Molecular testing for indeterminate thyroid nodules: Performance of the Afirma gene expression classifier and ThyroSeq panel

Abstract Background: Molecular analysis of indeterminate thyroid nodules has been shown to reduce unnecessary surgeries for benign thyroid nodules. Afirma Gene Expression Classifier (GEC) has a reported benign call rate (BCR) of 38-61%, and the newer generation Genomic Sequencing Classifier (GSC) has a reported BCR of 42-76%. Both GEC and GSC have a high sensitivity of 88-100% and negative predictive value (NPV) of 94-100%. Specificity and positive predictive value (PPV) have improved with GSC when compared to GEC, largely due to improvements in the classification of hurtle cell neoplasms. GSC PPV is reported as 47-76%. The aim of our study was to determine surgical and malignancy rates for patients at our institution with GEC, GSC, or for those who did not undergo molecular testing. Methods: Retrospective analysis of all Bethesda III and IV nodules with available follow up data at our institution between January 2013 and December 2018. We evaluated cytopathology, molecular testing with Afirma GEC or GSC, surgical rate, and malignancy rate between groups. Univariate descriptive statistics and bivariate analyses were calculated using Chi-squared and Fisher’s exact testing for categorical variables and one-way analysis of variance for continuous variables. Results: A total of 376 patients had Bethesda III and IV indeterminate thyroid nodule biopsies and met inclusion criteria for analysis. Of these, 262 patients did not undergo molecular testing, 50 underwent GEC, and 64 GSC testing. There was no difference between the groups for gender, age, or BMI. The overall surgical rate was 66.4, 60.0, and 46.9%, respectively (p=0.014). There was no difference in BCR for GEC or GSC with 44.0% versus 54.7% (p=0.38). There was no difference in malignancy rate with no molecular testing 19.5%, 22.7% if GEC suspicious, and 29.2% if GSC suspicious (p=0.619). GEC had a PPV of 22.7%, NPV of 100%, sensitivity of 100%, and specificity of 56.4% compared with GSC with PPV of 29.2%, NPV of 100%, the sensitivity of 100%, and specificity of 67.3%. Our overall rate of incidentally noted malignancy for indeterminate thyroid nodules who ultimately underwent surgery was 23 of 234 (9.9%). Conclusions: At our institution, the surgical rate was not different between patients who did not have molecular testing and those with GEC, however, there was a significant reduction in overall surgeries when using GSC. GSC BCR improved when compared to GEC, consistent with previous studies, but PPV remained low at 29.2%, which is lower than previously reported.

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Evaluation of the Afirma Gene Expression Classifier in Repeat Indeterminate Thyroid Nodules

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2016-0328-oa ◽

2017 ◽

Vol 141 (7) ◽

pp. 985-989 ◽

Cited By ~ 26

Author(s):

Grant Harrison ◽

Julie Ann Sosa ◽

Xiaoyin Jiang

Keyword(s):

Gene Expression ◽

Positive Predictive Value ◽

Surgical Resection ◽

San Francisco ◽

Predictive Value ◽

Thyroid Nodules ◽

Surgical Pathology ◽

Molecular Testing ◽

Fine Needle ◽

Gene Expression Classifier

Context.— Molecular testing in indeterminate thyroid nodules is a rapidly evolving field with variable reported outcomes. Objective.— To report our experience at a tertiary thyroid referral center with the Afirma Gene Expression Classifier (Veracyte, San Francisco, California) in repeat fine-needle aspirations of thyroid nodules with a previous indeterminate cytologic result. Design.— Results of cytopathology and the Afirma test were collected from August 2013 to March 2015, as were diagnoses from surgical resection when performed. Results.— One hundred and fifteen thyroid nodules were evaluated by Afirma. The fine-needle aspiration diagnostic categories for these nodules were 100 (87%) Bethesda III, 10 (9%) Bethesda IV, 3 (2%) Bethesda II, 1 (1%) Bethesda V, and 1 (1%) Bethesda I. Afirma results for 52 of the nodules (45%) were benign, 57 (50%) were suspicious, and 6 (5%) specimens yielded no result because of low messenger RNA content. Three of the benign nodules (6%) were treated surgically, and all were benign on final surgical pathology. Forty-six (81%) of the suspicious nodules were treated surgically; final surgical pathology revealed 30 (65%) were benign and 16 (35%) malignant, yielding a positive predictive value of 35%. Conclusions.— In our experience, 50% of the indeterminate nodules were classified as suspicious by Afirma, with a 35% rate of malignancy in these nodules at surgical resection, in comparison with a historical rate of malignancy at our institution of 11% for Bethesda III nodules and 23% for Bethesda IV. Our use of Afirma is consistent with prior reports in that it has a low positive predictive value in indeterminate thyroid nodules.

