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Example clinical scenario

A 35-year-old woman is diagnosed with a grade 3 ER-positive, PR-positive and HER2-negative breast cancer. Staging investigations reveal metastases in her bones. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) or somatic (tumour) testing is available and appropriate for her. 

When to consider genomic testing

Constitutional (germline) testing

  • Women with breast cancer or high-grade ductal carcinoma in situ (primary or metastatic) are eligible for constitutional (germline) genomic testing of the BRCA1, BRCA2PALB2, 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;
    • breast cancer (grade 2 or higher) diagnosed <40 years;
    • bilateral breast cancer and both cancers diagnosed <50 years;
    • breast cancer <45 years and a first-degree relative with breast cancer <45 years;
    • Ashkenazi Jewish ancestry and breast cancer at any age; or
    • pathology-adjusted Manchester score ≥15 or CanRisk carrier probability of ≥10%. (These tools can be used to calculate risks. If you are not confident to do so, seek support from your local clinical genetics service.)
  • Women diagnosed with breast cancer ≤30 years or HER2-positive breast cancer ≤35 years are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
  • PARP inhibitors have been licensed in Europe for the second line treatment of metastatic triple negative breast cancer with an underlying germline pathogenic variant in BRCA1/BRCA2 but have not yet been approved by NICE for use in the NHS. They may be available in the context of clinical trials.
  • Consider referral to 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 cleft lip/palate, macrocephaly, mucocutaneous lesions, or a history of intussusception, which may be features of an underlying syndromic cause of breast cancer predisposition.
  • Women with lobular breast cancer may be eligible for CDH1 testing if they meet one of the following criteria:
    • lobular breast cancer <70 years and diffuse gastric cancer <70 years;
    • lobular breast cancer and ≥first-degree/second-degree relative has diffuse gastric cancer (≥ 1 case occurred < 70 years); and/or
    • two cases of lobular breast cancer <50 years, such as bilateral or multiple ipsilateral tumours.
  • Patients who are considered for palliative chemotherapy with capecitabine palliative chemotherapy should undergo germline testing of the dihydropyrimidine dehydrogenase (DPYD) gene.
    • Certain variants in the DPYD gene result in a deficiency of the enzyme DPD (dihydropyrimidine dehydrogenase) and a subsequent reduction in metabolism of fluoropyrimidine chemotherapy drugs (for example, 5-FU 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

  • Somatic (tumour) testing for PI3KCA mutations is available if this information will aid diagnosis or management.
  • The PI3KCA mutation inhibitor alpelisib is licensed in combination with fulvestrant for the treatment of postmenopausal women, and men, with ER-positive, HER2-negative locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine-based therapy.
    • This treatment is currently being reviewed by NICE; a free of charge access scheme is available in the meantime.
  • 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 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) in order to explore clinical trial options.

What do you need to do?

Constitutional (germline) testing:

  • For constitutional (germline) testing of patients affected with breast cancer, the panel to request is:
    • R208: This tests for constitutional (germline) mutations in BRCA1 and BRCA 2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • Women diagnosed with breast cancer <30 years, or women <35 with triple positive (ER-positive, PgR-positive, HER2-positive) breast cancer are also eligible for TP53 testing (R216) after appropriate counselling.
  • Patients being considered for palliative chemotherapy with capecitabine palliative should undergo germline DPYD hotspot testing 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 Genomics Laboratory Hub (GLH) for details of test request forms and where to send samples.
  • A record of discussion (RoD) form is required for constitutional (germline) tests. If you have not completed a RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form. An RoD form is currently not required for DPYD mutation testing.
  • Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s/their family’s (if appropriate) DNA. These tests include (but are not restricted to):

Somatic (tumour) testing

  • Somatic (tumour) PI3KCA mutation testing can be requested as test M3.6.
    • This is performed as part of a multi-target NGS panel.
  • NTRK fusion gene analysis of the tumour can be requested as test M3.5.
    • This consists of NGS 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 requires access to a fresh tumour sample and a matched blood (EDTA) sample for germline testing.
    • An RoD must be completed for this investigation. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.


For clinicians


Tagged: Breast cancer

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  • Last reviewed: 28/03/2023
  • Next review due: 28/03/2024
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh