Study: Newly Identified Genes Linked with Higher Risk for Triple-Negative Breast Cancer

gloved hand points to a dna test sequence

This image is an example of the kind of gel pictures researchers use to understand the order, or sequence, of genes or to look for mutations in genes.


Out of 100 people with breast cancer about 15 will have triple-negative breast cancer (TNBC). It’s one of the most challenging types of breast cancer to treat. That’s due to several things:

  • TNBC tends to be more aggressive than other common types of breast cancer.
  • Women usually don’t learn they have it until the cancer has already spread to other parts of the body (metastasized), so it may be more complicated to treat.
  • Treatment options remain limited. Hormone therapies and targeted therapies that help treat people with some types of breast cancer, don’t work for a woman with TNBC. Doctors use chemotherapy to treat these patients, but it isn’t very effective and may have a lot of side effects.

If doctors had a way to identify women at risk for TNBC, they might be able to find cancer earlier, before it spreads. And, if doctors had a way to personalize treatment for women with TNBC, they might be able to improve a woman’s outlook and survival. One approach researchers are using to identify women at risk for TNBC and possible treatment options for TNBC is by studying inherited mutations in cancer genes. 

Understanding Breast Cancer Risk Genes

team of researchers in Rochester, Minnesota recently discovered mutations in 5 genes that seem to increase the risk for TNBC. These genes are known by several names: breast-cancer-risk genes, cancer-predisposition genes, and cancer-susceptibility genes. The research team was led by Fergus J. Couch, PhD, the Zbigniew and Anna M. Scheller Professor of Medical Research and Chair of the Division of Experimental Pathology and Laboratory Medicine at the Mayo Clinic. 

About the Study

About 10 to 15% of triple-negative breast cancers in Caucasians test positive for mutations in the BRCA1 gene. In the African American population, about 35% do.

Until recently, BRCA1 was the only gene linked to TNBC. In the past, researchers weren’t able to identify other breast cancer risk genes, because the technology was too cumbersome to check the genes in large numbers of people, Couch says.

“We used to check one gene at a time, which was very time consuming. But about 4 or 5 years ago, sequencing technology changed dramatically, so now we’re able to do these gene panels and check many genes at a time.”

Couch and his research team used a technology called multigene panel testing on blood samples taken from people with triple-negative breast cancer. The technology looks at multiple genes simultaneously, looking for mutations that could be linked to breast cancer.

The team studied how often mutations occurred in people with TNBC compared with a control group of people who didn’t have cancer. This was the first study to identify which mutated genes are linked to a highly increased risk for TNBC. They are: BARD1, BRCA1, BRCA2, PALB2, and RAD51D.

Women who carried any of these gene mutations had a more than 20% lifetime risk for any type of breast cancer. By comparison, women in the general population have about a 12% —or 1 in 8—lifetime risk of getting breast cancer.

“That means,” Couch says, “doctors should consider that women who have any of these mutations will have an increased risk for triple negative breast cancer. Also if a woman with breast cancer has one of these mutations, her doctor may need to consider using specific treatments.

The team was not able to learn why African American women have an increased risk for TNBC and suggest that larger studies with African American patients be done.

The team also found strong support that 3 other mutated genes (BRIP1, RAD51C, and RAD51D) moderately increase the risk for TNBC, when they were previously thought to only cause ovarian cancer.

Why It's Called Triple Negative

Most breast cancers are classified by 3 substances that can affect the cancer’s growth:

  1. The female hormone estrogen
  2. The female hormone progesterone
  3. The human epidermal growth factor receptor 2 (HER2)

Estrogen and progesterone bind with their specific receptors and move to the cell nucleus and alter the activity of many genes. That can result in some genes helping cancers grow.

The binding of HER2 and its receptor can also switch on many genes and influence how much a cancer cell grows.  

If the cancer cell doesn’t have a receptor for estrogen, then estrogen doesn’t help the cancer grow. That cancer is classified as estrogen-receptor negative (ER negative).

The same is true if the cancer cell doesn’t have a receptor for progesterone or for HER2. If a breast cancer cell doesn’t have receptors any of these, the cancer is called triple negative.

It may seem like no receptors would be good because the hormones and HER2 can't help the cancer grow. But having a triple-negative breast cancer isn’t good.

Here's why: current breast cancer treatments either reduce the amount of these hormones or block the receptors. That means hormone therapy won’t work against TNBC and neither will drugs that target HER2.

What the Results Could Mean

With the identification of these TNBC genes, doctors who are concerned about risks of breast cancer in their patients can focus on using cancer genetic tests that include this set of genes. And their identification allows researchers to now focus on developing drugs that could target specific gene mutations in tumors.

New guidelines for gene testing for those at risk for triple-negative breast cancer. Current guidelines from the National Comprehensive Cancer Network (NCCN) recommend that people be tested for BRCA1 and BRCA2, if they have an increased risk for breast cancer due to a personal or family history of cancer such as:

  • A family history of breast or ovarian cancer
  • A diagnosis of TNBC at age 60 or younger
  • A diagnosis of breast cancer under age 40

There are no guidelines to test people for predisposition genes other than BRCA1 or BRCA2. However, this may change as more information about which genes increase risk of breast cancer becomes available.

Plus, only mutations in certain genes qualify women for breast MRI in addition to mammograms for screening and early cancer detection. Some of the genes indentified by Couch are not currently on that list. “The hope is that breast cancer screening guidelines might change based on our findings,” Couch says. “Those at high risk could then get additional screening with a breast MRI, which studies show can improve survival,” he says.

Drugs for treatment of people who have gene mutations (called mutation carriers) and who have been diagnosed with triple-negative breast cancer. “This enhanced understanding of the genetic risks for TNBC opens the door to test the effectiveness of current targeted treatments,” Couch says.

For instance, there’s some evidence that BRCA1 and BRCA2 carriers with TNBC might respond well to platinum agents, such as cisplatin (Platinol AQ) or carboplatin (Paraplatin).

Mutation carriers may also be helped by a type of drug called PARP inhibitors. PARP is an enzyme that helps both healthy and cancer cells repair DNA damage so they can live. Blocking PARP in cancer cells prevents them from repairing DNA damage, ultimately leading to their demise.

Some of the new TNBC genes work the same way as BRCA1 and BRCA2, so studies are underway to learn if tumors with mutations in these other genes can also benefit from platinum drugs or PARP inhibitors.

 

Journal article: Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. Journal of the National Cancer Institute. 2018. 

Journal author’s affiliation with ACS: Senior and corresponding author, Fergus J. Couch, PhD, received a 4-year grant from the American Cancer Society in July of 2004 for his research project Cancer Predisposing BRCA1 and BRCA2 Missense Mutations.