BRCA1/2 and Prostate Cancer risk:
- Male carriers of BRCA1/2 had a 3.8-4.89 increased standardized incidence risk of prostate cancer
- Higher with BRCA2
- Known carriers have worse response to treatment (RP, XRT) and developing more aggressive pathology
- 2/3 of BRCA2 carriers that developed PCa developed high-risk PCa
- In the metastatic PCa setting
- 11.8% of patients with mPCa had germline mutation in DNA repair gene
- Compared to 4.6% incidence in overall population
Germline DNA repair mutations have implications in screening and patient counseling as well. It may identify patients for specific treatment selection.
Concept of “synthetic lethality”:
In an abnormal cell with multiple pathways of DNA repair being disrupted, if you also target the base-excision pathway with PARP inhibitors, then the cell cannot complete any DNA repair – leading to apoptosis and cell death.
- TOPARP-A trial (2015) – Olaparib in mCRPC – men who were deficient with homologous repair pathways had an improvement in survival
- 90% of the patients with homologous repair pathways had some improvement with treatment
- Patients with DNA repair mutations appear to respond to platinum based chemotherapy due to inability to recover from the DNA damage induced by platinum based therapy
- Overall 24% had at least one mutation in a key DNA repair pathway
- Looking at distribution of mets, patients with those specific mutations tended to have brain and visceral mets compared to bone/LNs
In summary, key DNA-repair gene mutations are common in prostate cancer. With their earlier identification in a subset of patients, we may be able to identify novel pathways for treatment. Men with these mutations have a higher risk of aggressive, lethal prostate cancer. While BRCA2 is the most common, there are other important mutations that need to be identified. In doing so, we may be able to predict response to platinum chemotherapy and PARP inhibitors.
Presented by: Marc Dall’Era
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal