Results: Patient with carcinoma of unknown primary and somatic (tumour) NTRK rearrangement

A 66-year-old female is diagnosed with unfavourable carcinoma of unknown primary (CUP). Somatic (tumour) testing via a multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel reveals an NTRK1 fusion 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 rare in CUP, occurring in less than 0.3% of cases.
• 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 currently available via the Cancer Drugs Fund. They are approved 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.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

• 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
• 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
• Krämer A, Bochtler T, Pauli C and others. ‘Cancer of unknown primary: ESMO clinical practice guideline for diagnosis, treatment and follow up‘. Annals of Oncology 2023: volume 34, issue 3, pages 228–246. DOI: 10.1016/j.annonc.2022.11.013
• 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-787

For patients

• Cancer Research UK: What is cancer of unknown primary?
• Macmillan Cancer Support: Cancer of unknown primary (CUP)