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

A 40-year-old woman with advanced medullary thyroid cancer has progressed through routine treatment options. Multi-target massively parallel sequencing (also known as next-generation sequencing) is performed on the tumour and identifies a somatic pathogenic rearrangement of the NTRK gene.

NTRK1, NTRK2 and NTRK3 encode the tropomyosin receptor kinases TRKA, TRKB and TRKC respectively.

NTRK fusion genes are formed when rearrangements – such as translocations or inversions – occur between or within chromosomes, in such a way that an NTRK gene is brought into contact and fuses with a partner, such as ETV6, LMNA or TPM3. This NTRK partner gene fusion results in a fusion protein product that constitutively activates downstream signalling pathways.

NTRK fusions are found in approximately 3.5% of adult thyroid cancers.

The presence of a somatic (tumour) NTRK fusion gene in a patient with advanced or metastatic cancer indicates a potential eligibility for treatment with an NTRK inhibitor.

• The NTRK inhibitors larotrectinib and entrectinib are approved by NICE for use in patients with solid tumours and a NTRK fusion gene if they:
  • have a locally advanced or metastatic disease, or if surgery could cause severe health problems;
  • have already been treated with all suitable systemic therapy options funded by NHS England; and
  • have not received previous treatment with an NTRK inhibitor.
• Larotrectinib and entrectinib are currently available via the Cancer Drugs Fund
• The finding of a somatic NTRK rearrangement should not precipitate any constitutional (germline) genomic NTRK testing.
• All patients with medullary thyroid cancer are eligible for constitutional (germline) RET testing (R218 Multiple endocrine neoplasia type 2 (single gene testing)) and may be eligible for broader testing if they have a personal or family history of other relevant cancers.
  • Consult the National Genomic Test Directory. From here you can access:
    • the rare and inherited disease eligibility criteria for information about constitutional (germline) tests for patients with cancer and their associated eligibility criteria;
    • the test directory for rare and inherited disease, a spreadsheet of all available constitutional (germline) tests; and
    • the test directory for cancer, a spreadsheet of all available somatic (tumour) tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
  • For information about the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• None of the tests outlined above include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and record of discussion (RoD) forms. If you have not completed an RoD form before and/or do not have access to one, see How to complete an RoD form.
• For constitutional (germline) testing, a blood sample in EDTA (typically a purple-topped tube) is required. The sample is best stored at 4°C until it can be posted to the genomic laboratory.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• NICE: Entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Larotrectinib for treating NTRK fusion-positive solid tumours

References:

• Doebele RC, Drilon A, Paz-Ares L and others. ‘Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials’. The Lancet Oncology 2020: volume 21, issue 2, pages 271–282. DOI: 10.1016/S1470-2045(19)30691-6
• Filetti S, Durante C, Hartl DM and others. ‘ESMO Clinical Practice Guideline update on the use of systemic therapy in advanced thyroid cancer‘. Annals of Oncology 2022: volume 33, issue 7, pages 674–684. DOI: 10.1016/j.annonc.2022.04.009
• 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
• Hong DS, DuBois SG, Kummar S and others. ‘Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials’. The Lancet Oncology 2020: volume 21, issue 4, pages 531–540. DOI: 10.1016/S1470-2045(19)30856-3
• Marchetti A, Ferro B, Pasciuto MP and others. ‘NTRK gene fusions in solid tumors: Agnostic relevance, prevalence and diagnostic strategies‘. Pathologica 2022: volume 114, issue 3, pages 199–216. DOI: 10.32074/1591-951X-78
• Perros P, Colley S, Boelaert K and others. ‘Guidelines for the management of thyroid cancer‘. British Thyroid Association 2014. DOI: 10.1111/cen.12515

For patients

• AMEND (Association for Multiple Endocrine Neoplasia Disorders)
• Butterfly Thyroid Cancer Trust
• Macmillan Cancer Support: Entrectinib (Rozlytrek®)
• Macmillan Cancer Support: Larotrectinib (Vitrakvi®)
• Macmillan Cancer Support: Medullary thyroid cancer
• Macmillan Cancer Support: Thyroid cancer – symptoms, types, treatment options