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Shear wave elastography and Afirma™ gene expression classifier in thyroid nodules with indeterminate cytology: a comparison study

Endocrine ◽

10.1007/s12020-017-1509-9 ◽

2018 ◽

Vol 59 (3) ◽

pp. 573-584 ◽

Cited By ~ 8

Author(s):

Ghobad Azizi ◽

James M. Keller ◽

Michelle L. Mayo ◽

Kelé Piper ◽

David Puett ◽

...

Keyword(s):

Gene Expression ◽

Shear Wave ◽

Thyroid Nodules ◽

Shear Wave Elastography ◽

Comparison Study ◽

Gene Expression Classifier ◽

Indeterminate Cytology

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UTILITY OF ULTRASOUND VERSUS GENE EXPRESSION CLASSIFIER IN THYROID NODULES WITH ATYPIA OF UNDETERMINED SIGNIFICANCE

Endocrine Practice ◽

10.4158/ep161231.or ◽

2016 ◽

Vol 22 (10) ◽

pp. 1199-1203 ◽

Cited By ~ 13

Author(s):

Carmen V. Villabona ◽

Vineeth Mohan ◽

Karla M. Arce ◽

Julia Diacovo ◽

Alisha Aggarwal ◽

...

Keyword(s):

Gene Expression ◽

Thyroid Nodules ◽

Versus Gene ◽

Gene Expression Classifier ◽

Undetermined Significance

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American Thyroid Association Sonographic Risk and Afirma Gene Expression Classifier Alone and in Combination for the Diagnosis of Thyroid Nodules with Bethesda Category III Cytology

Thyroid ◽

10.1089/thy.2019.0673 ◽

2020 ◽

Vol 30 (11) ◽

pp. 1613-1619

Author(s):

Marilyn Arosemena ◽

Anu Thekkumkattil ◽

Maria Linares Valderrama ◽

Russ Kuker ◽

Rosa Patricia Castillo ◽

...

Keyword(s):

Gene Expression ◽

Thyroid Nodules ◽

American Thyroid Association ◽

Gene Expression Classifier

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Validation and Multicenter Clinical Experience of the Afirma® Gene Expression Classifier

US Endocrinology ◽

10.17925/use.2014.10.02.117 ◽

2014 ◽

Vol 10 (02) ◽

pp. 117 ◽

Cited By ~ 2

Author(s):

Trevor E Angell ◽

Erik K Alexander ◽

◽

Keyword(s):

Gene Expression ◽

Thyroid Cancer ◽

Cancer Risk ◽

Clinical Experience ◽

Messenger Rna ◽

Expression Patterns ◽

Current Data ◽

Molecular Testing ◽

Gene Expression Classifier ◽

Indeterminate Cytology

The current assessment of clinically relevant thyroid nodules is imprecise and nonspecific, primarily due to the presence of indeterminate cytology. This cytologic category implies a low but clinically important risk for thyroid cancer, historically prompting consideration for diagnostic thyroidectomy in most patients. Over the last 5 years, novel molecular testing options have become available and appear able to modify preoperative thyroid cancer risk and better inform clinical decisions. The Afirma® gene expression classifier (GEC) measures messenger RNA (mRNA) expression patterns in fine-needle aspiration (FNA) tissue and seeks to identify a benign signature despite indeterminate cytology. When detected, the cancer risk is low and allows for prevention of unnecessary surgeries. The results of a large, multicenter, blinded validation trial of the Afirma GEC demonstrated the test’s high negative predictive value. Subsequent independent studies of the Afirma GEC in clinical use have documented the influence these results have on preoperative management recommendations. This review summarizes the current data regarding the Afirma GEC, including the original validation trial and recent multicenter clinical experience.

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