these tumors has evolved over the past decade, with 6 drugs/drug combinations that are US Food and Drug Administration approved.

Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes.

Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors.

TGFß1 Genetic Variants Predict Clinical Outcomes of HPV-Positive Oropharyngeal Cancer Patients after Definitive Radiotherapy.

Purpose: TGFß1 plays a critical role in inflammation and immune responses and treatment response and survival. TGFß1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP).Experimental Design: We determined tumor HPV16 status and genotyped three TGFß1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival.Results: Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGFß1 rs1982073 had statistically significant associations with survival, whereas TGFß1 rs1800469 and TGFß1 rs1800471 did not. Patients with TGFß1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P < 0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGFß1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized.Conclusions: Our findings support that the TGFß1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings. Clin Cancer Res; 24(9); 2225-33. ©2018 AACR.