Risk can be a complicated and confounding concept, particularly when it comes to life-or-death situations like cancer. The discovery of the BRCA1 and BRCA2 genes in the 1990s enabled many women to learn they are at high risk of developing breast cancer. More than a dozen other breast cancer genes have been identified since, but the risks associated with them have been far less certain. Research from Mayo Clinic has filled critical gaps in the understanding of how these genes predispose women to disease, in ways that directly influence patient care.

"This is truly bench to bedside research," says Siddhartha Yadav, M.D., a medical oncologist and breast cancer researcher. "Just finding out you have one of these genetic alterations is not good enough — we need to know the risk so we can mitigate that risk."

Dr. Yadav has been working with cancer geneticist Fergus Couch, Ph.D., for the last six years to define the risks that come with inheriting various genetic variants. In 2021, they and nearly 60 other researchers published a seminal study in the New England Journal of Medicine that provided more accurate risk estimates for 28 different breast cancer genes.

"We’ve known about these genes for quite some time," says Dr. Couch. "But nobody ever had enough information or enough data to really say anything about the risks associated with them."

Aggregating Data to Estimate Risks

In 2016, Dr. Couch and his colleagues built a large, population-based study drawing from 17 established epidemiology studies such as the Harvard Nurses’ Health Study and the American Cancer Society’s Cancer Prevention Studies. The result was the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, which amassed a collection of samples from approximately 35, 000 women with breast cancer and another 35,000 women without breast cancer.

Analyzing these samples revealed that the risks associated with mutations for women in the general population were lower than previous estimates, which had been based on high-risk populations with a personal or family history of breast cancer. The analysis, published in the seminal NEJM study, indicated that 16 of the 28 genes previously thought to play a role in breast cancer did not increase a woman’s risk of disease.

"There was a lot of false information out there about what genes may or may not increase risk," says Matthew Goetz, M.D., breast cancer oncologist and director of Mayo Clinic’s Breast Cancer SPORE, which has funded research in this area since its creation in 2005. The SPORE, or Specialized Program of Research Excellence, is a cornerstone of the National Cancer Institute's efforts to promote collaborative, interdisciplinary translational cancer research.

"Dr. Couch’s work brought clarity, and led to the National Comprehensive Cancer Network (NCCN) taking at least one gene off their list of genes to test for," says Dr. Goetz.

Updating Guidelines, Understanding Outcomes

The NCCN is one of several organizations, including the American Society of Clinical Oncology and the American Society of Breast Surgeons, that have set guidelines for screening for inherited breast cancer gene changes, known as germline genetic testing. "Deciding who needs testing is one of the biggest controversies in the field," says Dr. Yadav. "Some have suggested all women get tested; others have recommended testing only women of a certain age."

Dr. Yadav and his colleagues evaluated these criteria, applying them to a large patient registry that included nearly 4,000 women treated for breast cancer at Mayo Clinic. They found that the NCCN guidelines missed 35-50% of patients with disease-causing genetic mutations. The findings, published in 2020 in the Journal of Clinical Oncology, led NCCN and other organizations to expand their guidelines on germline genetic testing.

Another area where the Mayo team has made a significant impact is in linking breast cancer genes to clinical outcomes. According to Dr. Yadav, women newly diagnosed with cancer in one breast often want to know the chances that the disease will spread to the other breast or to other parts of the body. "For BRCA1 and BRCA2 carriers, we knew that their risks were high," he says. "But for these other genes that cause breast cancer, what happens to those women? There were no answers to that."

Using data from the CARRIERS consortium, the researchers determined the risks that women carrying different germline genetic mutations had of developing cancer in both breasts, known as contralateral breast cancer. For example, they found that carriers of ATM mutations did not have a significantly elevated risk of contralateral breast cancer, whereas those with BRCA1, BRCA2 and CHEK2 mutations had double the risk. The researchers believe the findings make genetic information more actionable, as different breast cancer genes appear to create tumors that behave quite differently.

At the molecular level, breast cancer is typically broken down into four major subtypes — triple-negative, HER2-positive, luminal A and luminal B — each with different degrees of aggressiveness and responses to treatment. Through an industry collaboration with a genetic testing company, the Mayo team analyzed testing results from nearly 55,000 breast cancer patients and found that different breast cancer genes appear to drive each of the different subtypes.

"Those insights into tumor biology are critically important for treatment and prevention," says Dr. Goetz. "There are some drugs, for example, that work fairly well to reduce the risk of developing luminal A breast cancer, but they don’t do anything to reduce the risk of triple-negative breast cancer."

Examining Variants of Uncertain Significance

BRCA1, BRCA2 and most of the other genes associated with breast cancer are normally involved in repairing damage to DNA. When these genes are defective, DNA damage can accumulate, allowing cells to grow out of control and turn cancerous. Researchers have identified hundreds of genetic alterations that are known to cause breast cancer, but they have also uncovered thousands more that could either cause disease or be benign. These variants of uncertain significance (VUS), as they are called, are a big problem for clinicians and patients alike.

"There’s 30,000 women, probably more, in the United States carrying these types of variants and we don’t know what to do with them," says Dr. Couch. "We’re supposed to just ignore those results, but the psychological impact is already there. We hear stories about women getting prophylactic surgeries on the basis of VUS results just because they’re so worried about them."

Dr. Couch has led extensive efforts to reclassify the VUS lurking in breast cancer genes, methodically reproducing one variant after another in the lab and assessing their effect on DNA repair. "Our approach has proved invaluable in improving our understanding of these different variants, but it has been slow-going," he says. "In 15 years, we’ve done about 500 variants of BRCA2." Recently, his team ramped up its research by using high-throughput, CRISPR-based gene editing technology to generate each variant, which will enable them to create a catalog of every possible VUS and their impacts.

In the future, the researchers plan to continue probing the connections between genes and breast cancer, examining how cancers with different genetic mutations respond to therapy and even searching for previously undiscovered breast cancer genes.

"This is not just some esoteric research that stays in the lab or an academic publication," says Dr. Couch. "These findings get rapidly integrated into the clinical workflow, informing patients about the risks they face and how to manage them."

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