Example clinical scenario
A 42-year-old woman is diagnosed with locally advanced lobular breast cancer (ER positive, HER2 negative), and is undergoing neoadjuvant chemotherapy prior to proposed surgical resection. She mentions that her brother, aged 38, has recently been diagnosed with diffuse gastric cancer, a condition her uncle died of in his 20s. You wish to consider constitutional (germline) genomic testing for the hereditary diffuse gastric cancer gene CDH1, given the patient’s diagnosis and family history.
When to consider genomic testing
Constitutional (germline) testing
- Hereditary diffuse gastric cancer is characterised by diffuse gastric cancer or lobular breast cancer, a family history of one or more first-/second-degree relatives with diffuse gastric cancer, and the identification of a pathogenic, constitutional (germline) CDH1 variant.
- Hereditary lobular breast cancer is characterised by lobular breast cancer or a family with one or more cases of lobular breast cancer in first-degree relatives (FDR) or second-degree relatives (SDR) but no history of diffuse gastric cancer, and the identification of a pathogenic, constitutional (germline) CDH1 variant.
- Constitutional (germline) testing of CDH1 should be offered to individuals affected by diffuse gastric or lobular breast cancer if they fulfil one of the following criteria:
- double primary diffuse gastric cancer and lobular breast cancer (both <70 years old);
- lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥1 case occurred <70 years); or
- two cases of lobular breast cancer <70 years, such as bilateral or multiple ipsilateral tumours.
- Constitutional variants in the CTNNA1 gene have been identified in a small number of families fulfilling clinical criteria for a diagnosis of hereditary diffuse gastric cancer. At present, testing of CTNNA1 is not available through NHS genomic laboratories but may be considered in future iterations of the National Genomics Test Directory.
Somatic (tumour) testing
- Somatic testing is currently not routinely available within the NHS for patients with lobular breast cancer, with the exception of molecular tumour profile testing (such as Oncotype, Prosigna or EndoPredict) for selected ER-positive, HER2-negative, node-negative primary breast cancer.
- Somatic testing for primary breast cancer may be available within clinical trials.
What do you need to do?
- 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. In this instance, the option is:
- R215: CDH1-related cancer syndrome. At present, this test may only be requested by specialists in clinical genetics or gastroenterology.
- A record of discussion (RoD) form is required prior to 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 DNA. These tests include (but are not restricted to):
- For constitutional (germline) DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub for details of test request forms and where to send samples.
- For tumour profile tests of ER-positive, HER2-negative breast cancers, liaise with your local cellular pathology department to confirm local contract and request arrangements.
- 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)
- Blair VR, McLeod M, Carneiro F and others. ‘Hereditary diffuse gastric cancer: updated clinical practice guidelines’. Lancet Oncology 2020: volume 21, issue 8, pages: e386-e397. doi: 10.1016/S1470-2045(20)30219-9
- Corso G, Figueiredo J, La Vecchia C and others. ‘Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect‘. Journal of Medical Genetics 2018: volume 55, issue 7, pages 431-41. doi: 10.1136/jmedgenet-2018-105337
- Stjepanovic N, Moreira L, Carneiro F and others. ‘Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up‘. Annals of Oncology 2019: volume 30, issue 10, pages 1,558-71. doi: 10.1093/annonc/mdz233
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