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Original Investigation
December 10, 2020

Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules: A Randomized Clinical Trial

Author Affiliations
  • 1Section of Endocrine Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles
  • 3Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 4Division of Endocrinology, Diabetes & Metabolism, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 5Division of Endocrinology, Diabetes, and Metabolism, VA Greater Los Angeles Healthcare System, Los Angeles, California
  • 6Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 7Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California
JAMA Oncol. 2021;7(1):70-77. doi:10.1001/jamaoncol.2020.5935
Key Points

Question  Does an RNA test or a DNA-RNA test offer superior performance in estimating the risk of malignancy of thyroid nodules with indeterminate cytology?

Findings  In this randomized clinical trial of 346 patients with 372 indeterminate thyroid nodules, the RNA test and the DNA-RNA test demonstrated no statistically significant difference in sensitivity (100% vs 97%, respectively) and specificity (80% vs 85%, respectively).

Meaning  The molecular testing techniques assessed showed no statistically significant difference in diagnostic performance and allowed 49% of patients with indeterminate thyroid nodules to avoid diagnostic surgery.

Abstract

Importance  Approximately 20% of thyroid nodules display indeterminate cytology. Molecular testing can refine the risk of malignancy and reduce the need for diagnostic hemithyroidectomy.

Objective  To compare the diagnostic performance between an RNA test (Afirma genomic sequencing classifier) and DNA-RNA test (ThyroSeq v3 multigene genomic classifier).

Design, Setting, and Participants  This parallel randomized clinical trial of monthly block randomization included patients in the UCLA Health system who underwent thyroid biopsy from August 2017 to January 2020 with indeterminate cytology (Bethesda System for Reporting Thyroid Cytopathology category III or IV).

Interventions  Molecular testing with the RNA test or DNA-RNA test.

Main Outcomes and Measures  Diagnostic test performance of the RNA test compared with the DNA-RNA test. The secondary outcome was comparison of test performance with prior versions of the molecular tests.

Results  Of 2368 patients, 397 were eligible for inclusion based on indeterminate cytology, and 346 (median [interquartile range] age, 55 [44-67] years; 266 [76.9%] women) were randomized to 1 of the 2 tests. In the total cohort assessed for eligibility, 3140 thyroid nodules were assessed, and 427 (13.6%) nodules were cytologically indeterminate. The prevalence of malignancy was 20% among indeterminate nodules. The benign call rate was 53% (95% CI, 47%-61%) for the RNA test and 61% (95% CI, 53%-68%) for the DNA-RNA test. The specificities of the RNA test and DNA-RNA test were 80% (95% CI, 72%-86%) and 85% (95% CI, 77%-91%), respectively (P = .33); the positive predictive values (PPV) of the RNA test and DNA-RNA test were 53% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33). The RNA test exhibited a higher PPV compared with the prior test version (Afirma gene expression classifier) (54% [95% CI, 40%-67%] vs 38% [95% CI, 27%-48%]; P = .01). The DNA-RNA test had no statistically significant difference in PPV compared with its prior version (ThyroSeq v2 next-generation sequencing) (63% [95% CI, 48%-77%] vs 58% [95% CI, 43%-73%]; P = .75). Diagnostic thyroidectomy was avoided in 87 (51%) patients tested with the RNA test and 83 (49%) patients tested with the DNA-RNA test. Surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up.

Conclusions and Relevance  Both the RNA test and DNA-RNA test displayed high specificity and allowed 49% of patients with indeterminate nodules to avoid diagnostic surgery. Although previous trials demonstrated that the prior version of the DNA-RNA test was more specific than the prior version of the RNA test, the current molecular test techniques have no statistically significant difference in performance.

Trial Registration  ClinicalTrials.gov Identifier: NCT02681328

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