Most people who develop breast cancer have no family history of the disease, but that’s not always the case. An individual’s family history, genetics, race, and ethnicity are all important factors that can contribute to their breast cancer risk.
This year, BCRF is investing more than $10 million in understanding the inherited causes of breast cancer. Our investment is committed to defining how inherited mutations and race and ethnicity influence breast cancer risk. Armed with this knowledge, clinicians may be able to identify those at high-risk and employ personalized interventions to improve breast cancer outcomes.
Understanding BRCA Mutations and Improving Outcomes
An estimated 10 to 15 percent of breast cancers are thought to be caused by inherited genetic factors that are passed from generation to generation through our DNA. These include changes in a person’s genetic code that severely affect the normal functioning of a gene. The most common and best-known genes associated with a higher risk for breast cancer are the BRCA1 and BRCA2 genes.
In landmark discoveries in the 1990s, BCRF investigators Drs. Mary-Claire King, Alan Ashworth, and their colleagues identified BRCA1 and BRCA2, respectively. These findings launched new avenues for research that propelled our understanding of hereditary breast cancer—and led to the development of genetic tests that are in use today.
In the general population, about 12 percent of women in the U.S. will develop breast cancer in their lifetime. By contrast, about 72 percent of those with a BRCA1 mutation and about 69 percent of those with a BRCA2 will develop breast cancer by the age of 80. In men with BRCA2 mutations, the risk of developing breast cancer increases to 8 percent (compared with 0.1 percent in the general population).
BCRF investigators are tackling BRCA1/2 mutations from every angle. They are devising ways to increase and optimize screening for these mutations and move beyond standard-of-care prophylactic surgery and enhanced surveillance to offer non-surgical preventative treatments, such as vaccines, in BRCA1/2 carriers. In carriers who are unfortunately diagnosed with breast cancer, researchers are also working to improve treatment outcomes and reduce their high recurrence risk through trials such as OlympiA and OlympiAD spearheaded by BCRF investigators including Drs. Judy Garber, Susan Domchek, and Andrew Tutt.
Uncovering BRCA Mutations by Race and Ethnicity
While BRCA mutations are rare, certain populations have a much higher risk of inheriting one. In those with Ashkenazi Jewish (Eastern European) heritage, the chance of inheriting a BRCA gene mutation is 1 in 40, compared to 1 in 500 in the general population. In Jewish people of Ashkenazi descent, BRCA mutations are responsible for 10 percent of breast cancer and 40 percent of ovarian cancer cases.
In a groundbreaking project—the New York Breast Cancer Study—led by Dr. King, 1,007 Ashkenazi Jewish women with breast cancer were tested using a multigene panel. The team found that among this population, approximately 11 percent of all breast cancers are caused by one of only three BRCA1 or BRCA2 mutations, while one percent of those tested carried mutations in other known breast cancer genes (mostly CHEK2). This study supported screening in the Ashkenazi Jewish population and inspired BCRF investigators Drs. Domchek, Garber, Kenneth Offit, and Katherine Nathanson to develop and test a novel screening program in women and men with Ashkenazi ancestry in the U.S. to identify families at risk of breast and other cancers.
Less is known, however, about the prevalence of BRCA mutations in other populations, making this a research priority. BCRF investigators Drs. King, Ephrat Levy-Lahad, and Moien Kanaan have conducted genetic testing in 1,300 breast cancer patients of Arab ancestry—the largest cohort of Arab women in the world to participate in cancer genetics testing. As a result of their BCRF-supported research, genetic testing and counseling is now routine for breast cancer patients at most major Palestinian hospitals.
Studies on breast cancer–associated genetic mutations have typically been conducted in white women, leaving a big question mark as to whether women of color are affected similarly. To address this disparity, BCRF investigators have led the way by conducting studies involving Black and Hispanic women.
Investigating Genetic Mutations Beyond BRCA
BRCA mutations account for only 5 to 10 percent of hereditary breast cancers. Through the aforementioned New York Breast Cancer Study, Dr. King and her colleagues showed that mutations in CHEK2 double a person’s risk of breast cancer—a significant increase, but not nearly as severe as the more than ten-fold increase due to BRCA1 or BRCA2 mutations.
Other work by BCRF researchers Drs. Offit, Couch, Mark Robson, James Ford, and their teams, has enriched our understanding of inherited risk, expanding it to include mutations in genes such as PALB2, BARD1, TP53, ATM, and others. Investigators are also examining ways to leverage a person’s risk assessment score to more accurately define their level of risk. Known as a polygenic risk score, it is calculated by surveying an individual’s whole genome andsummarizing the net effect of many genetic variants which by themselves may not increase risk but together can elevatean individual’s chances of developing diseases such as breast cancer.
Dr. Couch has also led several large studies that yielded the first-ever estimates of breast cancer risk for women of different races and ethnicities with inherited gene mutations other than BRCA1 and BRCA2. In one study, his team, which included BCRF investigators Drs. Priyanka Sharma and Garber, assessed genes in more than 10,000 people with TNBC and found mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with a high risk of TNBC, while BRIP1, RAD51C, and TP53 mutations were associated with moderate risk. These results were similar in Black and white women.
In early 2021, Dr. Couch and fellow BCRF investigators Ambrosone, Nathanson, and Domchek published the results of the first large study to examine inherited mutations in breast cancer susceptibility genes in women without a family history of the disease (previous studies had focused on high-risk populations). Analyzing DNA from 32,247 women with breast cancer and 32,544 unaffected women yielded several important insights. Among them:
These studies are ongoing and will provide additional new insights into differences in specific gene mutations associated with race as well as breast cancer subtype.
BCRF researchers are leading numerous investigations into inherited mutations and ways to provide genetic risk assessment and prevention strategies more broadly. Among some of the notable projects we are supporting:
These are a few highlights of how BCRF is investing in this area of research and funding research that has already advanced screening and genetic testing. Other BCRF studies are examining the underlying mechanisms of hereditary breast cancer and deciphering key biological and molecular steps that are involved. With this depth and breadth of research, BCRF’s investment potentially provides a myriad of benefits for those facing a high risk of developing breast cancer—from improved screening, risk management, and cancer prevention strategies to specific targeted therapies to improve outcomes.
A version of this article was published on September 24, 2019. This piece has since been updated.
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