BCRF-Supported Study First to Determine Breast Cancer Risk for Women With Gene Mutations, But No Family History

Results have the potential to improve breast cancer screening and risk assessment in all women

Today, BCRF investigator Dr. Fergus Couch published the results of the first large, multi-center study to improve the accuracy of breast cancer risk assessment for women without a family history of the disease in the New England Journal of Medicine. Fellow BCRF investigators Drs. Christine Ambrosone, Katherine Nathanson, Susan Domchek, and Jeffrey Weitzel were part of the collaborative, multi-institution study team.

Investigators analyzed germline (inherited) DNA from 32,247 women with breast cancer and 32,544 unaffected women—all participants in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium—to derive this important data.

“We started this project about four years ago, because we realized that all the genetic risk estimates for breast cancer were focused on BRCA1 and BRCA2 genes when there are now 12 genes that are accepted to be predisposing for breast cancer,” Dr. Couch said. “The BRCA1 and BRCA2 studies were in high-risk patients—those with a family history or early onset of the disease. There were no genetic risk estimates for women that didn’t have such a family history or young age of onset.”

The need for accurate estimates of gene mutations

Inherited breast cancer risk is most commonly associated with mutation in the genes BRCA1 and, to a lesser extent, BRCA2, but these are not the only established breast cancer susceptibility genes. Between seven and 10 percent of women with breast cancer have been estimated to have mutations in breast cancer predisposition genes. But these estimates were based on studies of limited size and in high-risk populations. With early and sustained BCRF support, Dr. Couch and his colleagues undertook the CARRIERS study to examine genetic risk that could be applied to the general population, including African American, Asian, and Hispanic women.

Dr. Couch’s team sequenced 12 established and 16 candidate predisposition genes to answer two key questions: How frequently do mutations occur among these genes, and can these gene mutations provide an accurate estimate of one’s risk of developing breast cancer? By utilizing the dataset of participants from the CARRIERS consortium, Dr. Couch and his colleagues could answer these questions for a large and varied population of women—particularly those with no family history of breast cancer who harbor inherited mutations in breast cancer predisposition genes.

New insights into gene mutation frequencies

Investigators evaluated the frequency of mutations in 12 established predisposition genes, including BRCA1, BRCA2, PALB2, BARD1, and ATM. Mutations were detected in five percent of women with breast cancer, compared to 1.6 percent of unaffected women. Similar frequencies were observed among non-Hispanic white, African American, and Hispanic women. Not surprisingly, the highest frequency of mutations was observed in BRCA1 and BRCA2. Mutations in PALB2 were also correlated with moderate risk.

The researchers also correlated specific gene mutations with subtypes of breast cancer. Mutations on the BARD1, RAD51C, and RAD51D genes, while very uncommon, were associated with an increased risk of ER-negative breast cancer and triple-negative breast cancer (TNBC) and were more frequent in African American women with breast cancer. Mutations in ATM, CDH1, and CHEK2 were linked to an increased risk of ER-positive breast cancer and more frequent in non-Hispanic white women—providing new insight into the racial difference in frequency of ER-negative versus ER-positive breast cancers.

The impact of this new data

While the risk of developing breast cancer is generally lower for women without a family history of the disease, this study showed that 30 to 50 percent of breast cancer mutations occur in women who have traditionally not been considered high risk. This is the first comprehensive study to examine the prevalence of inherited mutations in established breast cancer susceptibility genes in this population. This study brings us closer to understanding the prevalence and breast cancer risk associated with gene mutations among all women.

“There has been a lot of discussion about population-based testing—potentially testing all breast cancers and even testing all women over 30 for mutations in various genes,” Dr. Couch said. “I think the numbers we are providing here will be informative for those discussions.”

Evaluation of genetic mutations as part of breast cancer screening practices could personalize risk assessment and improve clinical management for all women in the general population. For example, screening for mutations identified in this study and shown to be associated with an increased risk of TNBC—mutations in the BARD1, RAD51C and RAD51D genes, in addition to BRCA1 and BRCA2 genes—would be particularly meaningful for African American women who are disproportionately affected by this aggressive form of the disease. Moreover, these findings will inform treatment decisions and provide doctors with comprehensive data to better communicate breast cancer risk, particularly to women with no family history.

As Dr. Couch noted, the data obtained from this study is “going to be very valuable going forward, as people will then embark upon risk management strategies and understand their personal risk.”

“This study is a hallmark of BCRF-funded research—spanning institutions and specialties,” BCRF Chief Scientific Officer Dr. Dorraya El-Ashry said. “It also moves us closer to a key goal of arming patients with a more precise assessment of risk to inform prevention.”

WATCH: Hear more about the CARRIERS study in this interview with Dr. Couch below or on YouTube.