When a woman is diagnosed with BRCA mutated (BRCAm) breast cancer she is currently faced with very difficult decisions about how to improve her long-term prognosis. Should she have radical surgery to remove both her breasts and potentially her ovaries in an effort to reduce her risk of recurrence or dying from the disease? Or will a more conservative approach enable her to avoid such invasive surgery without jeopardising her chances of survival?
Recent progress in understanding the underlying mechanisms through which BRCA mutations increase the risk of breast and other cancers is at last opening up a wider range of potential treatment options for women with cancer caused by BRCA1 or BRCA2 mutations. We still have much to learn, but technological advances are enabling us to dig deeper into how BRCA mutations increase the likelihood of a normal breast cell becoming cancerous.
What is BRCAm breast cancer?
About 12% of women will develop breast cancer at some point during their life, but this rises to 55-65% of women who inherit a harmful BRCA1 mutation and 45% of those with a BRCA2 mutation.1 In fact, BRCA 1 or BRCA2 gene mutations account for up to a quarter of hereditary breast cancers and about 5-10% of all breast cancers.1
There are currently no treatments targeting BRCA1 and BRCA2 mutations for women with BRCAm breast cancer. Like other women with breast cancer, women with BRCAm disease are likely to be offered surgery, radiotherapy and chemotherapy, depending on the characteristics of their tumour and how far it has spread. However, instead of a simple lumpectomy to remove their breast lump, many women will decide to have a mastectomy to remove all of the affected breast because of the high risk of recurrence and possibly remove their unaffected breast in an effort to prevent new primary tumours
The importance of DNA Damage Response mechanisms
BRCA1 and BRCA2 are the genes that hold the genetic code for making BRCA1 and BRCA2 proteins that are involved in the repair of damage to a cell’s DNA.1 Mutations in BRCA1 and BRCA2 do not cause cancer on their own. However, an individual whose cells carry a mutation in either of these genes is more at risk of developing cancer. This is because their cells are more likely to accumulate faulty DNA as they are less able to repair the DNA damage that occurs in all cells on an ongoing basis.2
Every day, DNA in our cells is damaged tens of thousands of times by natural causes and external factors. This damage can cause changes to the structure of the DNA within our cells which, if not corrected, may lead to cancer.3
DNA Damage Response (DDR) is a collective term for the large number of intra- and inter-cellular signalling events and enzyme activities (including those involving BRCA1 and BRCA2) that arise in response to DNA damage and lead to arrest of the cell cycle, regulation of DNA replication, repair or bypass of DNA damage, and, if necessary, cell death.3
A normal cell has a full set of DDR mechanisms and, even if one pathway is lost, the cell can continue to repair damage through a back-up pathway and survive, or if the damage cannot be repaired it will be programmed to die (apoptose).3 Cancer cells may have defective DDR mechanisms which allow them to grow in an uncontrolled way or evade death, while accumulating DNA damage.3
Many DDR defects in cancer cells, have the potential to be exploited by using highly targeted DDR inhibitors that block the remaining response systems that cancer cells rely on to survive.3
Following the science in search of new treatments
In recent years, considerable interest has focused on a repair enzyme called poly (ADP ribose) polymerase (PARP). This routinely helps to repair single strand breaks in DNA but, if it is faulty or missing, there is a build up of single strand damage. This results in more serious double stranded breaks in DNA which, if they too cannot be repaired, can lead to cell death.4
This is of particular interest in relation to BRCAm breast cancer as both BRCA1 and BRCA2 proteins are needed to repair double stranded breaks in DNA. Cells of individuals with mutations in genes for either of these proteins have reduced ability to repair this type of DNA damage. Recent research suggests that, while genomic instability is greatest in cells with defects in both copies of the BRCA1 or BRCA2 genes, even a defect in just one copy is enough to increase the likelihood of cancer.5 We don’t yet fully understand the reason for this, but accumulating DNA damage arising from defective BRCA activity appears to lead to uncontrolled cell growth.4,5
This faulty mechanism represents another opportunity for targeted DDR inhibitor treatment aimed at leaving breast cancer cells with so much DNA damage that they cannot replicate and so they apoptose. If we can block single strand DNA repair with drugs that inhibit PARP, the resulting build up of double strand breaks due to lack of BRCA proteins may lead to death of tumour cells.
Further research is needed to understand the entire process that changes a normal breast cell into a cancerous cell and how we can make best use of DDR mechanisms for treatment. This may involve combining novel DDR inhibitors or combining DDR inhibitors with more traditional forms of chemotherapy to overwhelm breast cancer cells with irreparable damage to their DNA.
Such research also has important implications for women currently living with the uncertainty of knowing that they or family members are carriers of BRCA mutations. It may, in the future, offer them alternatives to their current limited options for intervention based around preventive surgery or intensive screening and or medication. We do not yet have all the answers, but we are gradually finding the key pieces of the scientific puzzle of BRCAm breast cancer that will hopefully impact on both long term survival and quality of life for families affected by the disease.
1. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#q1. Last accessed: May 2017
2. The Royal Marsden NHS Foundation Trust. A beginner’s guide to BRCA1 and BRCA2. Available at: https://www.royalmarsden.nhs.uk/sites/default/files/files_trust/beginners-guide-to-brca1-and-brca2.PDF. Last accessed: May 2017
3. O’Connor M. Targeting the DNA damage response In cancer. Molecular Cell 2015; 60:547-560
4. Livraghi L. Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Medicine (2015) 13:188; DOI 10.1186/s12916-015-0425-1
5. Venkitaraman AR. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 2014; 343(6178):1470-5