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Oncology

Presentation: Patient with prostate cancer

Genomic testing in prostate cancer can affect clinical management of the patient’s current cancer, as well as of their future cancer risk and that of their relatives.

Example clinical scenario

A 48-year-old man has been diagnosed with prostate cancer. There is no significant family history of cancer. You wish to undertake genomic testing and are considering which constitutional (germline) and somatic (tumour) tests are available and appropriate for him.

When to consider genomic testing

Constitutional (germline) testing

  • Constitutional (germline) genomic testing of BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, ATM* and CHEK2* (*truncating variants only) is available for individuals with prostate cancer who meet one of the following eligibility criteria:
    • prostate cancer diagnosed at <50 years of age;
    • prostate cancer in an individual with Ashkenazi Jewish ancestry;
    • metastatic prostate cancer diagnosed at <60 years of age;
    • proband with prostate cancer and a family history of prostate cancer, with a CanRisk estimated likelihood of detecting a pathogenic variant in one of the above genes of at least 10%. (CanRisk is a tool that can be used to calculate risks. If you are not confident in using it, seek support from your local clinical genetics service.)
  • Prostate cancer is increasingly being recognised as a Lynch syndrome-associated cancer. Consider referral to clinical genetics if the affected individual has a strong family history of colorectal, endometrial or other Lynch syndrome-associated cancers, or if there is demonstrated evidence of mismatch repair deficiency and/or microsatellite instability in the tumour.
  • Constitutional (germline) genomic testing of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM* and CHEK2* (*truncating variants only) is available for individuals with prostate cancer and a family history of breast, ovarian, prostate or pancreatic cancer, with a pathology-adjusted Manchester score of at least 15 and/or a CanRisk estimated likelihood of detecting a pathogenic variant in one of the above genes of at least 10%.
    • Age of diagnosis and family history of prostate cancer will be important factors that are likely to influence a patient’s chance of carrying a relevant constitutional (germline) pathogenic variant. Broader constitutional testing is available as part of a number of ongoing clinical trials.
  • If, during somatic (tumour) testing, a pathogenic variant is identified in a gene that is known to be associated with prostate cancer predisposition (such as in BRCA1 or BRCA2), constitutional (germline) testing for the same variant is appropriate to determine whether the variant is of germline origin. A negative somatic-based genomic test does not replace the need for germline testing in those individuals who fulfil the testing criteria, as somatic testing is unlikely to detect large genomic rearrangements.
  • Much of the heritable basis for prostate cancer is thought to be polygenic. Testing of polygenic risk scores is currently not available outside of research studies.

Somatic (tumour) testing

  • Patients with metastatic castration-resistant prostate cancer who are potentially eligible for treatment with a PARP inhibitor can have testing for BRCA1 and/or BRCA2 variants performed on tumour tissue.
  • Data from the PROfound clinical study indicates that in patients with metastatic castration-resistant prostate cancer who experienced disease progression while receiving enzalutamide or abiraterone, and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival than either enzalutamide or abiraterone.
  • Treatment with the PARP inhibitor olaparib has now been approved by NICE for patients with metastatic castration-resistant prostate cancer with a BRCA1 or BRCA2 pathogenic somatic (tumour) or constitutional (germline) variant, and is available via the Cancer Drugs Fund.
  • If somatic (tumour) testing for BRCA1 and/or BRCA2 variants is unsuccessful (for example, the tissue sample is found to be inadequate) in the context of a metastatic castration-resistant prostate cancer patient potentially eligible for PARP inhibitor treatment, constitutional (germline) BRCA1 and/or BRCA2 testing may be requested, even for those patients not otherwise fulfilling eligibility criteria for constitutional testing.
  • Somatic (tumour) testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic prostate cancer patients as a biomarker for treatment with an NTRK inhibitor if all other approved lines of treatment have been exhausted.
  • The TMPRSS2-ERG fusion is found in around 50% of prostate cancers; somatic (tumour) testing for this fusion can be requested if there is diagnostic uncertainty, with prostate cancer among the differentials.
  • Additional somatic (tumour) testing is mostly only available as part of a clinical trial or with pharmaceutical company funding.
  • All patients with solid tumours who have exhausted all standards-of-care testing and treatment are eligible for whole genome sequencing (WGS) to explore clinical trial options.

What do you need to do?

Constitutional (germline) testing

  • For constitutional (germline) testing of patients with prostate cancer, the current options are as follows.
    • R430 Inherited prostate cancer. The test directory eligibility criteria states that this test code should be used to request testing for ‘living affected individuals’ who fulfil the criteria outlined above. You can find more details about the R430 panel in the NHS GMS Signed Off Panels Resource.
    • R208 Inherited breast cancer and ovarian cancer. The test directory eligibility criteria states that this test code should be used to request testing for living affected individuals with prostate cancer at any age and a family history of breast, ovarian, prostate or pancreatic cancer. It tests for higher-risk constitutional (germline) pathogenic variants in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM and CHEK2.
    • R240 Diagnostic testing for unknown mutation(s). This should be requested when you require constitutional (germline) testing for variants found during somatic (tumour) testing to determine whether the variant is of germline origin.
    • R444 NICE-approved PARP inhibitor treatment. This tests for constitutional (germline) pathogenic variants in BRCA1 and/or BRCA2, and should be used if the patient has metastatic castration-resistant prostate cancer and is potentially eligible for PARP inhibitor therapy, if somatic (tumour) testing for BRCA1 and/or BRCA2 variants has failed and if the patient does not otherwise qualify for R430 panel testing.
  • A record of discussion form is required prior to arranging constitutional (germline) genomic testing.
  • For DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomic Laboratory Hub for details of test request forms and where to send samples.

Somatic (tumour) testing

For somatic (tumour) testing in patients with prostate cancer, the current options are as follows.

  • M218.1 Multi-target NGS panel. This tests for pathogenic variants in BRCA1 and BRCA2 in patients with a diagnosis of metastatic castration-resistant prostate cancer who are potentially eligible for PARP inhibitor therapy. It uses massively parallel sequencing (sometimes called next-generation sequencing).
  • M218.2 Multi-target NGS panel for NTRK1, NTRK2 and NTRK3 structural variants.
  • If there is any doubt about the aetiology of the tumour based on morphology and prostate cancer is in the differential, further panels can be used:
    • M218.2 Multi-target NGS panel (TMPRSS2-ERG, NTRK1, NTRK2, NTRK3); and
    • M218.3 Fluorescent in situ hybridisation (FISH) (TMPRSS2-ERG).
  • 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 include (but are not restricted to):
  • WGS of solid tumours where the patient has exhausted all standards-of-care treatment is requested as code M232. WGS requires access to a fresh tumour sample and a matched EDTA blood sample for constitutional (germline) testing. An RoD form must be completed for this investigation. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.
  • 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: 07/12/2023
  • Next review due: 07/12/2024
  • Authors: Dr Georgina Wood
  • Reviewers: Dr Ramsay Bowden, Dr Ellen Copson, Dr Terri McVeigh, Dr Amal Singh

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