Introduction: Thyroid nodule management is guided by ultrasound findings and cytology. Genomic profiling has become part of the standard workup for nodules with Bethesda “indeterminate” category. This study was performed to investigate the potential benefit of genomic profiling in “benign” nodules.

Methods: This study is a subgroup analysis of the prospective registry on thyroid nodule evaluation by molecular testing. Under the Miami thyroid oncology consortium project 02 (MTOCP–02), all patients underwent distended clinical evaluations, ultrasound, and fine-needle aspiration biopsy of suspicious thyroid nodules. Genomic profiling was performed using Thyroseq molecular testing. Cytology results were compared to the results of molecular testing. Patients were followed up clinically. Decisions for surgical treatment were made based on clinical assessment.

Results: Total of 25 patients had benign cytology (Bethesda category 2) with Positive Thyroseq results. 3 patients had more than one genomic change. Genomic changes included RAS N and H, TSHR, EIF1AX, CNA, ETV6/NTRK3, TP53. There were TSHR/GNAS mutations found in 8 out of 25 (32%) of the nodules. RAS mutations were detected in 8 out of 24 (33.3%) nodules. EIF1X was detected in 5 cases (20%), TP53 in 1 case (5.2%), ETV6/NTRK3in 1 case (5.2%) and CNA in 1 case (5.2%). Totally, 37.5% of these patients with benign cytology (Bethesda 2) and positive thyroseq ended up having surgical intervention. Surgical pathology in 4 cases (16.6%) showed malignancy. All of these 4 cases were positive for papillary thyroid cancer.

Conclusions: The molecular blueprint has a theranostic value, allowing better anticipation of tumor behavior. The high risk genomic changes such as BRAF or RAS with TERT mutations confer a 100% risk of thyroid cancer. Non-operative clinical follow-up is standard for patients with nodules deemed benign by cytology. The current guidelines recommend follow-up ultrasound in 6-12 months to check for nodule growth and reassess the management plan. Our study suggested that genomic profiling has the potential to alter the management for benign nodules by identifying patients with markers of early neoplastic changes who could benefit from surgery. If the molecular diagnostics show certain intermediate or high risk mutations, the patient may benefit from surgery rather than follow-up. Clinical follow-up can be more reliably pursued when genomic profiling indicates negative results for neoplasia. Our study has shed light on the broader application of genomic profiling. We must investigate further the use of genomic profiling-guided surgical decision-making.

Citation Format: Oranus Mohammadi, Lacey Avila, Alex Breslin, Edmond Benedetti, Karen Toronczyk, Katayoon Behshid, Daniel Weingrad, Seza Gulec. Genomic and molecular profiling in thyroid nodules with benign cytology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1138.