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In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico-epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPVmi ). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic-HPVsero model incorporating a composite of 20 HPV serological antibodies (HPVsero ) and 4 clinical factors (c-index: 0.96) performed better than using HPVsero (c-index: 0.92) or HPVmi (c-index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic-s1-16E6; c-index: 0.95). When defining HPV status by HPVsero , s1-16E6, HPVmi or through p16 IHC, each of these definitions demonstrated improved overall and disease-free survival in HPV-positive OPSCC patients, when compared to HPV-negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1-16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.
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Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/imunologia , Neoplasias Orofaríngeas/sangue , Neoplasias Orofaríngeas/mortalidade , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/virologia , Proteínas Repressoras/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Taxa de SobrevidaRESUMO
CONTEXT: Pediatric papillary thyroid carcinoma (PTC) is usually treated with total thyroidectomy followed by radioactive iodine (RAI). Recently, RAI is being used more selectively based on surgical pathology and postoperative dynamic risk stratification (DRS). OBJECTIVE: To describe patients with pediatric PTC not initially treated with RAI and their disease outcomes. METHODS: This was an ambispective study at a tertiary cancer center of patients < 19 years diagnosed from 1/1/1990 to 12/31/2021 with stage I PTC who intentionally were not treated with RAI within a year of diagnosis. We assessed clinical characteristics, management, and disease outcomes using DRS. RESULTS: Of 490 PTC patients, we identified 93 eligible patients (median age at diagnosis 16y; 87% female), including 46 (49%) with cervical lymph node metastases. Initial management included: total thyroidectomy ± neck dissection (n=69, 75%), lobectomy ± neck dissection (n=20, 21%), or a Sistrunk procedure for ectopic PTC (n=4, 4%). After a median follow-up of 5.5 years (range 1-26), most patients (85/93; 91%) remained disease-free with no further therapy. Persistent (n=5) or recurrent (n=3) disease was found in 9% of the entire cohort. Four patients ultimately received RAI, of which only one clearly benefited, and additional surgery was performed or planned in four patients, two of whom had an excellent response at last follow-up. CONCLUSIONS: Selected pediatric PTC patients, even those with lymph node metastases, may not require therapeutic 131I and can avoid the unnecessary risks of RAI while still benefitting from the excellent long-term outcomes that are well-described for this disease.
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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.
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Imidazóis , Piridonas , Pirimidinonas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica , Oximas , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , MutaçãoRESUMO
BACKGROUND: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in PTC. The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. METHODS: Two independent cohorts of PTC patients were used: 1) the Cancer Genome Atlas (TCGA) thyroid cancer study (N=372), 2) MD Anderson Cancer Center (MDACC) cohort (N=111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. RESULTS: In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (aHR 0.67, 95%CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E-mutated tumors across cohorts after adjusting for overall stage (TCGA: aHR 0.60, 95% CI: 0.33-1.07; MDACC: aHR 0.59, 95% CI: 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR=0.78, 95% CI:0.63-0.96), where the median duration of follow-up was 12.9 years. CONCLUSION: TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E-mutated tumors.
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BACKGROUND: Use of postoperative radiation therapy (PORT) in locoregionally advanced medullary thyroid cancer (MTC) remains controversial. The objective was to evaluate the effect of PORT on locoregional control (LRC) and overall survival (OS). METHODS: Retrospective cohort study of 346 MTC patients separated into PORT and no-PORT cohorts. Relative indications for PORT, as well as changes in patterns of treatment, were recorded. RESULTS: 49/346 (14%) received PORT. PORT was associated with worse OS; adjusted HR = 2.0 (95%CI 1.3-3.3). PORT was not associated with improved LRC, even when adjusting for advanced stage (Stage III p = 0.892; Stage IV p = 0.101). PORT and targeted therapy were not associated with improved OS compared to targeted therapy alone; adjusted HR = 1.2 (95%CI 0.3-4.1). CONCLUSIONS: Use of PORT in MTC has decreased and its indications have become more selective, coinciding with the advent of effective targeted therapies. Overall, PORT was not associated with improved LRC or OS.
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Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Carcinoma Neuroendócrino/radioterapia , Carcinoma Neuroendócrino/cirurgia , Estadiamento de Neoplasias , Radioterapia AdjuvanteRESUMO
Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.
