Independent Comparison of the Afirma Genomic Sequencing Classifier and Gene Expression Classifier for Cytologically Indeterminate Thyroid Nodules

Background: For thyroid nodules with indeterminate cytology, the Afirma Gene Expression Classifier (GEC) identified benign nodules to reduce diagnostic surgery, though many nodules classified as suspicious still proved histopathologically benign. The current Afirma Genomic Sequencing Classifier (GSC) demonstrates improved specificity, suggesting more nodules will have a benign result (benign call rate [BCR]), but independent data are needed to confirm this in clinical practice. Methods: Retrospective analysis was performed of all Bethesda III or IV cytology thyroid nodules >= 1 cm tested with GEC (between January 1, 2011, and July 19, 2017) or GSC (between July 20, 2017, and August 27, 2018) at the authors' institution. Afirma testing was not performed reflectively for all nodules with Bethesda III or IV cytology, but rather was applied based on physician-patient decision making. Demographic, sonographic, and cytologic data were collected. The BCR for GEC- versus GSC-tested nodules was compared and further stratified by Bethesda classifications. Results: The study evaluated 600 nodules in 563 patients tested with either GEC (n = 486) or GSC (n = 114). The BCR was 233/486 (47.9%) for the GEC compared to 75/114 (65.8%) for the GSC (p = 0.0006). Hurthle-cell cytology was present in 99/486 (20.4%) nodules in the GEC group compared to 31/114 (27.2%) nodules in the GSC group (p = 0.28). The GSC BCR was significantly higher than the GEC BCR for Bethesda III nodules characterized by Hurthle cells (p = 0.006), but the BCRs were similar for nodules with architectural or cytologic atypia. In Bethesda IV nodules suspicious for follicular neoplasm, BCR for the GEC and GSC were similar (p = 0.68), but for cytology suspicious for Hurthle-cell neoplasm, the GSC BCR was 68.2% (15/22) compared to the GEC BCR of 16.4% (10/61; p < 0.0001). Positive predictive value in resected nodules with a suspicious result was 16/32 (50%) for GSC nodules and 75/221 (33.9%) for GEC nodules (p = 0.1). Conclusions: The higher BCR for the GSC compared to the GEC for indeterminate thyroid nodules, predominantly among nodules with Hurthle-cell cytology, will likely lead to further reduction in surgical management.