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      Detection of BRAFV600E in Liquid Biopsy from Patients with Papillary Thyroid Cancer Is Associated with Tumor Aggressiveness and Response to Therapy

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          Abstract

          The detection of rare mutational targets in plasma (liquid biopsy) has emerged as a promising tool for the assessment of patients with cancer. We determined the presence of cell-free DNA containing the BRAFV600E mutations (cf BRAFV600E) in plasma samples from 57 patients with papillary thyroid cancer (PTC) with somatic BRAFV600E mutation-positive primary tumors using microfluidic digital PCR, and co-amplification at lower denaturation temperature (COLD) PCR. Mutant cf BRAFV600E alleles were detected in 24/57 (42.1%) of the examined patients. The presence of cf BRAFV600E was significantly associated with tumor size ( p = 0.03), multifocal patterns of growth ( p = 0.03), the presence of extrathyroidal gross extension ( p = 0.02) and the presence of pulmonary micrometastases ( p = 0.04). In patients with low-, intermediate- and high-risk PTCs, cf BRAFV600E was detected in 4/19 (21.0%), 8/22 (36.3%) and 12/16 (75.0%) of cases, respectively. Patients with detectable cfBRAFV600E were characterized by a 4.68 times higher likelihood of non-excellent response to therapy, as compared to patients without detectable cf BRAFV600E (OR (odds ratios), 4.68; 95% CI (confidence intervals)) 1.26–17.32; p = 0.02). In summary, the combination of digital polymerase chain reaction (dPCR) with COLD-PCR enables the detection of BRAFV600E in the liquid biopsy from patients with PTCs and could prove useful for the identification of patients with PTC at an increased risk for a structurally or biochemically incomplete or indeterminate response to treatment.

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          Most cited references 30

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          BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.

          Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.
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            Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial

            About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer.
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              The potential of liquid biopsies for the early detection of cancer

              Precision medicine refers to the choosing of targeted therapies based on genetic data. Due to the increasing availability of data from large-scale tumor genome sequencing projects, genome-driven oncology may have enormous potential to change the clinical management of patients with cancer. To this end, components of tumors, which are shed into the circulation, i.e., circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or extracellular vesicles, are increasingly being used for monitoring tumor genomes. A growing number of publications have documented that these “liquid biopsies” are informative regarding response to given therapies, are capable of detecting relapse with lead time compared to standard measures, and reveal mechanisms of resistance. However, the majority of published studies relate to advanced tumor stages and the use of liquid biopsies for detection of very early malignant disease stages is less well documented. In early disease stages, strategies for analysis are in principle relatively similar to advanced stages. However, at these early stages, several factors pose particular difficulties and challenges, including the lower frequency and volume of aberrations, potentially confounding phenomena such as clonal expansions of non-tumorous tissues or the accumulation of cancer-associated mutations with age, and the incomplete insight into driver alterations. Here we discuss biology, technical complexities and clinical significance for early cancer detection and their impact on precision oncology.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                02 August 2020
                August 2020
                : 9
                : 8
                Affiliations
                [1 ]Department of Pediatrics, Endocrine Division, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; kirk.jensen@ 123456usuhs.edu (K.J.); aneeta.patel@ 123456usuhs.edu (A.P.); maria.mendonca-torres@ 123456usuhs.edu (M.C.M.-T.); john.costello.ctr@ 123456usuhs.edu (J.C.); dorina.ylli@ 123456umed.edu.al (D.Y.); vasyl.vasko.ctr@ 123456usuhs.edu (V.V.V.)
                [2 ]National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814, USA; shilpa.thakur@ 123456nih.gov (S.T.); cjglima@ 123456gmail.com (C.J.G.-L.); waltermf@ 123456niddk.nih.gov (M.W.)
                [3 ]MedStar Health Research Institute, MedStar Washington Hospital Center, Washington, DC 20010, USA; leonard.wartofsky@ 123456medstar.net (L.W.); Kenneth.D.Burman@ 123456medstar.net (K.D.B.); athanasiosbikas@ 123456gmail.com (A.B.)
                [4 ]Endocrinology Division, University of Medicine, 1005 Tirana, Albania
                Author notes
                [* ]Correspondence: joanna.klubogwiezdzinska@ 123456nih.gov ; Tel.: +301-496-5052
                Article
                jcm-09-02481
                10.3390/jcm9082481
                7464493
                32748840
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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