Results: Patient with metastatic papillary thyroid cancer and a RET rearrangement

A 40-year-old woman is diagnosed with a T3 N1 papillary thyroid cancer. Staging investigations reveal the presence of lung metastases. Multi-target next-generation sequencing (NGS) is performed on the tumour and identifies a somatic (tumour) pathogenic rearrangement of the RET gene.

• RET is a proto-oncogene which encodes a transmembrane receptor tyrosine kinase involved in numerous cellular processes.
• Rearrangement of the RET gene can result in a fusion protein that promotes dimerisation and activation of the tyrosine kinase.
• Approximately 10%–20% of papillary thyroid cancers (PTCs) have pathogenic rearrangements of RET.
• RET rearrangements are found more frequently in paediatric PTCs and PTCs occurring after childhood radiation exposure.
• Selpercatinib is a small molecule selective RET inhibitor. A phase 1–2 clinical trial of selpercatinib monotherapy (LIBRETTO-001) included 19 patients with previously treated RET fusion–positive thyroid cancer. The objective response rate in these patients was 79% (95% CI, 54 to 94), and one-year progression-free survival was 64% (95% CI, 37 to 82).

• NICE guidelines recommend that selpercatinib monotherapy is indicated for the treatment of advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib in adults whose disease does not respond to radioactive iodine.
• Selpercatinib is currently available via the Cancer Drugs Fund for patients meeting these eligibility criteria.
• The identification of a somatic (tumour) RET rearrangement in a PTC does not indicate a need for constitutional (germline) testing of this gene. Constitutional (germline) pathogenic variants in RET predispose to medullary type thyroid cancer as part of multiple endocrine neoplasia type 2, and constitutional (germline) RET testing is not recommended for patients with non-medullary thyroid cancer.

For clinicians

• NICE: Selpercatinib for treating advanced thyroid cancer with RET alterations

References:

• Fugazzola L, Elisei R, Fuhrer D and others. ‘2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer‘. European Thyroid Journal 2019: volume 8, issue 5, pages 227–245. DOI: 10.1159/000502229
• Perros P, Colley S, Boelaert K and others. ‘British Thyroid Association Guidelines for the Management of Thyroid Cancer’. Clinical Endocrinology 2014: volume 81, issue 1. DOI: 10.1111/cen.12515
• Wirth LJ, Sherman E, Robinson B and others. ‘Efficacy of Selpercatinib in RET-Altered Thyroid Cancers‘. The New England Journal of Medicine 2020: volume 383, issue 9, pages 825–35. DOI: 10.1056/NEJMoa2005651
• Salvatore D, Santoro M, Schlumberger, M. ‘The importance of the RET gene in thyroid cancer and therapeutic implications‘. Nature Reviews Endocrinology 2021: volume 17, issue 5, pages 296–306. DOI: 10.1038/s41574-021-00470-9

For patients

• Macmillan Cancer Support: Papillary and follicular thyroid cancer
• Macmillan Cancer Support: Selpercatinib | Macmillan Cancer Support
• British Thyroid Foundation: Low Iodine Diet
• Butterfly Thyroid Cancer Trust