SIU 2017: DNA Repair Mutations and Prostate Cancer

Lisbon, Portugal (UroToday.com) Dr. Dall’Era presented on DNA repair mutations and their role in localized prostate cancer. DNA damage repair pathways are extensive with numerous genes involved. However, abnormal function of any of these genes result in greater rate of genetic mutations that are unable to be repaired quickly enough. This subsequently leads to more genetic instability (microsatellite instability MSI), and greater neoantigen loads. Many DNA repair genes are important to the development of malignancy as well. Specifically, the best known are BRCA1/2, though others include ATM, CHEK1/2, MSH6, ERCC2, ATR, FANCA, FANCC, etc.

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

Why is this important?

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.

PARP Inhibitors:

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

Chemotherapy response:

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

Dr. Dall’Era then went on to a study in which his group looked at 936 prostate cancer specimens harvested from the prostate and metastatic sites

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 30 men with untreated hormone sensitive high-risk localized or metastatic PCa facing systemic therapy, they underwent targeted sequencing. Nearly 1/3 had important mutations in DNA repair mutations, including BRCA2 and Lynch syndrome.

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

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