Skip to main content
Public beta This website is in public beta – please give your feedback.

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) if they meet at least one of the following criteria:
    • triple-negative breast cancer diagnosed <60 years of age;
    • breast cancer diagnosed <40 years of age;
    • bilateral breast cancer, with both cancers diagnosed <50 years of age;
    • breast cancer diagnosed <45 years of age and a first-degree relative with breast cancer diagnosed <45 years of age;
    • Ashkenazi Jewish ancestry and breast cancer at any age; or
    • combined pathology-adjusted Manchester score of ≥15 or CanRisk carrier probability of ≥10%. (These tools can be used to calculate risks. If you are not confident in using them, seek support from your local clinical genetics service.)
  • 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 has recently been approved by NICE and is now 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. ER-positive patients should have received prior endocrine treatment (again, unless this is unsuitable).
  • Women diagnosed with breast cancer ≤30 years of age, or with HER2-positive breast cancer ≤35 years of age, are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
  • 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 the European Medicines Agency 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), and is also now approved by NICE and available via the Cancer Drugs Fund.
  • Somatic (tumour) testing for NTRK1, NTRK2 and NTRK3 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.
  • All patients with solid tumours who have exhausted all standards-of-care testing and treatment are eligible for whole genome sequencing (WGS) to explore clinical trial options. In addition, patients with triple-negative breast cancer of any stage are currently eligible for WGS in the context of a pilot study.

What do you need to do?

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).
  • Constitutional (germline) testing of TP53 is requested using the code R216 after appropriate counselling.
  • 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 solid tumours where the patient has exhausted all standards-of-care testing and treatment is requested as code M232.
  • WGS for triple-negative breast cancer of any stage (pilot study) can be requested as code M234.
  • WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for constitutional (germline) testing. An RoD 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.
  • 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


For patients

Tagged: Breast cancer

↑ Back to top
  • Last reviewed: 06/02/2024
  • Next review due: 06/02/2025
  • Authors: Dr Nida Pasha
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh