The Mutational Landscape of 774 Variants and 132 Fusions in 513 Genes Measured in Thyroid FNAs from a Multi-Center, Blinded Cohort


Interview with Joshua E. Babiarz, Ph.D., Veracyte

Dr. Joshua Babiarz is associate director of discovery research at Veracyte and was on the team that developed the company’s next-generation Afirma Genomic Sequencing Classifier. The Afirma GSC combines RNA sequencing and machine learning to further increase the specificity of Afirma genomic testing so that more benign nodules can be identified and thus more patients potentially spared an unnecessary diagnostic surgery when their cytopathology results are indeterminate. Here he spoke with us about the new Afirma Xpression Atlas platform, which he previewed in an oral presentation at ENDO 2018.

Q: What exactly is the Afirma Xpression Atlas?

Dr. Babiarz: It’s a panel of rich genomic content – 761 DNA variants and 130 RNA fusions derived from 511 unique genes – obtained through RNA sequencing, which we can use to evaluate thyroid cytology samples. We plan to make this available as an add-on product to our Afirma GSC in order to help inform physicians’ surgery decisions and treatment options for patients with suspicious thyroid nodules who are likely headed to surgery.

Q: What is the significance of all of these gene alterations?

Dr. Babiarz: These gene alternations are shown to be associated with thyroid cancer. We curated the Xpression Atlas from an extensive literature review, including findings from the National Institutes of Health’s Cancer Genome Atlas study of papillary thyroid carcinoma. Some, like BRAF V600E, are well-validated and others’ clinical significance remains investigational.

Q: What level of confidence do you have that the additional benign calls generated by the Afirma GSC are, indeed, benign?

Dr. Babiarz: The additional benign calls generated by the Afirma GSC represent a significantly higher proportion of patients who likely will be monitored without referral for surgery. The previously reported clinical validation results – which were generated from a prospective, multicenter, blinded cohort study with a large sample (191 indeterminate nodules) – give me tremendous confidence that these GSC benign calls are reliable.

Q: Your team has previously published data on the role of these variants and fusions in evaluating cytologically indeterminate thyroid nodules. What did you find?

Dr. Babiarz: In a previously published study, we found that these variants and fusions were present in both benign and malignant nodules, based on histopathology results as the clinical-truth reference. Essentially, the sensitivity of the variants and fusions alone was too low to rule out cancer in indeterminate cases, while their specificity is similar to the Afirma GSC. In other words, they did not significantly alter the Afirma GSC performance.

Q: So what role can this extensive genomic content play in patient care?

Dr. Babiarz: To understand the potential value of this rich genomic content, it’s important to look at the bigger picture. The Afirma GSC identifies nearly two thirds of indeterminate nodules as benign, which means these patients can avoid unnecessary thyroid surgery. The remaining patients are likely headed for surgery because their nodules are more likely to be cancerous. Physicians are increasingly interested in having gene alteration data for patients with nodules that are suspicious for cancer to help inform decisions such as how extensive a surgery to perform or whether the patient may potentially be treated without radioactive iodine. We believe that this information will be more meaningful because it will be applied to patients in whom cancer has not already been ruled out by the Afirma GSC.

Q: Is the Afirma Xpression Atlas available now?

Dr. Babiarz: Not yet. We plan to share results of our analytical verification study in the coming months and to then make the test available as part of a comprehensive offering to physicians managing patients with thyroid nodules.
Read the Abstract Here