Genomic landscape of FNAs positive for medullary thyroid cancer (MTC) and potential impact on systemic therapy

6087 Background: Systemic therapies targeting specific genomic alterations in advanced MTC are available or under investigation. The Afirma Genomic Sequencing Classifier (GSC) uses RNA sequencing to assess FNA specimens from cytologically indeterminate thyroid nodules, which are also tested for specific molecular aberrations associated with thyroid cancer via a suite of highly accurate malignancy classifiers. This suite can be applied independently to Bethesda V/VI nodules. The Afirma Xpression Atlas (XA) is an additional test that can be combined with Afirma GSC to report nucleotide variants and fusions across 511 cancer-associated genes. Here we report the prevalence and genomic landscape of MTC classifier positive (MTC+) FNA samples. Methods: All Afirma GSC and malignancy classifier tests run in the Veracyte Clinical Laboratory between July 2017 and January 2019 were deidentified and examined for MTC+ cases. Afirma XA was run on all such cases, and all variants and fusions were tabulated. Results: Examination of 29,895 FNAs revealed 90 MTC cases. Of 22,793 Bethesda III cases, 32 (0.14%) were MTC+. Of 5,491 Bethesda IV cases, 33 (0.60%) were MTC+. Provider-ordered testing was done on an additional 16 and 9 MTC cases from Bethesda V and VI nodules, respectively. 58% of all MTC+ samples harbored a RET variant (+/- others), 9% contained a KRAS variant (+/- others), 6% included an HRAS variant, 1% had a BRAF fusion, 1% demonstrated other fusions, and 26% held no variant/fusion. Conclusions: In our cohort, Afirma XA identified a variant or fusion in 74% of MTC+ FNAs. Currently approved or investigational therapies exist for cancers with RET, BRAF and HRAS alterations, suggesting that 64% of our series might be eligible for treatment based on genomic information from FNA. In advanced MTC, noninvasive FNA sample collection at the time of diagnosis may ultimately impact on targeted therapy selection, with the option to repeat FNA testing should the disease progress. Future studies may investigate how finding a genomic alteration by FNA can inform the management of MTC and, in the case of progressive disease, improve our understanding of the mechanisms of disease progression and drug resistance.