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Next-Generation Sequencing in Differentiated Thyroid Cancer Patients Treated with Lenvatinib: Results and Challenges
Matteo Ferrari1,2, Alice Nervo1, Francesca Maletta3
1Oncological Endocrinology Unit, Città Della Salute E Della Scienza Hospital, Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy.
Objective:
Our objectives were to describe molecular profiling in a real-life cohort of patients with radioiodine-resistant (RAI-R) differentiated or poorly differentiated thyroid cancer (DTC or PDTC) treated with lenvatinib and to focus on factors potentially influencing the quality of tissue samples for molecular analysis, including the impact of storage time, defined as the interval between tissue collection and molecular testing.
Design:
We retrospectively included all lenvatinib-treated RAI-R DTC or PDTC patients tested with DNA- and/or RNA-based next-generation sequencing (NGS) in our center, also analyzing the results of fluorescence in situ hybridization (FISH) for RET fusions if the sample did not satisfy quality criteria for RNA-based NGS analysis. We investigated differences in terms of histotype, biopsy site, or storage time between adequate and inadequate samples for RNA-based NGS.
Results:
At least one gene alteration was detected in 50% of the cohort (18 out of 36 patients); RAS and BRAF were the most frequent mutations, while gene fusions accounted for 5.6% of cases. Tissue samples were more frequently adequate for DNA-based NGS compared to RNA-NGS analysis (93.9% vs. 58.3%, p < 0.001). The median storage time was significantly longer in the case of inadequate samples for RNA-based NGS compared with adequate specimens (41.5 vs. 9.5 months, p = 0.016); samples archived for ≥3 years led more frequently to an inadequate result.
Conclusions:
Advanced RAI-R TC candidates for systemic therapy often harbor gene alterations. An adequate result was less frequently achieved in cases of RNA-based NGS than in DNA-based NGS, especially if the interval between tissue collection and molecular analysis was longer; nevertheless, the limited cohort size precludes definitive conclusions.
Insights
Molecular profiling of radioiodine-resistant thyroid cancer (RAI-R TC) treated with lenvatinib reveals common gene alterations. Longer tissue storage times negatively impact RNA next-generation sequencing (NGS) adequacy for molecular analysis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Radioiodine-resistant (RAI-R) differentiated or poorly differentiated thyroid cancer (DTC or PDTC) presents a therapeutic challenge.
- Lenvatinib is a targeted therapy used for advanced RAI-R thyroid cancer.
- Molecular profiling is crucial for understanding treatment response and identifying actionable mutations.
Purpose of the Study:
- To characterize molecular alterations in a real-world cohort of RAI-R DTC/PDTC patients treated with lenvatinib.
- To evaluate factors affecting tissue sample quality for molecular testing, specifically storage time.
- To assess the impact of storage duration on the success of DNA- and RNA-based next-generation sequencing (NGS).
Main Methods:
- Retrospective analysis of lenvatinib-treated RAI-R DTC/PDTC patients undergoing DNA/RNA-based NGS.
- Inclusion of fluorescence in situ hybridization (FISH) for RET fusions in samples inadequate for RNA-based NGS.
- Investigation of histotype, biopsy site, and storage time effects on sample adequacy for RNA-based NGS.
Main Results:
- Gene alterations were detected in 50% of patients, with RAS and BRAF mutations being most frequent.
- DNA-based NGS yielded adequate samples more often than RNA-based NGS (93.9% vs. 58.3%).
- Inadequate RNA-NGS samples had significantly longer median storage times (41.5 vs. 9.5 months), with samples stored ≥3 years being more frequently inadequate.
Conclusions:
- Patients with advanced RAI-R thyroid cancer eligible for systemic therapy frequently exhibit targetable gene alterations.
- RNA-based NGS is less successful than DNA-based NGS, particularly with extended tissue storage intervals.
- While molecular profiling is feasible, longer storage times pose a challenge for RNA integrity in thyroid cancer diagnostics.
