Presentation: Patient with prostate cancer

A 70-year-old man is diagnosed with prostate cancer. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) and somatic (tumour) genomic testing is available and appropriate for him.

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 in the following circumstances:
  • Prostate cancer diagnosed at <50
  • Prostate cancer in an individual with Ashkenazi Jewish ancestry
  • Metastatic prostate cancer diagnosed at <60 years
  • Proband with prostate cancer and a family history of prostate cancer, such that the CanRisk estimated likelihood of detecting a pathogenic variant in one of these genes is at least 10%. (This tool can be used to calculate risks. If you are not confident to do so, 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 evidence of mismatch repair deficiency or microsatellite instability in the tumour.
• Much of the heritable basis of prostate cancer is thought to be polygenic. Testing of polygenic risk scores is currently not available outside of research studies.
• 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, such that the pathology-adjusted Manchester score is at least 15 and/or the CanRisk estimated likelihood of detecting a pathogenic variant in one of these genes is 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 pathogenic variant. Broader constitutional (germline) testing is available as part of a number of clinical trials ongoing in prostate cancer.
• If, during tumour testing, a pathogenic variant is identified in a gene that is known to be associated with prostate cancer predisposition (such as in BRCA1/BRCA2), then constitutional (germline) testing for the same variant is appropriate to determine if of germline origin. A negative somatic (tumour) based genomic test does not replace the need for constitutional germline testing in those individuals fulfilling the testing criteria, as somatic testing is unlikely to detect large genomic rearrangements.
• Much of the heritable basis of prostate cancer is thought to be polygenic. Testing of polygenic risk scores is currently not available outside of research studies.

Somatic (tumour) testing

• All men with prostate cancer are eligible for somatic (tumour) testing of the BRCA1 and BRCA2 genes. Men with metastatic castrate-resistant prostate cancer are also eligible for ATM and CDK12 somatic gene testing.
• 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.
• PARP inhibitors are currently not available in the NHS for treatment of prostate cancer outside of clinical trials, but olaparib treatment for metastatic prostate cancer with a BRCA1 or BRCA2 pathogenic somatic mutation is currently the subject of a review by NICE.
• Somatic (tumour) testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic prostate cancer patients as an biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• The fusion gene TMPRSS2-ERG is found in around 50% of prostate cancers; somatic testing for this fusion gene can be requested if there is diagnostic uncertainty with prostate cancer among the differentials.
• Additional somatic 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) in order to explore clinical trial options.

• Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing. You can also refer to this spreadsheet 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.
• Decide which of the panels best suits the needs of your patient. For patients affected with prostate cancer, the current options are:
  • M218.1 Multi-target next-generation sequencing (NGS) panel: BRCA1 and BRCA2 for all patients with prostate cancer. In addition, ATM and CDK12 for patients with metastatic castrate-resistant prostate cancer.
  • 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).
    • M218.3 FISH (TMPRSS2-ERG).
  • PanelApp: Prostate cancer pertinent cancer susceptibility
• For constitutional (germline) genomic tests for patients affected with prostate cancer, the current options are:
  • R208 (Inherited breast cancer and ovarian cancer) for living affected individuals affected with prostate cancer at any age with a family history of breast, ovarian, prostate or pancreatic cancer fulfilling eligibility criteria. This tests for constitutional pathogenic variants in BRCA1, BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • Constitutional (germline) testing for variants found in somatic testing to determine if of germline origin is requested as R240: Diagnostic testing for known mutation(s).
• A record of discussion (RoD) form is required prior to arranging constitutional (germline) genomic testing. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s/their family’s (if appropriate) DNA. These include (but are not restricted to):
  • Single gene
  • Gene panel
  • MLPA
• For DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub (GLH) for details of test request forms and where to send samples.
• WGS of solid tumours where the patient has exhausted all standards of care testing and treatment is requested as code M232. WGS requires access to a fresh tumour sample and a matched EDTA blood sample for germline testing. An RoD must be completed for this investigation – see how to complete an RoD form. 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.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease)
• NICE: Guidance on olaparib for previously treated, hormone-relapsed metastatic prostate cancer with homologous recombination repair gene mutations 

References:

• Cimadamore A, Lopez-Beltran A, Massari F and others. ‘Germline and somatic mutations in prostate cancer: focus on defective DNA repair, PARP inhibitors and immunotherapy‘. Future Oncology 2020: volume 16, issue 5, pages 75–80. DOI: 10.2217/fon-2019-0745
• Compérat E, Wasinger G, Oszwald A and others. ‘The Genetic Complexity of Prostate Cancer‘. Genes 2020: volume 11, issue 12, page 1,396. DOI: 10.3390/genes11121396
• De Bono J, Mateo J, Fizazi K and others. ‘Olaparib for metastatic castration-resistant prostate cancer‘. New England Journal of Medicine 2020: volume 382, issue 22, pages 2,091–2,102. DOI: 10.1056/NEJMoa1911440
• Ni Raghallaigh H, Eeles R. ‘Genetic predisposition to prostate cancer: an update‘. Familial Cancer 2022: issue 22, pages 101–114.  DOI: 10.1007/s10689-021-00227-3

For patients

• Prostate Cancer UK: Are You At Risk?
• Prostate Cancer UK: BRCA genes myth busters