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Oncology

Presentation: Patient with carcinoma of unknown primary

Genomic testing in carcinoma of unknown primary may have implications for the clinical management of the patient’s current cancer, as well for their family members.

Example clinical scenario

A 55-year-old woman is admitted with abdominal pain, weight loss and shortness of breath. Imaging reveals multiple sites of metastatic disease but no obvious primary tumour. After a liver biopsy the patient is diagnosed with unfavourable (subtype) carcinoma of unknown primary (CUP). You wish to undertake genomic testing and are considering which constitutional (germline) and/or somatic (tumour) genomic testing is available and appropriate for her.

When to consider genomic testing

Importance of genomic testing

  • The mutational profile of unfavourable CUP has been investigated in a number of clinical trials. TP53 variants are found in approximately 50% of unfavourable CUPs. Beyond this, CUPs demonstrate a very heterogeneous mutational landscape, with a diverse set of potentially actionable genetic alterations.
  • Initial data from the CUPISCO randomised trial, which assessed the clinical utility of massively parallel sequencing-based (sometimes called next-generation sequencing, or NGS) management approaches in CUP, indicates a favourable impact on progression-free survival associated with a molecularly directed treatment approach. However, overall survival data are pending.

ctDNA testing

  • ctDNA/liquid biopsy analysis is available for patients with CUP (M226.7) with the following eligibility criteria:
    • ECOG performance status 0–2;
    • diagnosis of CUP as per the ESMO NICE guidelines;
    • not currently on treatment; and
    • discussion at a local CUP MDT confirming diagnosis.
  • For up-to-date information about the minimum set of targets analysed through ctDNA testing, please review the National Genomic Test Directory or consult your local Genomic Laboratory Hub (GLH).

Important: Currently there is also one important exclusion criteria to this testing: Patients with a malignancy of unknown origin or a non-epithelial/non-neuro-endocrine malignancy of unknown origin are not eligible for ctDNA testing.

ctDNA-informed germline genetic testing

  • If, during ctDNA testing, a pathogenic variant is identified in a gene known to be associated with cancer predisposition that is suspected to be of constitutional (germline) origin (for example, because of variant allele frequency, variant type or clinical factors), follow-up constitutional testing for the same variant may be appropriate (R240 Diagnostic testing for known mutation(s)), if constitutional testing has not already been undertaken through whole genome sequencing (WGS). Such cases are best discussed through a genomic tumour advisory board (GTAB) or with clinical genetics.

Whole genome sequencing (WGS)

  • Patients with CUP are eligible for WGS (paired tumour/germline) at any time after diagnosis, as long as adequate fresh/fresh-frozen tissue is available for DNA extraction. Consider WGS if:
    • ctDNA/tumour testing has been undertaken but is uninformative;
    • ctDNA/tumour testing has been undertaken and is somewhat informative but WGS may yield additional results; or
    • ctDNA/other tumour testing has not been undertaken and is likely to be less informative than upfront WGS (for example, limited available tumour/non-shedding tumour).

Tumour-only testing

  • Somatic (tumour-only) testing for fusions involving NTRK1, NTRK2 and NTRK3 genes is available within the NHS for CUP patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.

DPYD testing

  • Patients who are considered for palliative chemotherapy with capecitabine should undergo constitutional (germline) testing of the dihydropyrimidine dehydrogenase (DPYD) gene. Certain variants in this gene result in a deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) and a subsequent reduction in metabolism of fluoropyrimidine-based chemotherapies such as 5FU and capecitabine. This results in serious and sometimes life-threatening toxicity, including diarrhoea, mucositis and skin reactions, if these chemotherapy agents are given at standard doses.

What do you need to do?

  • 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.

Constitutional (germline) testing

  • Patients being considered for palliative chemotherapy with capecitabine should undergo constitutional (germline) DPYD testing using test code M226.3.
  • For constitutional (germline) DNA-based tests, an EDTA blood sample is required. Please refer to your local GLH for details of test request forms and where to send samples.

Somatic (tumour) testing

  • NTRK fusion gene analysis can be requested as test M226.1. This consists of massively parallel sequencing structural variant analysis.
  • WGS of CUP is requested as code M226.4. WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for constitutional (germline) testing. A record of discussion form must be completed for this investigation. Please discuss the case with your local GLH before submitting samples for WGS to confirm the local test pathway details.
  • ctDNA analysis (M226.7) requires a blood sample, taken in specialised cell-free DNA‑stabilising blood tubes that prevent lysis of cells. It is important that you check with your local laboratory as to which tube they require. Further information regarding ordering and sample handling is available in this Knowledge Hub article.
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 14/11/2024
  • Next review due: 14/11/2026
  • Authors: Professor Ellen Copson
  • Reviewers: Dr Sarah Ellis, Dr Terri McVeigh

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