Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology

Steward, David L.; Carty, Sally E.; Sippel, Rebecca S.; Yang, Samantha Peiling; Sosa, Julie Ann; Sipos, Jennifer A.; Figge, James; Mandel, Susan J.; Haugen, Bryan R.; Burman, Kenneth D.; Baloch, Zubair W.; Lloyd, Ricardo V.; Seethala, Raja R.; Gooding, William E.; Chiosea, Simion I.; Gomes-Lima, Cristiane; Ferris, Robert L.; Folek, Jessica M.; Khawaja, Raheela; Kundra, Priya; Loh, Kwok Seng; Marshall, Carrie B.; Mayson, Sarah E.; McCoy, Kelly L.; Nga, Min En; Ngiam, Kee Yuan; Nikiforova, Marina N.; Poehls, Jennifer L.; Ringel, Matthew D.; Yang, Huijie; Yip, Linwah

doi:10.1001/jamaoncol.2018.4616

Cited by 348 publications

(427 citation statements)

References 48 publications

(122 reference statements)

Supporting

Mentioning

371

Contrasting

Unclassified

Order By: Relevance

“…It demonstrated that the NPV of the ThyroSeq GC is expected to remain at ≥95% in populations with a disease prevalence of up to 40% for thyroid nodules classified as AUS/FLUS and up to 60% for nodules classified as SFN/FN. 20 This is well within the range of cancer/NIFTP prevalence expected in these TBSRTC diagnostic categories. 7,9,24 Therefore, a ThyroSeq V3 GC-negative result may prevent diagnostic surgery for patients with thyroid nodules diagnosed as either AUS/FLUS or SFN/FN in most clinical settings.…”

Section: Clinical Validation Of the Thyroseq V3 Gcsupporting

confidence: 73%

“…The ThyroSeq V3 GC demonstrated a fairly high PPV of 66% in thyroid FNA specimens diagnosed as AUS/FLUS and SFN/FN. As shown in Table 2, 20 the test correctly identified all Hurthle cell (oncocytic) carcinomas and NIFTP nodules as positive. There were 34 test-positive samples diagnosed by pathology as benign after surgery.…”

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 85%

“…The final study cohort included 154 thyroid nodules and 93 thyroid nodules diagnosed as AUS/FLUS and SFN/FN, respectively. As shown in Table 1 20 All of the missed cancers were intrathyroidal, low-risk, and low-stage tumors with no vascular invasion, extrathyroidal extension, or other aggressive features.…”

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

“…A prospective, double-blinded, multicenter study recently published by Steward et al reported the results of clinical validation of the ThyroSeq v3 GC in thyroid nodules with indeterminate FNA cytology. 20 This study initially recruited 782 patients with 1013 thyroid nodules at 9 institutions in the United States and 1 institution in Singapore. Samples were collected by either rinsing the residual material in the aspiration needle from all passes or by placing a dedicated pass into the collection tube containing nucleic acid preservative solution.…”

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

“…The results of the study demonstrated that among 105 test-positive samples, the probability of a histological diagnosis of cancer/ NIFTP varied by 57% to 100% based on a specific group of genetic alterations (Table 3). 20 The high-risk (TERT and TP53) and BRAF V600E -like mutations conferred a cancer probability of 100%. Furthermore, the BRAF V600E -like mutations were found to be strongly predictive of classic papillary carcinoma in these nodules.…”

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

See 4 more Smart Citations

Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology

Nikiforov

Baloch

2019

Cancer Cytopathology

Self Cite

View full text Add to dashboard Cite

Molecular testing of thyroid fine‐needle aspiration specimens has been developed with the primary goals of resolving the uncertainty of indeterminate cytology and avoiding the diagnostic surgeries generally recommended for these patients. A recent prospective, double‐blinded, multicenter study reported the results of the clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate fine‐needle aspiration cytology.

show abstract

Section: Clinical Validation Of the Thyroseq V3 Gcsupporting

confidence: 73%

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 85%

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

Section: Clinical Validation Of the Thyroseq V3 Gcmentioning

confidence: 99%

See 3 more Smart Citations

Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology

Nikiforov

Baloch

2019

Cancer Cytopathology

Self Cite

View full text Add to dashboard Cite

show abstract

Development of a Molecular Assay for Detection and Quantification of theBRAFVariation in Residual Tissue From Thyroid Nodule Fine-Needle Aspiration Biopsy Specimens

