Liquid Biopsy Can Accelerate the Genotyping of Anaplastic Thyroid Cancers
2021; Mary Ann Liebert, Inc.; Volume: 33; Issue: 6 Linguagem: Inglês
10.1089/ct.2021;33.285-287
ISSN2329-972X
Autores Tópico(s)Thyroid Cancer Diagnosis and Treatment
ResumoClinical ThyroidologyVol. 33, No. 6 Thyroid CancerFree AccessLiquid Biopsy Can Accelerate the Genotyping of Anaplastic Thyroid CancersBrian W. KimBrian W. KimDivision of Endocrinology and Metabolism, Department of Medicine, Rush University Medical Center, Chicago, Illinois, U.S.A.Search for more papers by this authorPublished Online:8 Jun 2021https://doi.org/10.1089/ct.2021;33.285-287AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Qin YU, Wang JR, Wang Y, Iyer PC, Cote G, Busaidy N, Dadu R, Zafereo M, Williams MD, Ferrarotto R, Gunn B, Wei P, Patel K, Hofmann MC, Cabanillas M 2021 Clinical utility of circulating cell-free DNA mutations in anaplastic thyroid carcinoma. Thyroid. Epub 2021 Apr 19. PMID: 33599171.SUMMARYBackgroundThe term liquid biopsy refers to an expanding range of highly sensitive assays capable of detecting tumor-specific products ranging from DNA fragments to whole tumor cells that circulate in the blood. These assays could potentially facilitate the diagnosis and genotyping of certain solid tumors that may not be accessible for needle biopsy, and it is hoped that their relatively noninvasive nature may help actualize real-time monitoring of genetic changes occurring in the tumors as they progress and as they respond to or become resistant to therapy (1).Thyroid cancer studies involving liquid biopsy have focused largely on cell-free DNA (cfDNA), double-stranded DNA fragments thought to be released into the bloodstream via apoptosis or necrosis, with encouraging results for a number of cfDNA assays in patients with medullary (2), papillary (3,4), and anaplastic (5) cancers. Anaplastic thyroid cancer may be a particularly fertile ground for cfDNA studies, presumably due to the tendency of these aggressive cancers to have a relatively high mutational burden and to rapidly progress to advanced stages, a setting in which cfDNA is more likely to be shed. The current study examines the concordance of genotyping results between a commercial cfDNA assay with a tumor-tissue next-generation sequencing assay in 87 subjects with anaplastic thyroid cancer, with the goal of investigating the clinical potential of liquid biopsy in this setting (6).MethodsThe study cohort comprised 87 subjects diagnosed with anaplastic thyroid cancer at the MD Anderson University of Texas Cancer Center between January 2015 and February 2018. These patients underwent cfDNA testing of peripheral blood using the Guardant360 platform (7). This test covers genomic alterations, including 73 somatic point mutations, 18 gene amplifications, and 6 gene fusions. Tumor tissue genotyping was performed using an in-house NGS platform, CM50, which detects point mutations, amplifications, short insertions, and deletions in 50 genes (8). All testing and data collection were performed as part of standard-of-care treatment and under a protocol approved by an institutional review board.ResultsA total of 80 of 87 (92%) of the patients had at least one mutation detected in their cfDNA. No fusions were detected in the cfDNA analyzed. The median number of mutated genes detected per patient was 3 (range, 0–16). The most frequently mutated genes detected in cfDNA were TP53 (60.9%), BRAF V600E (34.4%), PIK3CA (16.1%), EGFR (14.9%), RAS (13.8%), and NF1 (13.8%).In a subset of 28 treatment-naive patients, the concordance of cfDNA results with tissue-sequencing for the most frequent (at least 3 cases of 28) mutations were: TP53 (82.1%), BRAF V600E (92.9%), PIK3CA (92.9%), and NRAS (92.9%). In comparison, concordance for patients who had undergone therapy for their cancers was generally lower: TP53 (59.2%), BRAF V600E (83.7%), and PIK3CA (87.8%). (NRAS was not specified for this group.)The median turnaround time of the cfDNA test was 11 days (range, 5–16), as compared with 21 days (range, 11–63) for tumor tissue sequencing.ConclusionsIn treatment-naive patients with anaplastic thyroid cancer, a liquid biopsy assay of cfDNA demonstrated high concordance for BRAF V600E and several other common driver mutations as compared with tumor tissue next-generation sequencing. For some genes, the concordance was notably lower in patients who had already been treated for their cancer.COMMENTARYThe 2021 American Thyroid Association guidelines for anaplastic thyroid cancer recommend that molecular profiling should be performed at the time of diagnosis (9). The potential for rapid disease progression and the advent of FDA-approved mutation-specific therapies create a mandate for rapid genotyping, at least in the case of BRAF V600E; the text of the 2021 guidelines acknowledges a potential role for cfDNA testing in this setting. The tone of the document, however, is guarded with respect to liquid biopsy: “at the present time, further work is required to create robust and clinical-grade assays that can use tumor DNA shed to patient blood for routine genotyping of ATC” (9).The current study is a step forward toward establishing a role for cfDNA liquid biopsy in the management of anaplastic thyroid cancer. This work is an expansion of a 2017 pilot study that included 37 of these same patients (5), and to date, this is the largest study of its kind in this clinical setting. The key finding of high concordance of the liquid biopsy with tissue biopsy in treatment-naive patients lends credence to the idea that liquid biopsy of cfDNA can be an accurate, rapid, and noninvasive method for quickly establishing the presence or absence of certain mutations. However, liquid biopsy would not be expected to supplant tumor tissue sequencing in the long run, given that many genomic alternations seen in the tumors are not reflected in cfDNA. In considering how liquid biopsy might be operationalized, I imagine that it would be logical to order both immunohistochemistry and liquid biopsy as soon as anaplastic cancer is suspected. Parallel rather than sequential testing would speed the process, and in addition to potentially outracing the traditional method, liquid biopsy could provide some insurance that a negative tissue staining result is not a false negative stemming from tumor histologic heterogeneity.A number of limitations apply to this study and to the liquid biopsy approach. Technical challenges remain, as evidenced by a low concordance for TERT mutations, and the observation that gene fusions were not found in the cfDNA. From the perspective of research limitations, the cohort is too small to allow for examination of low prevalence mutations. While a number of clinical prognostic observations are reported regarding specific cfDNA mutations, the design does not clarify whether mutations seen in cfDNA have different prognostic significance than the same mutations being found in tissue assays.If liquid biopsy is to be used to track the expected changes in the tumoral genetic landscape that occur in the course of disease progression and also in response to therapy, it would be important that concordance with tissue genotyping results remains high. The observation that the cfDNA analysis of previously treated patients had a lower concordance with tissue sequencing results than seen with the treatment-naive patients is quite striking when seen from this perspective. It remains to be seen whether this treatment-associated discordance is a technical challenge to overcome, a biologic phenomenon requiring further study, or perhaps both.REFERENCES1. 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Link, Google ScholarFiguresReferencesRelatedDetails Volume 33Issue 6Jun 2021 InformationCopyright 2021 American Thyroid Association, Inc.To cite this article:Brian W. Kim.Clinical Thyroidology.Jun 2021.285-287.http://doi.org/10.1089/ct.2021;33.285-287Published in Volume: 33 Issue 6: June 8, 2021PDF download
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