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

A 49-year-old man is diagnosed with adenocarcinoma of the prostate. His mother was diagnosed with breast cancer in her 50s. Constitutional (germline) testing of a panel of prostate cancer susceptibility genes (BRCA1, BRCA2, MLH1, MSH2, MSH6, ATM, PALB2 and CHEK2) is undertaken and a pathogenic BRCA2 variant is identified.

• BRCA2 is a tumour suppressor gene with a central role in the homologous recombination repair (HRR) pathway.
• Prostate cancer occurring in males with a BRCA1 or BRCA2 variant is typically more aggressive, occurs at younger-than-expected ages, and has higher metastatic potential than prostate cancer occurring in the general population.

Management of the current cancer

• Identification of a constitutional (germline) BRCA1 or BRCA2 variant (which is also present in the tumour genome) in a patient with metastatic castration-resistant prostate adenocarcinoma indicates that the patient may be eligible for treatment with PARP inhibitors.
• Selected PARP inhibitors are licenced for use as a monotherapy in homologous recombination (HR)-deficient (due to somatic (tumour) or constitutional (germline) events) metastatic castration-resistant prostate cancer (mCRPC). This is based on the results of the TOPARP-B and PROfound clinical trials.
• The PARP inhibitor olaparib has been approved by NICE for use in mCRPC associated with constitutional (germline) or somatic (tumour) BRCA1 or BRCA2 variants since May 2023.
• Combination treatment with niraparib or abiraterone (MAGNITUDE clinical trial) is licenced by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in BRCA1- or BRCA2-altered disease, and olaparib and abiraterone (PROpel clinical trial) are licenced by the FDA in ‘deleterious or suspected deleterious BRCA-mutated’ mCRPC. Olaparib monotherapy is now also licenced by the EMA for mCRPC in BRCA wildtype patients for whom chemotherapy is not an option. These indications are not approved by NICE at present.

Management of future cancer risk

• Identification of a constitutional (germline) BRCA variant means that this patient is at significantly increased risk of male breast cancer, pancreatic cancer and possibly other cancers.
• The exact advice provided to those with genetic variants will be individualised, depending on their result and associated cancer risk, as well as on the treatment and overall prognosis of their current cancer.
• Refer patient to clinical genetics services for post-test counselling and to discuss cascade testing and onward management of risk.

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.
• First-degree relatives (males and females) are at a 50% risk of having the BRCA variant. Refer to clinical genetics services to discuss cascade screening of relatives at risk.

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.

Somatic (tumour) testing

• Somatic (tumour) testing for BRCA1 or BRCA2 variants is available for patients who are eligible for NICE-approved PARP inhibitor treatment, have a diagnosis of mCRPC and have not previously been identified as having a constitutional (germline) BRCA1 or BRCA2 variant.
• Somatic (tumour) testing for NTRK1, NTRK2 and NTRK3 fusions is available for patients with metastatic prostate cancer as a 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 (tumour) testing for this fusion can be requested if there is diagnostic uncertainty with prostate cancer among the differentials.
• 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.

Somatic (tumour) tests for prostate cancer are requested using the following codes:

• M218.1 Multi-target massively parallel sequencing (MPS) (also known as next-generation sequencing (NGS)) panel for BRCA1 and BRCA2 small variants; and
• M218.2 Multi-target MPS panel for NTRK1, NTRK2 and NTRK3 structural variants.

This somatic (tumour) test can be performed on formalin-fixed tumour samples.

WGS of any solid tumour where the patient has exhausted all standards of care, testing and treatment is requested as code M232. For WGS:

• you will require access to a fresh tumour sample and a matched blood (EDTA) sample (WGS requires paired somatic (tumour) and constitutional (germline) DNA analysis);
• a record of discussion (RoD) form must be completed; and
• you should discuss the case with your local Genomic Laboratory Hub before submitting samples for WGS to confirm the local test pathway details.

For clinicians

• NICE: Olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer

References:

• Chi KN, Rathkopf DE, Smith MR and others. ‘Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations‘. Journal of Clinical Oncology 2022: volume 40, issue 6. DOI: 10.1200/JCO.2022.40.6_suppl.012
• 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
• Mateo J, Porta N, Bianchini D and others. ‘Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): A multicentre, open-label, randomised, phase 2 trial‘. The Lancet Oncology 2020: volume 21, issue 1, pages 1,470–2,045. DOI: 10.1016/S1470-2045(19)30684-9
• Saad F, Clarke NW, Oya M and others. ‘Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): Final prespecified overall survival results of a randomised, double-blind, phase 3 trial‘. The Lancet Oncology 2023: volume 24, issue 10, pages 1,094–1,108. DOI: 10.1016/S1470-2045(23)00382-0
• Sandhu SK, Hussain M, Mateo J and others. ‘PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations‘. Annals of Oncology 2019: volume 30, issue 9, pages IX188–IX189. DOI: 10.1093/annonc/mdz446.007

For patients

• Macmillan Cancer Support: BRCA2 and cancer risks for men and people assigned male at birth
• The Royal Marsden NHS Foundation Trust: A beginner’s guide to BRCA1 and BRCA2