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 due to several things:
If doctors had a way to identify women at risk for TNBC, they might be able to find cancer earlier and before it spreads when it might be easier to treat. And, if doctors had a way to personalize treatment for women with TNBC, they might be able to improve a woman’s outlook (prognosis). One approach researchers are using to identify women at risk for TNBC and possible treatment options for TNBC is by studying inherited changes (mutations) in cancer genes.
A 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 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% test positive.
Until recently, BRCA1 was the only gene linked to TNBC. In the past, researchers weren’t able to find other breast cancer risk genes, because the technology was too complicated 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 at once, 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 find mutated genes that are linked to an 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 they 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 be associated with ovarian cancer.
Breast cancers are mainly classified by 3 proteins that can affect the cancer’s growth:
Estrogen and progesterone hormones attach to their specific receptors on the cancer and help breast cancer grow (hormone-positive). One-third of breast cancers make too much of the HER2 receptor which causes them to grow very quickly (HER2-positive).
However, if the cancer doesn’t have the estrogen and progesterone receptor (hormone-negative) and doesn't make too much of the HER2 receptor (HER2-negative), it is called triple negative breast cancer.
Triple-negative breast cancers grow and spread more quickly than most other types of breast cancer. Since the cancer cells don't have hormone receptors, hormone therapy won't work for these cancers. And because they don't have much HER2, drugs that target HER2 aren't helpful, either. Chemotherapy is usually the standard treatment.
With the identification of these TNBC genes, doctors can use genetic tests that include this set of genes to find patients with an increased risk for TNBC. Finding these TNBC genes also allows researchers to focus on developing drugs that could target specific 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 multiple reasons including a personal or family history of cancer such as:
Additional guidelines to test patients for genes other than BRCA1 or BRCA2 may become available as more breast cancer risk genes are found.
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 found 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 for those who have been diagnosed with triple-negative breast cancer. Couch explains that now that we better understand the genes associated with a risk for TNBC, we can start testing current targeted therapy drugs. For instance, there’s some evidence that BRCA1 and BRCA2 carriers with TNBC might respond well to platinum drugs, such as cisplatin or carboplatin.
People with certain gene mutations may also be helped by a type of drug called PARP inhibitors. PARP is a protein that helps both healthy and cancer cells repair DNA damage so they can live. PARP inhibitors work by blocking PARP proteins in cancer cells. That prevents them from repairing DNA damage, and often leads to their death.
Some of the new TNBC genes work the same way as BRCA1 and BRCA2, so studies are underway to learn if tumors with these gene mutations might 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.
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