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Hereditary Breast Cancer: How BCRF Researchers Are Uncovering Inherited Risk Factors

Family history, race and ethnicity are breast cancer risk factors that have long been part of the BCRF research agenda

Most people who develop breast cancer have no family history of the disease, but that’s not always the case. A person’s family history, genetics, race, and ethnicity are all important risk factors that can contribute to an individual’s breast cancer risk.

This year, BCRF is investing more than $8 million in understanding the underlying causes of breast cancer—half of which is committed to researching the influence of inherited mutations and ethnicity, as well as how to reduce risk or prevent breast cancer in high-risk groups.

BRCA Genetic Mutations

Up to 10 to 15 percent of breast cancers are thought to be due to hereditary factors. The most common genes involved in hereditary risk for breast cancer are the BRCA genes, BRCA1 and BRCA2. BCRF researchers Drs. Mary-Claire King and Alan Ashworth propelled our understanding of the role of BRCA1 and BRCA2 in hereditary breast cancer, which led to the development of genetic tests that are in use today.

About 12 percent of women in the general population in the U.S., will develop breast cancer during their lives. 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 from .1 percent to 8 percent.

While BRCA mutations are rare, certain populations have a much higher risk of inheriting a BRCA mutation. 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. BRCA mutations are responsible for 10 percent of breast cancer and 40 percent of ovarian cancer cases in Jewish people of Ashkenazi origin.

Less is known about the prevalence of BRCA mutations in other populations. BCRF investigators Drs. Ephrat Levy-Lahad, Mary-Claire King, 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 have cancer genetics testing. Thanks to BCRF, genetic testing and counseling is now routine for breast cancer patients at most major Palestinian hospitals. Cancer-predisposing mutations in patients are identified and their relatives are subsequently tested. New cancer-causing mutations reveal biology important to women worldwide, and when correlated with genomics of tumors, reveal the consequences of inherited cancer susceptibility.

Other Genetic Mutations

BRCA mutations, however, account for only 5 to 10 percent of hereditary breast cancers. Because of work by BCRF researchers Drs. Kenneth OffitMark RobsonFergus Couch, James Ford, and others, our understanding of inherited risk has expanded to include additional cancer-predisposing genes including PALB2, CHK2, BARD1 TP53, and ATM. Many more have been identified, but their level of risk is unclear.

2020 BCRF Research Highlights

This year, BCRF investigators continue their quest to better understand hereditary breast cancer. Below are some of the studies we are currently supporting:

BRCA Mutations

  • BCRF researchers Drs. Susan Domchek, Kenneth OffitKatherine Nathanson,  and Judy Garber are testing a novel screening program in women and men with Ashkenazi ancestry to identify families at risk of breast and other cancers.
  • Dr. Robert Vonderheide is developing immune therapies for patients with breast cancer, with special focus on the prospect of a prevention vaccine. He is testing one such vaccine in healthy women who carry a BRCA mutation.

Inherited Genes

  • BCRF researchers Drs. Fergus Couch, James Ford, Kenneth Offit, and Mark Robson are working to improve risk prediction in high-risk individuals and identify new genes responsible for the unexplained high rates of breast cancer in some families.

Race and Ethnicity

  • Dr. Jeffrey Weitzel and his team have provided genetic cancer risk assessment (GCRA) to more than 1,000 Latin American patients and identified 150 new high-risk families that would not have otherwise known of their breast cancer risk. Their studies have shown an increase in lifesaving risk-reduction surgery, despite limited resources.
  • Dr. Sandra Swain comparing the genetics and blood of African Americans and European Americans to uncover mechanisms behind differences in response to ribociclib, an FDA-approved drug for use in advanced breast cancers. She hopes this work will provide a foundation for future clinical treatment strategies.

A version of this article was published on September 24, 2019. This piece has since been updated.

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