Results: Patient with breast cancer and a constitutional (germline) BRCA1 or BRCA2 variant

A 44-year-old woman is diagnosed with a grade-two oestrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative T2N0M0 left-sided breast cancer. She has a strong family history of breast cancer and is referred for constitutional (germline) testing of the breast cancer susceptibility genes. The National Genomic Test Directory R208 panel is performed, testing for variants in BRCA1, BRCA2 and PALB2 and for truncating variants in ATM, CHEK2, RAD51C and RAD51D. A pathogenic variant in the BRCA2 gene is reported.

• BRCA1 and BRCA2 are large genes in which multiple different types of pathogenic variants have been identified.
• Constitutional (germline) pathogenic variants in BRCA1 and BRCA2 are associated with a high risk of breast, ovarian, prostate, pancreatic and other cancers.
• For the female patient in this scenario, as well as an increased risk of a second primary breast cancer, the estimated lifetime risk of ovarian cancer is 17%, compared with 1.6% in the general population. Her estimated lifetime risk of pancreatic cancer is 2.3%–3%, compared with 1% in the general population.

Management of the current cancer

• An underlying pathogenic constitutional (germline) variant in a BRCA1 or BRCA2 gene, and the associated risks of future breast cancers, should be taken into consideration when discussing breast surgery options for the primary breast cancer.
• Radiotherapy is not contraindicated in patients with constitutional (germline) BRCA1 variants based on current evidence.
• 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 and a ‘high-risk’ ER-positive, HER2-negative early breast cancer who have completed standard neoadjuvant chemotherapy treatment. For this indication, ‘high risk’ is defined as:
  • patients who have not had a pathological complete response, and whose clinical-pathologic scoring system incorporating oestrogen receptor status and nuclear grade (CPS + EG) score is three or over, following neoadjuvant treatment; and
  • patients with four or more positive axillary lymph nodes who have not received neoadjuvant chemotherapy following surgery and adjuvant chemotherapy.
• In the metastatic setting, NICE has recently recommended use of the PARP inhibitor talazoparib to treat HER2-negative, locally advanced or metastatic breast cancer in patients with constitutional (germline) BRCA1 or BRCA2 variants who have had:
  • an anthracycline or a taxane, or both, unless these treatments are not suitable; and
  • endocrine therapy if the patient has hormone receptor-positive breast cancer, unless this is not suitable.

Further somatic (tumour) testing

The somatic (tumour) testing options are outlined below.

• Test directory codes M3.2, M3.3 and M3.4 should be requested for tumour profile tests of intermediate-risk ER-positive, HER-2 negative early breast cancers (these are multi-target expression array tests).
• Patients with ER-positive, HER2-negative, lymph node-negative early breast cancer with an intermediate risk of recurrence are eligible for multi-target expression array testing of their tumour. This may provide additional information to guide decision-making around adjuvant chemotherapy. The most common tests available are Prosigna, Oncotype Dx and Endopredict, which are approved by NICE. The tests generate a score that suggests the additional benefit from adjuvant chemotherapy. The choice of test used will depend on local arrangements.
• These genomic tests are performed on formalin-fixed breast cancer tissue samples. You should contact your local cellular pathology department to confirm local contract and request arrangements.

Management of the patient’s risk of further primary cancers

• Individuals with inherited genetic alterations associated with high risk of cancer can manage their cancer risk through a combination of surveillance, risk-reducing surgery and other techniques. The exact advice provided to those with gene alterations will be individualised, depending on their result and associated cancer risk, as well as on the treatment and overall prognosis of their current cancer.

Management of the family’s risk

• Cancer predisposition associated with BRCA1 and BRCA2 constitutional (germline) variants is inherited in an autosomal dominant pattern. Biallelic variants in BRCA2 are associated with Fanconi anaemia, which may be relevant for family planning in individuals of child-bearing age in consanguineous relationships.
• First-degree relatives (children or siblings) of an individual with an inherited pathogenic variant in BRCA1 or BRCA2 are at a 50% risk (one in two) of inheriting the familial variant. Because most pathogenic BRCA1 and BRCA2 variants are inherited from a parent, the parents of an affected individual should also be offered genomic testing.
• Patients with breast cancer found to have a constitutional (germline) BRCA1 or BRCA2 variant should be referred to clinical genetics to discuss implications of the result for them and for their family members, and to facilitate cascade testing of relatives.

Family planning implications

• The Human Fertilisation and Embryology Authority have approved the use of preimplantation genetic testing (formerly called preimplantation genetic diagnosis) for couples in whom one or both intended parents have a likely pathogenic or pathogenic variant in BRCA1 or BRCA2.
• Other options may include prenatal testing (invasive, or non-invasive if the potential father has the variant) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

For clinicians

• NHS England: National Genomic Test Directory
• NICE: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• NICE: Olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy
• NICE: Talazoparib for treating HER2-negative advanced breast cancer with germline BRCA mutations
• NICE: Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer
• UK Cancer Genetics Group: BRCA2 germline pathogenic variant carriers management guidelines for healthcare professionals (PDF, one page)

References:

• Marmé F, Lederer B, Blohmer JU and others. ‘Utility of the CPS + EG staging system in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with neoadjuvant chemotherapy‘. European Journal of Cancer 2016: volume 53, pages 65–74. DOI: 10.1016/j.ejca.2015.09.022
• Litton JK, Rugo HS, Ettl J and others. ‘Talazoparib in patients with advanced breast cancer and a germline BRCA mutation‘. The New England Journal of Medicine 2018: volume 379, issue 8, pages 753–763. DOI: 10.1056/NEJMoa1802905
• 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: Breast cancer in families
• Breast Cancer Now: EndoPredict
• Breast Cancer Now: PARP inhibitors in breast cancer treatment
• Breast Cancer Now: Oncotype DX
• Breast Cancer Now: Prosigna
• The Royal Marsden NHS Foundation Trust: A beginner’s guide to BRCA1 and BRCA2