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New Research Estimates Non-Hereditary Breast Cancer Risk

New Research Estimates Non-Hereditary Breast Cancer Risk
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Published on February 19, 2021

What Are the Non-Hereditary Risk Factors for Breast Cancer?

It’s not just mutations of the BRCA1 and BRCA2 genes that increase a woman’s risk of breast cancer.

While a woman’s lifetime risk of developing breast cancer is markedly increased if she inherits a harmful variant in the BRCA1 or BRCA2 genes, two large studies published in the New England Journal of Medicine last month identified other breast cancer mutations in women with a moderate or low risk based on family history.  In both studies, mutations in eight genes ― BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 — were found to be significantly associated with breast cancer risk.

“Traditionally, genetic testing of inherited breast cancer genes has focused on women at high risk, who have a strong family history of breast cancer, or those who were diagnosed at an early age, such as under 45 years,” said the lead investigator of one of the studies, Dr. Fergus Couch, a pathologist at the Mayo Clinic in Rochester, Minnesota, in a Mayo Clinic news story.

He added: “[Although] the risk of developing breast cancer is generally lower for women without a family history of the disease… when we looked at all women, we found that 30% of breast cancer mutations occurred in women who are not high-risk.”

Researchers have been able to estimate the level of breast cancer risk (high, moderate-to-high, uncertain, etc.) that is associated with certain genetic mutations. For example, women with a PALB2 mutation have a 14% risk of developing breast cancer by age 50; that risk increases to 35% by age 70. For those with a family history, the risk of breast cancer by age 70 is 58%, according to the nonprofit For women with CHEK2 mutations and a family history of breast cancer, the lifetime risk (classified as moderate-to-high) of breast cancer is estimated to range from 28% to 37%.

In one of the studies, called the CARRIERS Consortium study, Dr. Couch and his colleagues examined a panel of 28 cancer-predisposition genes in approximately 64,000 women from the United States (32,247 with breast cancer). Mutations in 12 of those genes were detected in 5.03% of patients with breast cancer and in 1.63% of those without breast cancer.

The other study evaluated 34 genes in approximately 113,000 women (60,466 with breast cancer) from 25 countries in Europe and Asia participating in Breast Cancer Association Consortium studies. Mutations in ATM, BRCA1, BRCA2, CHEK2 and PALB2 were associated with a significant risk for breast cancer.

Dr. Steven A. Narod, of Women's College Research Institute in Toronto, wrote in an accompanying editorial that the results of both studies help establish which genes confer a predisposition to breast cancer. However, there is still a question about what best to do with the information.

“Should we start discussing with our patients each gene shown to have an association with breast cancer risk in these two studies before offering a panel test?" he asked. “Specifically, how well equipped are we to advise patients who have a variant in CHEK2 or ATM?

“The studies... are useful in that they help to establish the genes that confer a predisposition to breast cancer and those that do not,” he wrote. “These studies are less helpful in refining the lifetime cancer risks for women with mutations…More research is needed to determine the magnitude of cancer risk and the cancer spectrum for each of these genes.”

What This Means for You

If you have a family history of breast cancer, you have a higher risk of developing the disease, according to the American Cancer Society (ACS). However, the organization notes that most women with a family history of breast cancer do not have an inherited genetic mutation that greatly affects their risk.

A genetic counselor can help you decide if you should undergo genetic testing and what tests to perform, based on your personal or familial history. They can also explain what the results mean for you and your family.

If testing reveals an abnormal gene, you can reduce your risk of developing breast cancer with certain lifestyle choices: maintaining a healthy weight, not smoking, eating healthy and exercising regularly, according to There are also risk-reduction options for women at high risk, such as Tamoxifen, which, the organization says, has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in both postmenopausal and premenopausal women at high risk.

If you are concerned, suggests talking to your doctor, radiologist, and/or genetic counselor about developing a specialized program for early detection of breast cancer. That plan can assess your risk, meet your individual needs and give you peace of mind.

~Megan Trusdell

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