Chazen

MacMillan

et al. 2021

JAMA Netw Open

View full text Add to dashboard Cite

IMPORTANCE Thyroid cancer, predominantly papillary thyroid carcinoma (PTC), is common, but an estimated 30% of ultrasonography-guided fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate. BRAF variation, associated with poor clinicopathological characteristics, is a useful molecular marker for diagnostics. OBJECTIVETo develop a sensitive molecular assay for BRAF V600E detection in remaining tissue of thyroid FNA biopsies to identify patients with cancer carrying a BRAF variation. DESIGN, SETTING, AND PARTICIPANTSThis diagnostic study used tumor tissue from surgical formalin-fixed, paraffin-embedded (FFPE) specimens and residual tissue from thyroid FNA biopsies for genomic DNA extraction. FFPE specimens served as the validation set, and residual tissue from FNA biopsies served as the test set. A molecular assay was developed for accurate detection of BRAF V600E variation using locked nucleic acid (LNA) probe-based droplet digital polymerase chain reaction (dPCR), and the assay was validated by BRAF V600E immunohistochemical staining (IHC). The study was conducted between February 2019 and May 2021. RESULTS A total of 271 specimens, including 77 FFPE specimens (with a follow-up of 48 matched surgical specimens) and 146 residual FNA samples, were collected from 223 patients (mean [SD] age, 53.8 [15.3] years; 174 [78.0%] women; 49 [22.0%] men). The molecular assay by dPCR was first established to specifically and accurately detect and quantify wild-type BRAF and variant BRAF in DNA from human follicular thyroid carcinoma-derived FTC-133 and papillary thyroid carcinomaderived BCPAP cells. The linearity of quantification of BRAF V600E was calculated (y = 0.7339x;R 2 = 0.9996) with sensitivity at 0.02 copies/μL and reproducibility in detecting variant DNA at various dilutions(coefficient of variance in 0.3% DNA, 9.63%; coefficient of variance in 1.0% DNA, 7.41%). In validation testing, the dPCR assay and IHC staining exhibited 100% specificity in concordantly identifying BRAF V600E in PTCs (κ = 0.873; P < .001) and sensitivity of 32.0% (95% CI, 19.1% to 44.9%) in dPCR and 26.0% (95% CI, 13.1% to 38.9%) in IHC staining, with an improvement by 23.08% in dPCR compared with the IHC staining. The dPCR assay further detected BRAF V600E in 39 of 146 residual FNA specimens (26.7%). At short-term follow-up, 48 patients, including 14 of 39 patients with BRAF variation and 34 of 107 patients without BRAF variation on residual FNA specimens, underwent resection. The dPCR assay of BRAF status in the matched surgical specimens showed BRAF V600E variations in 12 patients and wild-type BRAF in 36 patients, with a high agreement to that in residual tissue of FNA specimens (κ = 0.789; P < .001). Among 14 patients with BRAF variations on residual FNA, 13 were diagnosed with PTC and 1 was diagnosed with anaplastic thyroid cancer at the thyroidectomy.

show abstract

Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules

Fu,

Chazen,

Monteiro

et al. 2023

JAMA Netw Open

View full text Add to dashboard Cite

ImportanceMolecular testing of the presence of pathogenic genomic variants in a tumor without quantifying the variant allele fraction (VAF) does not differentiate the variation extent among tumors, often resulting in an inconclusive diagnosis because of interpatient variability.ObjectiveTo examine the association between the quantification of VAFs of BRAF V600E and TERT promoter variants and a definitive cancer diagnosis of thyroid tumors.Design, Setting, and ParticipantsThis diagnostic study analyzed a cohort of 378 surgically resected thyroid tumors with a maximum dimension of 1 cm or larger between March 15, 2016, and March 16, 2020, and a separate cohort of 217 residual thyroid fine-needle aspiration (FNA) biopsy specimens obtained from January 22, 2020, to March 2, 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data analysis was conducted between February 1, 2021, and February 1, 2023.ExposuresQuantitative VAF assays of BRAF V600E and TERT promoter variants (C228T and C250T) were performed by digital polymerase chain reaction molecular assays.Main Outcomes and MeasuresThe VAFs of BRAF V600E and TERT promoter variants were correlated with tumor histologic diagnoses and histopathologic features to delineate the association of VAF assays with tumor malignancy. The receiver operating characteristic curve analysis, sensitivity, specificity, positive predictive value, negative predictive value, and logistic regression analysis based on follow-up histopathologic types were used to determine the diagnostic utility of the quantitative molecular assays.ResultsA total of 595 specimens, including 378 surgically resected thyroid tumors and 217 thyroid nodule FNA biopsy specimens, were collected from 580 patients (436 [75.2%] female with a mean [SD] age of 50 [16] years and 144 [24.8%] male with a mean [SD] age of 55 [14] years). Sensitive VAF assays of 378 thyroid tumors revealed the presence of the BRAF V600E variant in 162 tumors (42.9%), with 26 (16.0%) at a low VAF of 1% or less and 136 (84.0%) at a high VAF of greater than 1%, and the presence of TERT promoter variants in 49 tumors (13.0%), including 45 C228T variants (91.8%), 15 (33.3%) of which were quantified as having a low VAF (≤1%) and 30 (66.7%) as having a high VAF (&gt;1%), and 4 C250T variants (8.2%) with VAFs between 40.0% and 47.0%. All tumors detected with BRAF V600E and/or TERT promoter variants, whether at low or high VAFs, received a definitive cancer diagnosis. Further analysis delineated a significant association between high VAFs of either variant individually or different VAF levels for both variants in coexistence and aggressive histopathologic features of tumors. Excluding low VAFs assisted in identifying patients at an intermediate-to-high risk of recurrence (odds ratio, 5.3; 95% CI, 1.9-14.6; P = .001). The VAF assays on the residual FNA biopsy specimens showed a high agreement to those on surgical tissues (κ = 0.793, P &lt; .001) and stratified malignancy in 40 of 183 indeterminate FNA cases (21.9%), with a sensitivity of 93.8% (95% CI, 67.7%-99.7%), specificity of 90.0% (95% CI, 75.4%-96.7%), positive predictive value of 78.9% (95% CI, 53.9%-93.0%), and negative predictive value of 97.3% (95% CI, 84.2%-99.9%).Conclusions and RelevanceThis diagnostic study suggests that sensitive quantitative VAF assays of BRAF V600E and TERT promoter variants can elucidate the interpatient variability in tumors and facilitate a definitive cancer diagnosis of thyroid nodules by differentiating the variation extent of genomic variants, even at low VAFs.

show abstract

Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology

Cited by 348 publications

References 48 publications

Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology

Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology

Development of a Molecular Assay for Detection and Quantification of theBRAFVariation in Residual Tissue From Thyroid Nodule Fine-Needle Aspiration Biopsy Specimens

Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules

Contact Info

Product

Resources

About