Prostate cancer is one of the most heritable cancers.
BRCA genes and risk
BRCA1 and BRCA2 are tumour suppressor genes, in which mutations significantly increase the likelihood of developing certain epithelial cancers. The normal functions of these genes are to identify and repair DNA strand breaks.
Incidence in generally population between 1 in 300 and 1 in 800.
11 – 30 % of men with metastatic prostate cancer will have mutations on germline or somatic testing of DNA damage repair genes.
BRCA2 most common, followed by ATM, and BRCA1
More common in metastatic prostate cancer patients cf. organ confined.
BRCA mutations associated with:
- Higher ISUP / Gleason score
- Nodal involvement
- Metastatic disease
- T3 +
Other BRCA cancers include:
- Breast
- Ovarian
- Pancreatic
- Stomach
BRCA patients and active surveillance – no formal data – these patients should be aware that there is limited evidence for AS in known BRCA patients, and there is a potential that they harbour more aggressive disease.
BRCA patients and screening:
IMPACT study showed BRCA2 patients were more likely to be diagnosed with PCa, and more likely to be diagnosed at a younger age and with clinically significant cancer cf. non BRCA 2 men during routine screening
Known BRCA2 patients should probably undergo PSA screening from age 40.
PARP inhibitors
Inhibit the enzyme poly ADP ribose polymerase (PARP) – which is a DNA repair enzyme for single strand breaks.
BRCA mutated cancer cells rely on PARP to repair DNA damage – so inhibition of PARP leads to accumulation of DNA damage and apoptosis.
Olaparib is PBS listed for BRCA positive patients with mCRPC who have progressed on previous treatment including novel antiandrogen.
PROfound trial – Olaparib vs enza or abi (in patients who had progressed on the alternate antiandrogen) in patients with BRCA mutations
Median OS 19 months in olaparib vs 14 months abi/enza
300 mg BD.
Side effects:
- Anaemia most common and clinically relevant (wait until any myelotoxicity from chemo resolved)
- Reported potential risks of myelodysplastic syndrome, acute myeloid leukaemia and pulmonary toxicity (including PE)
- Anorexia
- Nausea, vomiting, diarrhoea and generalised side effects
Recommendations for genetic testing in prostate cancer
EAU – offer mCRPC patients somatic and/or germline mutation testing.
NCCN – recommend germline testing for all metastatic patients and high risk patients
AUA – offer genetic counselling and germline testing for all hormone sensitive metastatic patients
Germline testing – testing of healthy, non-cancerous cells (blood, saliva, buccal swab) DNA to evaluate for inherited mutations found in all cells. Familial implications.
Somatic testing – testing of tumour cells specifically – may need follow up germline testing