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Oncology

Results: Patient with breast cancer and a somatic (tumour) BRCA2 variant

The identification of a somatic (tumour) BRCA2 variant in a patient with metastatic breast cancer may have implications for the clinical management of the patient’s current cancer, as well as for their family members.

Example clinical scenario

A 45-year-old patient with progressive metastatic oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer undergoes a biopsy of her chest wall disease. As part of screening investigations for a clinical trial, the metastatic biopsy is submitted for massively parallel sequencing (sometimes called next-generation sequencing) of a large panel of cancer-related genes. A somatic (tumour) pathogenic variant in the BRCA2 gene is reported.

Impact of the genomic result

Somatic (tumour) BRCA1 and BRCA2 variants in breast cancer

  • Approximately 5%–10% of patients with breast cancer have an underlying constitutional (germline) variant in BRCA1 or BRCA2. The variant will also be present in their tumour DNA, and could therefore be identified as part of somatic (tumour) testing.
  • In addition, somatic (tumour) variants in BRCA1 and BRCA2 that have been acquired by chance by cancer cells will be identified in approximately 3% of breast tumours, in patients with no underlying constitutional (germline) variants in these genes.
  • It is not possible to determine whether a BRCA1 or BRCA2 variant identified in tumour-derived DNA is somatic (tumour-only) or constitutional (germline) in origin without analysis of constitutional (germline) DNA from normal cells (usually lymphocytes from whole blood). Therefore, the finding of a BRCA1 or BRCA2 variant during somatic testing should be followed by constitutional BRCA1 or BRCA2 testing to determine whether the variant is of germline or somatic origin.
  • Some BRCA pathogenic variants are not easily detected with standard somatic (tumour) testing technologies. Therefore, a negative somatic test for BRCA1 and/or BRCA2 variants does not negate the need for constitutional (germline) testing where clinically indicated.
  • The PARP inhibitors olaparib and talazoparib have been licensed for second-line treatment of metastatic HER2-negative breast cancers in patients with a constitutional (germline) pathogenic variant in BRCA1 or BRCA2 based on data from the OlympiAD and EMBRACA trials respectively, but are not currently available in the NHS. Adjuvant olaparib therapy for high-risk HER2-negative early breast cancer with germline pathogenic BRCA1 or BRCA2 variants is recommended by NICE.
  • Although PARP inhibitors are licensed for use in patients with somatic (tumour) BRCA variants in other tumour types, in breast cancer their use is currently limited to patients with constitutional (germline) BRCA variants. Clinical trials are in progress to investigate whether patients with breast cancer harbouring somatic BRCA1 or BRCA2 variants benefit from PARP inhibitors in the absence of constitutional variants.

What do you need to do?

Constitutional (germline) testing

  • Where a BRCA1 or BRCA2 variant has been identified during somatic (tumour) testing, constitutional (germline) testing is required to determine the origin of the variant.
  • Some patients will be eligible for constitutional (germline) testing to check for other variants in BRCA1, BRCA2 and other breast cancer susceptibility genes.
    • 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).
    • Where a variant in BRCA1 or BRCA2 has been identified as part of somatic (tumour) testing of DNA derived from the tumour of a patient with breast cancer, it is crucial that the laboratory be provided with the details of the variant identified during somatic testing, along with details of the technology applied, so that they can comment specifically on the presence or absence of the variant in constitutional (germline) DNA.
    • In the event that the somatic (tumour) testing has been done in a different laboratory from the laboratory arranging constitutional (germline) analysis, a copy of the report should be provided to the second laboratory. The laboratory may also request a representative sample of tumour-derived DNA to use as positive control during testing.
  • If the patient does not otherwise meet criteria for full diagnostic panel testing, site-specific testing for the specific variant can be requested on a constitutional (germline) sample (usually whole blood) under code R240 Diagnostic testing for known mutation(s). The case should be discussed with your local cancer geneticist before requesting constitutional testing.
  • For constitutional (germline) DNA-based tests (all the above listed constitutional tests), an EDTA sample is required. Please refer to your local Genomics Laboratory Hub for details of test request forms and where to send samples.
  • A record of discussion (RoD) form is required prior to constitutional (germline) tests.

Management of the current cancer

  • PARP inhibitors are currently not licenced for treatment of breast cancer patients with a somatic (tumour) BRCA1/ or BRCA2 variant in the absence of a constitutional (germline) variant.
  • However, PARP inhibitors may be accessible in the context of clinical trials.

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

Resources

For clinicians

References:

For patients

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  • Last reviewed: 27/12/2023
  • Next review due: 27/12/2024
  • Authors: Dr Ellen Copson, Dr Taha Khalid
  • Reviewers: Dr Terri McVeigh

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