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Intra-tumor heterogeneity is an important driver of tumor evolution and therapy response. Advances in precision cancer treatment will require understanding of mutation clonality and subclonal architecture. Currently the slow computational speed of subclonal reconstruction hinders large cohort studies. To overcome this bottleneck, we developed Clonal structure identification through Pairwise Penalization, or CliPP, which clusters subclonal mutations using a regularized likelihood model. CliPP reliably processed whole-genome and whole-exome sequencing data from over 12,000 tumor samples within 24 hours, thus enabling large-scale downstream association analyses between subclonal structures and clinical outcomes. Through a pan-cancer investigation of 7,827 tumors from 32 cancer types, we found that high subclonal mutational load (sML), a measure of latency time in tumor evolution, was significantly associated with better patient outcomes in 16 cancer types with low to moderate tumor mutation burden (TMB). In a cohort of prostate cancer patients participating in an immunotherapy clinical trial, high sML was indicative of favorable response to immune checkpoint blockade. This comprehensive study using CliPP underscores sML as a key feature of cancer. sML may be essential for linking mutation dynamics with immunotherapy response in the large population of non-high TMB cancers.
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The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) have been correlated with BRM loss and elevated cancer risk. The aim(s) of this study were to examine BRM expression in head and neck squamous cell carcinoma (HNSCC) and to correlate BRM polymorphisms with HNSCC risk. BRM expression studies were performed on eight HNSCC cell lines and 76 surgically resected tumor samples. A case-control study was conducted on 668 HNSCC patients (oral cavity, oropharynx, larynx and hypopharynx) and 700 healthy matched controls. BRM expression was lost in 25% of cell lines and 16% of tumors. The homozygous genotype of each polymorphism was significantly associated with increased HNSCC risk [BRM-741: adjusted odds ratio (aOR) 1.75, 95% CI 1.2-2.3, P < 0.001; BRM-1321: aOR 1.65, 95% CI 1.2-2.2, P < 0.001]. Individuals that were homozygous for both BRM polymorphisms had a more than 2-fold increase in the risk of HNSCC (aOR 2.23, 95% CI 1.5-3.4, P < 0.001). A particularly elevated risk was seen within the oropharynx, human papillomavirus-positive subgroup for carriers of both homozygous variants (aOR 3.09, 95% CI 1.5-6.8, P = 0.004). BRM promoter polymorphisms appear to act as susceptibility markers of HNSCC with potential utility in screening, prevention and treatment.
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Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Polimorfismo Genético , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
CONTEXT: Genome-wide association studies have identified germline variants associated with elevated PTC risk. It is also known that somatic driver mutations contribute to PTC development and as such PTCs can be further categorized into different molecular subtypes based on their somatic alterations. However, it remains unknown whether identified germline variants predictive of PTC risk are associated with specific molecular subtypes. OBJECTIVE: The primary goal of the present study is to determine whether germline genetic risk, as assessed using a polygenic score (PGS) is associated with molecular subtypes of papillary thyroid carcinoma (PTC), defined based on tumor driver mutation status. METHODS: This study was carried out using data from The Cancer Genome Atlas (TCGA) thyroid cancer study. A previously validated 10-single-nucleotide variation PGS for PTC derived from genome-wide association study hits was calculated to ascertain germline genetic risk. The primary molecular subtypes of interest were defined by tumor driver mutation status (BRAFV600E-mutated vs RAS-mutated vs "other"). We also explored associations between PGS and molecular subtypes defined by messenger RNA (mRNA) expression, microRNA expression, and DNA methylation patterns. Polytomous logistic regression analysis was used to assess the association between PGS and PTC molecular subtype with and without adjustment for clinical variables. Odds ratios (ORs) with their 95% CIs were estimated. RESULTS: A total of 359 patients were included in the study. PGS was significantly associated specific tumor molecular subtypes defined by tumor driver mutation status. Increasing germline risk was associated with having a higher odd of BRAFV600E-mutated PTC compared to PTCs without driver mutations in the "other" category. No significant difference was detected in terms of PGS tumor categorization in the RAS subtype compared to BRAFV600E. In exploratory analyses, PGS was also associated with mRNA-, microRNA-, and DNA methylation-defined molecular subtypes, as defined by the TCGA PTC study. CONCLUSION: PGS has molecular subtype-specific associations in PTC, which has implications for their use in risk prediction.
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Carcinoma Papilar , MicroRNAs , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Estudo de Associação Genômica Ampla , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , MicroRNAs/genética , RNA Mensageiro/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
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.
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Antineoplásicos , Neoplasias da Glândula Tireoide , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Radioisótopos do Iodo/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.
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Neoplasias , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Heterogeneidade Genética , Genômica , RNA Mensageiro/genética , Progressão da DoençaRESUMO
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.
