Presentation: Patient with breast cancer

A 42-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 breast cancer. There is no evidence of metastatic disease. The patient has 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.

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;
  • any 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 diagnosed with breast cancer ≤30 years of age or with HER2-positive 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.
• Treatment with adjuvant olaparib (a PARP inhibitor) is available via the Cancer Drugs Fund for patients with a pathogenic constitutional (germline) BRCA 1 or BRCA2 variant who have completed standard neoadjuvant chemotherapy treatment for a ‘high-risk’ HER2-negative early breast cancer, with ‘high-risk’ defined as follows:
• • ER-negative or HER2-negative primary tumour:
• • • residual disease post-neoadjuvant chemotherapy; or
• • • T2 or N1 if treated with adjuvant chemotherapy;
• • ER positive or HER2-negative primary tumour:
• • • residual disease post-neoadjuvant chemotherapy, where a clinical-pathologic scoring system incorporating ER status and nuclear grade (CPS + EG) score is three or over; or
• • • patients with four or more positive axillary lymph nodes who are treated with adjuvant chemotherapy.
• 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 one or more case(s) 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

• Somatic testing of ER-negative primary breast cancers is currently not routinely available.
• 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 (such as Oncotype DX, Prosignia, EndoPredict) to inform discussions about adjuvant chemotherapy.
• Other somatic (tumour) testing for primary breast cancer may be available via clinical trials.
• Whole genome sequencing (WGS) for triple-negative breast cancer of any stage may be available within the NHS as part of a pilot study.

• 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.
• For information on the genes that 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 (inherited breast cancer and ovarian cancer): This tests for constitutional (germline) variants in BRCA1, BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • Women diagnosed with breast cancer <30 years or age, or with triple-positive (ER+,PgR+, HER2+) breast cancer <35 years of age, are also eligible for TP53 testing (R216) after appropriate counselling.
• A record of discussion (RoD) form is required prior to 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).
• For DNA-based constitutional (germline) 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.
• For tumour profile tests of ER-positive, HER2-negative breast cancers, liaise with your local cellular pathology department to confirm your local contract and request arrangements.
• 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.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• 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: Genetic testing for people who have or have had breast or ovarian cancer
• NICE: Olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy
• NICE: Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer

References:

• Tutt ANJ, Garber JE, Kaufman B and others. ‘Adjuvant olaparib for patients with BRCA1– or BRCA2-mutated breast cancer‘. The New England Journal of Medicine 2021: volume 384, issue 25, pages 2,394–2,405. DOI: 10.1056/NEJMoa2105215

For patients

• Breast Cancer Now: Family history of breast cancer: Managing your risk
• Breast Cancer Now: Olaparib (Lynparza)
• Breast Cancer Now: Oncotype DX
• Cancer Research UK: Inherited genes and cancer types
• Macmillan Cancer Support: Inherited breast and ovarian cancer