Presentation: Patient with breast cancer and a family history of breast cancer

A 39-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. There is no evidence of metastatic disease. The patient reports a family history of breast cancer: her mother died of metastatic breast cancer at the age of 42. You wish to undertake genomic testing and are considering what constitutional (germline) and/or somatic (tumour) is available and appropriate for her.

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 <45 years of age;
  • Ashkenazi Jewish ancestry and breast cancer at any age; or
  • 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.)
• Women who do not meet these eligibility criteria but have high-risk early breast cancer and would potentially benefit from adjuvant olaparib treatment may also be tested for constitutional (germline) BRCA1 and BRCA2 variants. In this context, ‘high-risk’ early breast cancer is defined as:
• • triple-negative breast cancer treated with neo-adjuvant chemotherapy: residual invasive cancer in the breast and/ or lymph nodes;
• • triple-negative breast cancer treated with adjuvant hemotherapy: node-positive or primary tumour ≥ 2cm;
• • ER-positive, HER2-negative breast cancer treated with neoadjuvant chemotherapy: residual invasive cancer in the breast and/ or lymph nodes and a CPS + EG score of ≥3; or
• • ER-positive, HER2-negative breast cancer treated with adjuvant chemotherapy: four or more pathologically confirmed positive lymph nodes.
• Women diagnosed with breast cancer ≤30 years of age or 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 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 cleft lip or palate, macrocephaly, mucocutaneous lesions or a history of intussusception, which may be features of an underlying syndromic cause of a breast cancer predisposition syndrome.
• Women with lobular breast cancer may be eligible for CDH1 testing if they meet one of the following criteria:
• • lobular breast cancer <70 years of age and diffuse gastric cancer <70 years of age;
• • lobular breast cancer and ≥1 first- or second-degree relative with diffuse gastric cancer (with ≥1 case occurring <70 years of age); or
• • two cases of lobular breast cancer <70 years of age, such as bilateral or multiple ipsilateral tumours.

Somatic (tumour) testing

• No somatic (tumour) testing is currently available within the NHS solely on the basis of a positive family history of breast cancer.
• Selected ER-positive, HER2-negative, lymph node-negative breast cancers with an intermediate risk of distant recurrence (using a validated tool such as Predict or the Nottingham Prognostic Index) are eligible for tumour profile testing (for example, Oncotype DX, Prosignia, EndoPredict) to inform discussions about adjuvant chemotherapy.
• Other somatic (tumour) testing for primary breast cancer may be available within clinical trials.

• Consult the National Genomic Test Directory eligibility criteria to ensure that your patient is eligible for testing. You can also refer to a spreadsheet containing details of all available tests.
• To find out which genes are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service Signed Off Panels Resource.
• For constitutional (germline) testing of patients with breast cancer, the panel to request is:
  • R208: This tests for constitutional (germline) variants in BRCA1 and BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • Women diagnosed with breast cancer <30 years of age and women diagnosed with triple-positive (ER-positive, progesterone receptor (PR)-positive, HER2-positive) breast cancer <35 years of age are also eligible for TP53 testing (R216) after appropriate counselling.
• For patients who do not meet the R208 eligibility criteria but who have high-risk early breast cancer as defined above and would potentially benefit from adjuvant olaparib therapy, the test to request is:
  • R444.1: This tests for constitutional (germline) variants in BRCA1 and BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
• For constitutional (germline) DNA-based tests (all the above listed tests), an EDTA sample is required. Please refer to your local Genomic Laboratory Hub for details of test request forms and where to send samples.
• A record of discussion form is required prior to requesting constitutional (germline) tests.
• 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 and/or their family’s DNA. These tests include (but are not restricted to):
  • single gene sequencing;
  • gene panel sequencing; and
  • multiplex ligation-dependent probe amplification (MLPA).

• The tumour profile genomic tests detailed above can be requested using the following codes:
  • M3.2 Multi-target expression array (Oncotype DX);
  • M3.3 Multi-target expression array (EndoPredict); and
  • M3.4 Multi-target expression array (Prosignia).
• These somatic (tumour) genomic tests are all performed on formalin-fixed tumour samples. Liaise with your local cellular pathology department to confirm your local contract and request arrangements.
• 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

• Mainstreaming Cancer Genetics: BRCA toolkit
• NHS England: National Genomic Test Directory (note that somatic (tumour) tests are listed in the test directory for cancer, while constitutional (germline) tests are listed in the test directory for rare and inherited disease)
• NICE: Guidance on genetic testing for patients with breast and ovarian cancer

For patients

• Breast Cancer Now: Family history of breast cancer: Managing your risk
• Cancer Research UK: Inherited genes and cancer types
• Macmillan Cancer Support: Inherited breast and ovarian cancer