Presentation: Patient with ovarian cancer

A 64-year-old woman is diagnosed with high-grade serous ovarian 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 her.

Constitutional (germline) testing

• All women with high-grade non-mucinous epithelial ovarian cancer (at any age) are eligible for constitutional (germline) testing of a number of genes associated with ovarian cancer susceptibility as part of a multigene panel. At present, the panel includes BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1, MLH1, MSH2 and MSH6 genes.

Somatic (tumour) testing

• Somatic testing for BRCA1 and BRCA2 is available for all patients with a known high-grade serous ovarian cancer.
• If, during tumour testing, a pathogenic variant is identified in a gene that is known to be associated with ovarian cancer predisposition (such as BRCA1/BRCA2), then constitutional (germline) testing for the same variant is appropriate to determine if it is of germline origin, if constitutional testing has not already been undertaken. Patients with high-grade non-mucinous ovarian cancer are eligible for more comprehensive constitutional genomic testing, however. A negative tumour-based genomic test does not replace the need for constitutional testing in those individuals fulfilling constitutional genomic testing criteria, as somatic testing is unlikely to detect large genomic rearrangements.
• Tumour-based homologous repair deficiency testing is now available for patients with high-grade serous ovarian cancer being considered for first line PARP inhibitor treatment.
• Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic ovarian cancer patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• Other somatic testing may be available to help in identifying suitable clinical trials. Please refer to the National Genomic Test Directory for more information.
• Paired constitutional and tumour-based whole genome sequencing (WGS) is being rolled out for patients with high-grade serous ovarian cancer on a pilot basis in scenarios where the test will guide diagnosis and management. You should seek advice from your local Genomic Laboratory Hub (GLH) as to whether this is available in your region.
• In addition, all patients with solid tumours who have exhausted all standards of care testing and treatment are eligible for WGS in order to explore clinical trial options.
• In cases where histochemical confirmation is not possible, genomic testing of FOXL2, CTNNB1, APC and DICER1 can be requested to assist with the diagnosis of an ovarian sex cord stromal tumour.
• Where available, testing of the tumour for somatic BRCA1/BRCA2 variants can be requested as test M2.1. This consists of next-generation sequencing (NGS) small variant analysis.
• Testing of the tumour for homologous repair deficiency can be requested as test M2.5
• NTRK fusion gene analysis of the tumour can be requested as test M2.3, which uses NGS structural variant analysis.
• Testing of the tumour for FOXL2, CTNNB1, APC and DICER1 variants can be requested as test M245.1. This consists of NGS small variant analysis.

• Consult the National Genomic Test Directory to ensure your patient is eligible for testing. All tumour-based tests and indications, along with indications for DYPD testing, can be found in the test directory for cancer, while constitutional (germline) tests and testing criteria for cancer are outlined in the test directory for rare and inherited disease, and eligibility criteria document.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• 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.
• For constitutional (germline) genomic tests, decide which of the panels best suits the needs of your patient. For patients affected with ovarian cancer, the current options are:
  • R207 (inherited ovarian cancer (without breast cancer)) for living affected individuals with high-grade non-mucinous epithelial ovarian cancer and a family history of ovarian cancer that meets the criteria. This is a constitutional (germline) inherited ovarian cancer gene panel. You can view this up-to-date list of the genes included in this panel.
  • R208 (inherited breast cancer and ovarian cancer) for living affected individuals with ovarian cancer at any age and a family history of breast, ovarian, prostate or pancreatic cancer. This tests for constitutional (germline) variants in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM* and CHEK2* (*truncating variants only).
• A record of discussion (RoD) form is required. 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.
• For DNA-based constitutional (germline) tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local GLH for details of test request forms and where to send samples.
• Where available, testing of the tumour for somatic BRCA1/BRCA2 variants can be requested as test M2.1. This consists of next-generation sequencing (NGS) small variant analysis.
• Testing of the tumour for homologous repair deficiency can be requested as test M2.5. This consists of mutational signature detection.
• NTRK fusion gene analysis of the tumour can be requested as test M2.3. This consists of NGS structural variant analysis.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied. These include (but are not restricted to):
  • Single gene
  • Gene panel
  • MLPA
• WGS for high-grade serous ovarian cancer of any stage (pilot study) can be requested as code M233.1. 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 blood (EDTA) 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

• Mainstreaming Cancer Genetics: BRCA toolkit
• 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 genetic testing for patients with breast and ovarian cancer
• NICE: Guidance on ovarian cancer therapies
• Online Mendelian Inheritance in Man (OMIM): # 114480, # 604370, # 612555 and # 167000

References:

• Chandrasekaran D and Manchanda R. ‘Germline and somatic genetic testing in ovarian cancer patients‘. British Journal of Obstetrics and Gynaecology 2018: volume 125, issue 11, page 1,460. DOI: 10.1111/1471-0528.15225

For patients

• Ovarian Cancer Action: Genetic testing resources
• Royal Marsden NHS Foundation Trust: Beginner’s guide to BRCA (PDF, 48 pages)
• Target Ovarian Cancer: Genetic testing and hereditary ovarian cancer – a guide for women with ovarian cancer and their families (PDF, 27 pages)