Impact of molecular tests and precision oncology on patients with advanced thyroid carcinomas in a referral center: the OrienTHYring real-world study

Background: Thyroid carcinomas (TCs) can harbor a variety of oncogenic drivers, but their prevalence according to the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) is unknown. Timing and modalities of molecular testing are not standardized, and access to targeted therapies is heterogeneous across institutions and countries. We analyzed the clinical and molecular features of radioiodine-refractory (RAIR) TC and anaplastic TC (ATC) patients evaluated for actionable molecular targets (AMTs) at our referral center, with the aim of proposing a therapeutically relevant algorithm. Methods: Patients with RAIR TC and ATC who were candidates for systemic therapy underwent single-gene analyses (BRAF, RET, and NTRK) and/or DNA/RNA next-generation sequencing (NGS) on formalin-fixed, paraffin-embedded tissue. Actionability was assessed using ESCAT and discussed at the molecular tumor board (MTB). Eligible patients could receive novel therapies (NTs; i.e. targeted therapies ± immunotherapy) via basket clinical trials, managed access programs, or off-label use. Objective responses and the duration of NT treatments were recorded. Results: From 2019 to 2023, 133 consecutive patients were included in the study. Overall, 270 molecular tests were carried out, with 58.8% evaluating gene mutations and 41.1% assessing gene rearrangements. Formalin-fixed, paraffin-embedded tissue archived for ≥5 years yielded a high rate of nonevaluable NGS results (43.2% versus 9.7%; P = 0.0001). Overall, 66.9% of the study population harbored at least one AMT (21% ESCAT I, 45.9% II-IIIA), and 43.6% received matched therapies (71.4% ESCAT I, 34.4% II-IIIA). Based on the a priori probability of detecting specific oncogenic drivers across TC histotypes, a histology-driven algorithm was designed to optimize AMT identification and expand NT access. Conclusions: Advanced TCs harbor a high prevalence of ESCAT I-III AMTs. Patients eligible for clinical trials with experimental drugs should undergo comprehensive genomic profiling and evaluation by an MTB to assess therapeutic actionability. A new biopsy is recommended for formalin-fixed, paraffin-embedded specimens older than 5 years to increase the likelihood of obtaining evaluable results.