Targeted Cancer Treatment Therapies: The BRCA Genes and PARP Inhibitors
Breast Cancer

Targeted Cancer Treatment Therapies: The BRCA Genes and PARP Inhibitors

Caitlin Mauer, MA, MS, CGC

It is currently thought that 10-20% of cancers are hereditary, meaning that a genetic mutation is passed down through generations, putting individuals at an increased risk to develop cancer.

Genetic testing for these mutations is widely available to individuals, and finding a mutation can lead to multiple benefits. For some, it can answer questions like: “Why did I develop cancer?”or “Are my family members at risk to develop cancer?” For others, it can provide predictive guidance to help tailor cancer screenings and prevention options.

However, most recently, genetic testing can also help personalize and guide cancer treatment itself.

To set the stage, let’s first review two of the most well-known genes related to hereditary cancer: the BRCA1 and the BRCA2 genes (further referred to here as collectively the BRCA genes).

These are two very good genes when they are working correctly, as their job is to correct DNA damage that occurs throughout our lifetime. This DNA damage can come from a number of things, some that we can control, and others that we cannot. Examples include aging, diet, environmental exposures like smoking tobacco or drinking alcohol, or long-term hormone exposure (estrogen replacement, for example).

However, if one of the BRCA genes has a pathogenic variant (disease-causing alteration/mutation), it cannot perform its job to repair DNA damage.Thus, DNA damage accumulates over time, and eventually results in a cancer.

Since the BRCA genes primarily work to repair DNA damage in the breasts, ovaries, prostate, pancreas, and skin (to prevent melanoma), these are the organs at a higher risk to develop cancer if a BRCA mutation is present.

Cancers associated with BRCA mutations tend to occur at a younger age, since the DNA damage has accumulated since birth. It is important to note that while the BRCA genes are a significant DNA repair mechanism, they are not the only one. Fortunately, we have other genes that help repair DNA, and thus it is not a guarantee that someone with an inherited BRCA mutation will develop cancer.

After learning how the BRCA genes work, researchers thought about ways to turn BRCA mutations against themselves to help treat cancer. If the BRCA mechanism to repair DNA damage is already broken, what would happen if other DNA repair mechanisms were also broken?

Researchers hypothesized that this would allow too much DNA damage to accumulate in a cancer cell, and the cell would automatically destroy itself in a mechanism called “synthetic lethality.” So, they developed a group of medications called “poly-ADPribosepolymerase inhibitors” (PARPi), which inhibit the PARP pathway from repairing DNA.

They tested their hypothesis and found it worked. The cancer cells rapidly accumulated so much DNA damage that they end up dying off, effectively treating the cancer.

The Food and Drug Administration (FDA) has approved the use of PARPi to treat patients who have BRCA mutations and ovarian cancer, fallopian tube cancer, primary peritoneal cancer, HER2 negative metastatic breast cancer, metastatic prostate cancer, and most recently, metastatic castration resistant prostate cancer. 1

Additional research is actively ongoing to determine if PARPi work in patients who inherited mutations in other DNA repair genes beyond the BRCA genes, which may open up possibilities of treating other cancer types.

As our research and knowledge about targeted cancer treatments grows, knowing if you have an underlying genetic mutation can be imperative to your cancer treatment options.

While certainly no one wants to develop cancer, the future is promising with the development of targeted treatments and personalized medicine. Arming yourself and your family with as much knowledge about your genetics can help you and your medical team explore the best treatment options available for you or your loved ones.

1. Risdon EN, Chau CH, Price DK, Sartor O, Figg WD. PARP Inhibitors and Prostate Cancer: To Infinity and Beyond BRCA. Oncologist. 2021 Jan;26(1):e115-e129. doi: 10.1634/theoncologist.2020-0697.

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