Mayo Clinic pinpoints genes that raise the risk of triple-negative breast cancer

The ability to identify women who face the highest risk of triple-negative breast cancer could save lives, but only one inherited mutation—in the gene BRCA1—has been definitively linked to this subtype of the disease. Now researchers at the Mayo Clinic have discovered four additional gene alterations that are associated with an elevated risk of triple-negative breast cancer. They believe the discovery will pave the way to expanded genetic testing and improved prevention strategies.

Triple-negative breast cancer is the hardest subtype of the disease to treat because it doesn’t overexpress HER2, and it lacks progesterone and estrogen receptors, making it tough to tackle with targeted treatments. It accounts for 15% of diagnoses in Caucasian patients and 35% in African Americans.

The Mayo Clinic researchers tested the genes of more than 10,000 triple-negative breast cancer patients participating in two studies, according to a statement. In addition to finding alterations in BRCA1, they uncovered mutations in BRCA2, PALB2, BARD1 and RAD51D. They also found mutations in BRIP1 and RAD51C that were linked to a more moderate risk of triple-negative breast cancer. They published their findings in the Journal of the National Cancer Institute.

Although testing for breast-cancer risk genes has been available for several years, the National Comprehensive Cancer Network screening guidelines only recommend screening for BRCA mutations for people with a family history of breast cancer that was diagnosed at age 60 or younger.

Fergus Couch, Ph.D., a geneticist at Mayo Clinic and the research team leader for the new study, noted in a statement that expanding gene panels to test for elevated risk of triple-negative breast cancer could be a valuable strategy because the disease subtype is "associated with a high risk of recurrence and a poor five-year survival rate."

Women found to be at high risk for inherited breast cancer are generally advised to start screening mammograms at an early age, as well as periodic breast magnetic resonance imaging (MRI). And they have the option of reducing their risk further by undergoing prophylactic mastectomies.

In addition to improving screening for breast-cancer risk, scientists have been studying the triple-negative subtype of the disease to try to identify—and thwart—the forces that make it so aggressive. Earlier this year, a Cleveland Clinic team found a survival pathway in cancer stem cells, along with a protein called connexin 26 (Cx26), that they believe facilitates communication between cells, thereby driving tumor growth. Inhibiting Cx26, they believe, could be a new strategy for fighting triple-negative breast cancer.

There is some hope that PARP inhibitors like AstraZeneca’s Lynparza, which is approved for BRCA-mutated breast cancer, would improve outcomes in triple-negative breast cancer. Results have been mixed so far: Data presented earlier this year showed that Lynparza did improve progression-free survival by 42% in patients with triple-negative breast cancer. But two trials of AbbVie’s veliparib fell short.

The difficulties inherent in treating triple-negative breast cancer argue for expanded genomic treatment to catch people who face an elevated risk of developing the disease earlier, Couch argues. "Our findings provide the basis for better risk management," he said.

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