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Oncology

Presentation: Patient with metastatic triple-negative breast cancer

Genomic testing in breast cancer may affect clinical management of the current cancer, as well as the patient’s future cancer risk and that of their relatives.

Example clinical scenario

A 46-year-old woman is diagnosed with a grade-three oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2)-negative invasive ductal breast cancer (triple-negative breast cancer). Staging investigations reveal metastases in the lungs and liver. There is no significant family history of cancer. You wish to undertake genomic testing and are considering which constitutional (germline) and/or somatic (tumour) testing is available and appropriate for her.

When to consider genomic testing

Constitutional (germline) testing

Women with breast cancer (primary or metastatic) or high-grade ductal carcinoma in situ are eligible for constitutional (germline) genomic testing of the BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM (truncating variants and c.7271T>G only) and CHEK2 genes (truncating variants only), under indication R208, if they meet certain eligibility criteria, including triple-negative breast cancer diagnosed <60 years of age

Patients with metastatic HER2 negative breast cancer who do not meet the eligibility criteria above may still undergo testing for constitutional BRCA1/ BRCA2 variants if they would potentially benefit from PARP inhibitor therapy.

  • PARP inhibitors are licensed in Europe for the second-line treatment of metastatic HER2-negative breast cancer with an underlying constitutional (germline) pathogenic variant in BRCA1 or BRCA2.
  • Talazoparib and olaparib have been approved by NICE and are available via the Cancer Drugs Fund for HER2-negative, locally advanced or metastatic breast cancer in adults with constitutional (germline) BRCA1 or BRCA2 variants who have had an anthracycline or a taxane, or both, unless these treatments are not suitable.

Consider a referral to clinical genetics for any woman with breast cancer (primary or metastatic) who has a personal and/or family history of endometrial, thyroid, diffuse gastric cancers or non-cancerous features, such as a cleft lip or palate, macrocephaly, mucocutaneous lesions or a history of intussusception, which may be features of an underlying syndromic cause of breast cancer predisposition.

Patients who are considered for palliative chemotherapy with capecitabine should undergo constitutional (germline) testing of the dihydropyrimidine dehydrogenase (DPYD) gene. Certain variants in the DPYD gene result in a deficiency of the enzyme dihydropyrimidine dehydrogenase and a subsequent reduction in metabolism of fluoropyrimidine chemotherapy drugs (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.

Somatic (tumour) testing

Immunohistochemical testing of programmed death-ligand 1 (PD-L1) status of triple-negative breast cancer is available within the NHS.

  • Expression of PD-L1 at a level of 1% or more (as assessed using the SP142 antibody assay) confers eligibility for first-line treatment of metastatic, unresectable or locally advanced disease with nab-paclitaxel and the immunotherapy agent atezolizumab.
  • The immunotherapy agent pembrolizumab has been approved by NICE for first-line treatment of metastatic triple-negative breast cancer with a PDL-1 combined positive score of at least 10% (using the 22C3 antibody).
  • Atezolizumab and pembrolizumab are both available via the Cancer Drugs Fund.

Somatic (tumour) testing for NTTRK fusion genes is available for metastatic breast cancer patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted. Other somatic (tumour) testing may be available within clinical trials for metastatic breast cancer.

Patients >25 years with non-CNS solid tumours are now only eligible for whole genome sequencing (WGS) where there is a clear, clinical question and where results have expected utility/impact.

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.

Constitutional (germline) testing

  • For constitutional (germline) testing of patients with breast cancer, the panel to request is R208 (inherited breast cancer and ovarian cancer). This tests for constitutional (germline) variants in BRCA1, BRCA2, PALB2, ATM*, CHEK2*, RAD51C* and RAD51D* (*truncating variants only).
  • For constitutional (germline) testing of patients with HER 2 negative metastatic breast cancer who do not meet the R208 eligibility criteria but would be eligible for PARP inhibitor therapy the panel to request is R444. This tests for constitutional (germline) variants in BRCA1 and BRCA2 only.
  • Constitutional (germline) DPYD testing is requested using test code M3.7.
  • For constitutional (germline) DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomic Laboratory Hub (GLH) for details of test request forms and where to send samples.
  • A record of discussion (RoD) form is required prior to constitutional (germline) tests. It is not currently required for DPYD variant testing.
  • Depending on the details you provide and the test that is chosen, a range of genomic investigation techniques will be applied to your patient’s DNA. These include (but are not restricted to):

Somatic (tumour) testing

  • Immunohistochemical assessment of PD-L1 expression can be arranged with your local pathology service.
  • NTRK fusion gene analysis can be requested as test M3.5. This consists of massively parallel sequencing (sometimes called next-generation sequencing) structural variant analysis.
  • WGS of any solid tumour where the patient has exhausted all standard of care testing and treatment is requested as code M232 (but must be discussed on a case-by-case basis with your local GLH cancer lead).
  • For WGS, you will require:
    • access to a fresh tumour sample and a matched blood (EDTA) sample (WGS requires paired somatic (tumour) and constitutional (germline) DNA analysis);
    • a completed RoD form; and
    • a discussion with your local GLH before submitting samples, to confirm the local test pathway details.
  • 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: 07/01/2026
  • Next review due: 07/01/2027
  • Authors: Dr Nida Pasha, Dr Ellen Copson
  • Reviewers: Dr Amy Frost, Dr Terri McVeigh

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