Results: Patient with pancreatic cancer and a constitutional (germline) pathogenic BRCA variant

A 44-year-old man is diagnosed with pancreatic adenocarcinoma. There is no significant family history of cancer. Routine constitutional (germline) testing of the BRCA1, BRCA2, CDKN2A and PALB2 genes is undertaken and a pathogenic BRCA2 variant is identified.

Constitutional (germline) BRCA variants in pancreatic cancer

• Approximately 5% of unselected pancreatic cancer patients carry a pathogenic variant in BRCA1 or BRCA2, with a prevalence of up to 17% in patients with familial pancreatic cancer (depending on the definition criteria used).
• On the basis of the phase-three POLO trial results, treatment with the PARP inhibitor olaparib has been licensed by the European Medicines Agency for maintenance treatment of adults with constitutional (germline) BRCA1 or BRCA2 variants who have metastatic adenocarcinoma of the pancreas and have not progressed after over 16 weeks of platinum treatment within a first-line chemotherapy regimen. However, this is not currently approved by NICE.

Management of the current cancer

• Identification of a constitutional (germline) BRCA1 or BRCA2 variant (which is also present in the tumour genome) does not currently alter immediate clinical management guidelines within the NHS.
• However, the patient may be eligible for a clinical trial involving treatment with a PARP inhibitor.

Management of the future cancer risk

• Identification of a constitutional (germline) BRCA1 or BRCA2 variant means that the patient is at significantly increased risk of breast, prostate and possibly other cancers.
• You should refer the patient to clinical genetics for post-test counselling and discussion of cascade testing and onward management of risk.
• Issues around future cancer risk should be considered on an individual basis, and the patient’s prognosis from their pancreatic cancer should be taken into account.

Management of the family's risk

• The cancer risk associated with pathogenic constitutional (germline) variants in BRCA1 or BRCA2 is inherited as an autosomal dominant trait.
• This means that first-degree relatives are at a 50% risk of carrying the BRCA variant. You should refer the case to clinical genetics to discuss cascade screening of at-risk relatives.

Note that the above advice is only relevant when a constitutional (germline) BRCA variant is identified. Somatic (tumour-only) BRCA variants that are not present in the patient’s normal tissues have no implications for the patient’s future cancer risk, nor that of their relatives.

References for clinicians

• Golan T, Hammel P, Reni M and others. ‘Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer‘. The New England Journal of Medicine 2019: volume 381, issue 4, pages 317–327. DOI: 10.1056/NEJMoa1903387
• Kindler HL, Hammel P, Reni M and others. ‘Overall survival results from the POLO trial: A phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer‘. Journal of Clinical Oncology 2022: volume 40, issue 34, pages 3,929–3,939. DOI: 10.1200/JCO.21.01604
• Li S, Silvestri V, Leslie G and others. ‘Cancer risks associated with BRCA1 and BRCA2 pathogenic variants‘. Journal of Clinical Oncology 2022: volume 40, issue 14, pages 1,529–1,541. DOI: 10.1200/JCO.21.02112

For patients

• Pancreatic Cancer UK: Hereditary pancreatic cancers
• The Royal Marsden NHS Foundation Trust: A beginner’s guide to BRCA1 and BRCA2