BRCA, PARP Inhibitors and Cancer: What You Need to Know
DNA is constantly being damaged by environmental factors (i.e. UV light, radiation), toxins (i.e. smoking), aging and random/unknown factors. In order for all cells to survive, grow and divide, DNA damage must be repaired. The body maintains tight control over this process and uses what can be thought of as a built in “spell checker” to repair mutations and breaks in DNA.
Since DNA exists as a double stranded helix, there are two types of DNA damage; single stand breaks and double strand breaks. If a person inherits a mutation in a repair pathway gene, there is a resulting impaired ability of the body to repair DNA damage. As such, DNA is more fragile with the likelihood for the accumulation of genetic mutations and possibility of cancer.
PARP is one system for repairing single strand DNA damage. BRCA pathways are used for double strand break repair. If an individual carries a mutation in one of the repair pathways, i.e. BRCA mutation, then they must depend more heavily on the second repair pathway to mend DNA damage. In a novel approach to cancer therapy, this concept can be leveraged.
Tumor DNA damage, which must also be repaired by the tumor to survive, also relies on these same repair pathways. If a tumor lacks one pathway due to mutation (BRCA) then the other pathway can be targeted. This concept is termed in termed “synthetic lethality”, meaning a single impairment is not deadly, whereas silencing both pathways is deadly to the cell.
BRCA testing has become an important tool in the management of BRCA related cancer. It has multiple uses: predictive, prognostic and predisposition.
It aids in the development of a personalized treatment plan. BRCA testing may be associated with sensitivity to platinum based chemotherapy in both breast and ovarian cancer. It is also predictive of response to PARP inhibitors in ovarian cancer.
BRCA status allows one to gain knowledge about the course of disease. In ovarian cancer, BRCA carriers have a better survival rate. An association with survival in breast cancer has not been proven, however, there is evidence for worse recurrence free survival in BRCA1 mutation carriers.
BRCA testing provides an important assessment of the familial risk of cancer. Germline mutations are inheritable, meaning there is a familial risk for cancer. As such, genetic counseling may be appropriate.
Testing for BRCA
According to the National Comprehensive Cancer Network (NCCN), meeting one or more of the following criteria warrants further personalized risk assessment, genetic counseling, testing and management.
Current PARP inhibitors have been approved by the FDA as a fourth line, or greater, treatment in BRCA mutation carriers with ovarian cancer. There are many ongoing trials to establish the optimal treatment strategy, including combination with other agents.
The future will likely see increasing indications for PARP inhibitors, not just for ovarian cancer, but breast, prostate and other BRCA related cancers.
The DNA damage repair pathway represents an important line of attack in cancer therapy. If you or a close family member has been diagnosed with breast or ovarian cancer, ask your doctor about BRCA testing and PARP inhibitors.
del Rivero J, Kohn EC. PARP Inhibitors: The Cornerstone of DNA Repair-Targeted Therapies. Oncology. 2017 Apr 15;31(4):265-73.
National Comprehensive Cancer Network, Inc. 2016. Version 2.2017, 12/07/16.