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Ácidos Nucleicos Livres/genética , Mutação/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Feminino , Proteínas Ativadoras de GTPase/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Proteína Supressora de Tumor p53/genéticaRESUMO
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.
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Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fenótipo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Idoso , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
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Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Coleta de Dados , Progressão da Doença , Genes ras , Humanos , Imunoterapia , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Mutação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Inibidores de Proteínas Quinases/uso terapêutico , Câncer Papilífero da Tireoide/mortalidade , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/mortalidade , Resultado do TratamentoRESUMO
Importance: Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated. Objective: To evaluate rates of OS in patients with ATC over the last 2 decades. Design, Setting, and Participants: Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019. Main Outcomes and Measures: Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery. Results: Of 479 patients (246 men [51%]; median age, 65.0 [range, 21.1-92.6] years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (P < .001). The hazard ratio was 0.50 (95% CI, 0.38-0.67) for the 2017-2019 group compared with the 2000-2013 patients (P < .001). Factors associated with improved OS included targeted therapy (hazard ratio, 0.49; 95% CI, 0.39-0.63; P < .001), the addition of immunotherapy to targeted therapy (hazard ratio, 0.58; 95% CI, 0.36-0.94; P = .03), and surgery following neoadjuvant BRAF-directed therapy (hazard ratio, 0.29; 95% CI, 0.10-0.78; P = .02). Patients undergoing surgery following neoadjuvant BRAF-directed therapy (n = 20) had a 94% 1-year survival with a median follow-up of 1.21 years. Conclusion and Relevance: In this large single-institution cohort study spanning nearly 20 years, changes in patient management appear to be associated with significant increase in survival. The era of untreatable ATC is progressively being replaced by molecular-based personalized therapies, with integration of multidisciplinary therapies including surgery and radiation therapy.
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Antineoplásicos/uso terapêutico , Terapia Neoadjuvante/efeitos adversos , Carcinoma Anaplásico da Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto JovemRESUMO
BACKGROUND: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. METHODS: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. RESULTS: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. CONCLUSIONS: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19.
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Betacoronavirus , Infecções por Coronavirus/epidemiologia , Doenças do Sistema Endócrino/cirurgia , Seleção de Pacientes , Pneumonia Viral/epidemiologia , Triagem , Algoritmos , COVID-19 , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Doenças do Sistema Endócrino/patologia , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Guias de Prática Clínica como Assunto , SARS-CoV-2RESUMO
BACKGROUND: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel. METHODS: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular. RECOMMENDATIONS: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred. CONCLUSION: These guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.
Assuntos
Infecções por Coronavirus/epidemiologia , Neoplasias de Cabeça e Pescoço/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Pandemias/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Guias de Prática Clínica como Assunto/normas , Oncologia Cirúrgica/normas , Betacoronavirus , COVID-19 , Institutos de Câncer , Controle de Doenças Transmissíveis/normas , Consenso , Infecções por Coronavirus/prevenção & controle , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Humanos , Masculino , Saúde Ocupacional , Pandemias/prevenção & controle , Segurança do Paciente , Seleção de Pacientes , Pneumonia Viral/prevenção & controle , SARS-CoV-2 , Triagem/normas , Estados UnidosRESUMO
BACKGROUND: Head and neck cancer (HNC) and its treatment lead to functional impairments. Rehabilitation by speech-language pathology (SLP) and occupational/physical therapy (OT/PT) can decrease morbidity. METHODS: The Surveillance, Epidemiology and End Results-Medicare data for patients with HNC diagnosed between 2002 and 2011 was utilized to evaluate posttreatment rehabilitation. RESULTS: In 16 194 patients, the overall utilization rate was 20.7% for SLP and 26.2% for OT/PT services. Treatment modality was significantly associated rehabilitation utilization. Compared to patients treated with primary surgery, those treated with primary radiotherapy had significantly lower odds of OT/PT utilization. Patients treated with surgery plus adjuvant treatment and primary concurrent chemoradiation had higher odds of SLP utilization compared to patients treated with surgery alone. CONCLUSIONS: Rehabilitation services appeared to be underutilized by patients with HNC in the United States and vary with treatment modality. There is a need to improve integration of rehabilitation services into the HNC care continuum. SUMMARY: Rehabilitation services are underutilized by patients with HNC during posttreatment surveillance in the United States. Treatment modality significantly impacts rehabilitation utilization patterns.
Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Acessibilidade aos Serviços de Saúde , Terapia da Linguagem , Aceitação pelo Paciente de Cuidados de Saúde , Modalidades de Fisioterapia , Fonoterapia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Programa de SEER , Estados UnidosRESUMO
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.