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Example clinical scenario

A 35-year-old woman is diagnosed with a grade-three oestrogen receptor (ER)-positive, progesterone receptor (PR)-positive, human epidermal growth factor receptor-2 (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 which somatic (tumour) or constitutional (germline) tests are 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 BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM (truncating variants and c.7271T>G only) and CHEK2 (truncating variants only), if they meet at least one of the following criteria:
    • a triple-negative breast cancer diagnosed at <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 and a first-degree relative diagnosed with breast cancer <45 years of age;
    • a pathology-adjusted combined Manchester score ≥15, or a single gene pathology-adjusted Manchester score ≥10, or a CanRisk carrier probability of ≥10%; or
    • Ashkenazi Jewish ancestry and a diagnosis of breast cancer at any age.
  • Women diagnosed with breast cancer ≤30 years of age or a HER-2 positive breast cancer ≤35 years of age are also eligible for testing of the TP53 gene. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
  • PARP inhibitors are licensed for the second-line treatment of metastatic HER2-negative breast cancer in patients with a constitutional (germline) pathogenic variant in BRCA1 or BRCA2. Talazoparib has recently been recommended by NICE for treating HER2-negative, locally advanced or metastatic breast cancer with constitutional (germline) BRCA1 or BRCA2 variants in adults who have had:
    • an anthracycline or a taxane, or both, unless these treatments are not suitable; and
    • endocrine therapy if they have hormone receptor (HR)-positive breast cancer, unless this is not suitable.
  • Consider referral to clinical genetics for any woman with breast cancer (primary or metastatic) who also has a personal and/or family history of endometrial cancer, thyroid cancer, diffuse gastric cancer 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.
  • Women with lobular breast cancer may be eligible for CDH1 testing if they meet one of the following criteria:
    • lobular breast cancer at <70 years of age and diffuse gastric cancer at <70 years;
    • lobular breast cancer and at least one first- or second-degree relative with diffuse gastric cancer (where ≥1 case occurred at <70 years); or
    • two cases of lobular breast cancer at <70 years, such as bilateral or multiple ipsilateral tumours.
  • Patients who are considered for palliative chemotherapy with capecitabine palliative chemotherapy should undergo constitutional (germline) testing of the DPYD gene.
    • If these chemotherapy agents are given at standard doses, the result is serious and sometimes life-threatening toxicity, including diarrhoea, mucositis and skin reactions.

Somatic (tumour) testing

  • Somatic (tumour) testing for PI3KCA variants is available if this information will aid in diagnosis or management.
  • The PI3KCA inhibitor alpelisib is licensed in combination with fulvestrant for the treatment of men and postmenopausal women with ER-positive and HER2-negative locally advanced or metastatic breast cancer with a PIK3CA variant. This treatment is used after disease progression during first-line endocrine-based therapy, and was approved by NICE in July 2022 on the basis of the results from the SOLAR-1 clinical study. It is now 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.
  • Somatic (tumour) variants in ESR1 can result in oestrogen-independent ER activation and are associated with resistance to aromatase inhibitors. The oral selective ER degrader elacestrant has been licenced by the European Medicines Agency for use in postmenopausal women with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 variant who have disease progression following at least one line of endocrine therapy, including a cyclin dependent kinase inhibitor. This license was based on data from the EMERALD trial. Elacestrant is not yet approved by NICE.
  • 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 Inherited breast cancer and ovarian cancer. This tests for constitutional (germline) variants in the genes BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM (truncating variants and c.7271T>G only) and CHEK2 (truncating variants only).
  • Women diagnosed with breast cancer ≤30 years of age or a HER2-positive breast cancer ≤35 years of age are also eligible for TP53 testing (via test code R216 Li Fraumeni syndrome) after appropriate counselling.
  • Patients being considered for palliative chemotherapy with capecitabine palliative chemotherapy should undergo germline DPYD hotspot testing using test code M3.7 DPYD hotspot.
  • 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 for constitutional (germline) tests. Note that this form 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

  • Somatic (tumour) PI3KCA variant testing can be requested as test M3.6 Multi-target NGS panel – small variant (PIK3CA). This is performed as part of a multi-target massively parallel sequencing – also called next-generation sequencing – panel.
  • NTRK fusion gene analysis of the tumour can be requested as test M3.5 Multi-target NGS panel – structural variant (NTRK1, NTRK2, NTRK3). This test consists of massively parallel sequencing structural variant analysis.
  • WGS of solid tumours (where the patient has exhausted all standards-of-care testing and treatment) is requested as test code M232. 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. Before submitting samples for WGS, please discuss with your local GLH 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

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  • Last reviewed: 11/06/2023
  • Next review due: 11/06/2024
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh