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Multicenter Study
. 2019 Feb 1;5(2):204-212.
doi: 10.1001/jamaoncol.2018.4616.

Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study

David L Steward  1 , Sally E Carty  2 , Rebecca S Sippel  3 , Samantha Peiling Yang  4 , Julie A Sosa  5   6 , Jennifer A Sipos  7 , James J Figge  8 , Susan Mandel  9 , Bryan R Haugen  10 , Kenneth D Burman  11 , Zubair W Baloch  12 , Ricardo V Lloyd  13 , Raja R Seethala  14 , William E Gooding  15 , Simion I Chiosea  11 , Cristiane Gomes-Lima  11 , Robert L Ferris  16 , Jessica M Folek  8 , Raheela A Khawaja  7 , Priya Kundra  11 , Kwok Seng Loh  17 , Carrie B Marshall  18 , Sarah Mayson  10 , Kelly L McCoy  2 , Min En Nga  19 , Kee Yuan Ngiam  20 , Marina N Nikiforova  14 , Jennifer L Poehls  21 , Matthew D Ringel  7 , Huaitao Yang  22 , Linwah Yip  2 , Yuri E Nikiforov  14
Affiliations
Multicenter Study

Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study

David L Steward et al. JAMA Oncol. .

Erratum in

  • Typographical Errors in Table 2 and Text.
    [No authors listed] [No authors listed] JAMA Oncol. 2019 Feb 1;5(2):271. doi: 10.1001/jamaoncol.2018.6413. JAMA Oncol. 2019. PMID: 30543346 Free PMC article. No abstract available.

Abstract

Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery.

Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules.

Design, setting, and participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules.

Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3).

Main outcomes and measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules.

Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%.

Conclusions and relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Burman received Institutional Grants for Clinical Trials from AstraZeneca, Eisai, IBSA, Bayer, and Loxo. Drs Carty, Ferris, McCoy, Seethala, and Yip are employees of University of Pittsburgh Physicians, which is an affiliate of University of Pittsburgh Medical Center (UPMC). The University of Pittsburgh Medical Center has granted CBLPath Inc. a license to market ThyroSeq for commercial use. They receive no compensation, directly or indirectly, related to CBLPath Inc. Dr Chiosea receives compensation from his employer (UPMC) in connection with ThyroSeq analyses. Dr Mayson previously received research support from Rosetta Genomics. Dr Nikiforov and Dr Nikiforova have intellectual property rights related to ThyroSeq. They will receive royalties associated with commercial use of ThyroSeq. Dr Sipos received an honorarium for speaking for Veracyte and Genzyme. Dr Sosa is a member of the Data Monitoring Committee of the Medullary Thyroid Cancer Registry supported by GlaxoSmithKline, Novo Nordisk, Astra Zeneca, and Eli Lilly. Dr Steward received research funding from Rosetta, Veracyte, and GeneproDX. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment and Exclusion of Patients and Samples in the Study
FNA indicates fine-needle aspiration; TNA, total nucleic acids; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features.
Figure 2.
Figure 2.. Predicted Performance of Genomic Classifier (GC) Test in Populations With Different Cancer/NIFTP Prevalence
Predicted negative predictive value (NPV) (solid blue lines) and positive predictive value (PPV) (solid orange lines) with 95% CIs (dotted lines) based on sensitivity and specificity of the multigene GC test established in this study for Bethesda III and IV cytology thyroid nodules. NIFTP indicates noninvasive follicular thyroid neoplasm with papillary-like nuclear features.
See this image and copyright information in PMC

Comment in

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