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Higher Risk of Invasive Behaviour for Oncogenic Fusions–Driven Paediatric Thyroid Cancers

Genetic subtyping more accurately reflects clinical behaviour than reliance on pathologic classification only
21 Jan 2022
Cancer in Special Situations / Population;  Endocrine and neuroendocrine tumours;  Pathology/Molecular biology

Incidence of regional and distant metastasis is higher in paediatric patients compared with adults with differentiated thyroid cancer. A study performed by Prof. Andrew J. Bauer of the Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia in Philadelphia, PA, US and colleagues shows that RET and NTRK fusions are the most prevalent genetic alterations in paediatric differentiated thyroid cancer. Patients with RET/NTRK fusion had the highest risk of metastases and were less likely to achieve remission at 1 year after surgery. A 3-tiered classification of RAS-mutated versus BRAF-mutated versus RET/NTRK fusions more accurately correlates with phenotypic behaviour and outcomes in paediatric differentiated thyroid cancer according to study findings published on 11 January 2022 in the Journal of Clinical Oncology.

The authors wrote in the background that in 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that classification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behaviour than sole reliance on pathologic classification.

With the reduced costs of next-generation sequencing, the use of somatic cancer gene panel analysis in paediatric patients with differentiated thyroid cancer has expanded with current data showing a shifted distribution of driver alterations with a higher incidence of oncogenic fusions rather than point mutations in children and adolescents compared with adults.

The aim of the current study was to categorise the common oncogenic variants in paediatric differentiated thyroid cancer and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in paediatric differentiated thyroid cancer.

In this study somatic cancer gene panel analysis was completed on differentiated thyroid cancers from 131 pediatric patients. Differentiated thyroid cancers were categorised into RAS-mutated (H-K-NRAS), BRAF-mutated (BRAF p.V600E), and RET/NTRK fusion (RETNTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (TNM classification) as well as response to therapy 1 year after initial treatment had been completed.

Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behaviour, and the likelihood of remission at 1 year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mutated subgroups.

The authors concluded that their results provide greater clarity into the oncogenic alterations in paediatric differentiated thyroid cancer that confer the greatest risk for metastasis and persistent disease with RET/NTRK fusions having worse outcomes than those with BRAF-mutated disease.

The authors commented that future trials should consider inclusion of molecular subtype into risk stratification. Their findings support the incorporation of somatic cancer gene analysis to improve the diagnostic accuracy for fine needle aspiration, as well as the potential utility to incorporate oncogenic data to stratify the surgical approach and to identify tumours that may benefit from oncogene-specific systemic therapies. The findings also highlight the need to further define differences in the molecular landscape between paediatric and adult differentiated thyroid cancers to optimise clinical care and use of molecularly targeted therapies.

The study was supported in part by a grant from the US National Institute of Health, The Children's Hospital of Philadelphia Frontier Programs, and the Children's Hospital of Philadelphia Foerderer Grant.

Reference

Franco AT, Ricarte-Filho JC, Isaza A, et al. Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers. Journal of Clinical Oncology; Published online 11 January 2022. DOI: 10.1200/JCO.21.01861

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