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Oncology

Presentation: Patient with breast cancer who has had direct-to-consumer (DTC) genomic testing

DTC testing is not considered clinically valid, and results from such testing should not be used to guide management. Results from such tests should be validated through formal diagnostic laboratories. NHS-funded validation of results is available for individuals meeting criteria for constitutional (germline) testing.

Example clinical scenario

A 45-year-old woman is diagnosed with localised triple-negative breast cancer. There is no significant family history of cancer. She undergoes constitutional (germline) genomic testing as per national guidance and no pathogenic variants are found in BRCA1, BRCA2 or PALB2. She undergoes mastectomy and returns to the oncology clinic to discuss adjuvant treatment. She informs you that she has had a constitutional (germline) direct-to-consumer (DTC) genomic test which shows a pathogenic variant in the BRCA1 gene.

When to consider genomic testing

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* and CHEK2* genes (*truncating variants and exception variants only) if they meet at least one of the following criteria:
    • Breast cancer (age <40 years).
    • Bilateral breast cancer (age <60 years).
    • Triple negative breast cancer (age <60 years).
    • Assigned male at birth and affected with breast cancer (any age).
    • Breast cancer (age <45 years) and a first-degree relative with breast cancer (age <45 years).
    • Combined pathology-adjusted Manchester score ≥15 or single gene pathology adjusted score of ≥10 or BOADICEA/CanRisk score ≥10%.
    • Ashkenazi Jewish/Westray (Orkney) or Walsay (Shetland) ancestry and breast cancer at any age.
  • Women with early-stage breast cancer not otherwise fulfilling testing for constitutional (germline) testing may be eligible for constitutional testing of BRCA1 and BRCA2 if treatment with PARP inhibitors is being considered (R444.1)
  • Women diagnosed with breast cancer ≤30 years or HER2-positive breast cancer ≤35 years are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
  • Consider a 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/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 and ≥first-/second-degree relative has diffuse gastric cancer (≥1 case occurred <70 years).
    • Family history of two or more cases of lobular breast cancer.
    • Bilateral lobular breast cancer <70 years.

What are the pitfalls of DTC testing in this situation?

  • High false positive rates have been reported for rare variants detected following analysis of raw DTC sequencing data by a third-party company. Variants identified in this manner should be validated in a clinical laboratory before any change in management is recommended. At present, however, validation of DTC results is not routinely funded by the NHS unless the patient would otherwise meet criteria for germline genomic testing, but testing may be considered in exceptional circumstances (depending on the test technology and analytical sensitivity) following discussion at a specialist MDT with a cancer geneticist present
  • Conversely, a ‘negative’ DTC test should not replace the need for formal constitutional (germline) genomic testing in those women fulfilling eligibility criteria, as many DTC tests offer testing of only certain variants in certain genes rather than full sequencing (for example, some DTC tests will check only for the three Ashkenazi Jewish founder variants in BRCA1 or BRCA2, and will not detect the thousands of other potential pathogenic variants that have been reported in these genes).

What do you need to do?

  • Do not assume that the DTC testing that has been done is complete or that the results are accurate.
  • No clinical action should be taken based on results from DTC testing – formal confirmation of result (if appropriate) is required before any clinical decisions are made.
  • Only results that have been obtained from a clinical diagnostic laboratory should be used to determine management or plan preventative strategies.
  • In this case, as an NHS diagnostic test has already been performed, it may be helpful to contact the NHS laboratory directly to confirm that no pathogenic variants were identified, making sure to include details of the variant, and, ideally, a copy of the DTC report. It may provide reassurance to both you and the patient.
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 18/11/2024
  • Next review due: 18/11/2025
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh

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