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Researchers: Alpa Patel, PhD, and Lauren Teras, PhD
Institution: American Cancer Society
Area of Focus: Population Science
“Ultimately, the goal is to put together everything we know about what increases and decreases the risk for developing breast cancer and for surviving it. That ‘everything’ would include genetics, reproductive history, geographic location, socioeconomic factors, exposures to infections and pollutants, medical history, smoking and drinking history, diet, and more. When we can account for all of these factors together, we’ll be able to empower women with personalized, specific strategies to reduce their own risk of getting or dying from cancer.”
—Lauren Teras, PhD
The Challenge: About 5% to 10% of breast cancer cases are thought to be hereditary, meaning that they result directly from genetic changes (mutations) passed on from a parent. Breast cancer screening guidelines take into account whether a woman has a genetic mutation (pathogenic variant) in one of the rare, high-penetrance (also known as high-risk) breast cancer predisposition genes, such as BRCA1 and BRCA2.
But knowledge about genetic risks is growing faster than the understanding about how to apply that knowledge to screening guidelines. For example, guidelines for breast cancer screening haven’t been tailored for women who have pathogenic variants within moderate-penetrance breast cancer predisposition genes, such as CHEK2 and ATM. And the same guidelines don’t account for the much more common genetic variants that individually contribute a very, very small risk, but that are important for predicting a woman’s overall risk for developing breast cancer.
As genetic risk is better understood, genetic testing for mutations continues to evolve. It’s also important to apply genetic knowledge to cancer screening guidelines. The research and medical communities need better risk-prediction models to not only identify women at high risk for developing breast cancer, but also to identify women who might not need mammograms as frequently. They have a need to better understand which women are more likely to develop aggressive breast cancers that are hard to treat successfully. They also need to be able to better recognize when a woman has a type of breast cancer that could respond to fewer or different treatments than what might be the standard treatment.
The Research: To help fill this knowledge gap, the United States-based Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium studied a woman’s risk for breast cancer by adapting risk prevention models. Their model accounted for the combined effect of a family history of breast cancer, pathogenic variation in one of the 9 established breast cancer predisposition genes, and polygenic risk score (PRS). The PRS is the sum of small genetic changes. It’s calculated using a scoring system that essentially gives 1 “point” for every copy of the more common variants a woman has.
Permanent changes in the DNA sequence of a gene are called gene mutations. Some scientists think that “gene variant” is a more accurate term because changes in DNA do not always lead to disease. Sometimes they’re used as synonyms.
Genetic variants can have a large or small effect on the likelihood of developing a particular disease. The term “pathogenic” refers to something that causes a disease. When genetic variants lead to disease, they’re called pathogenic variants, or pathogenic mutations.
Genes that are vulnerable to cancer-causing variants or changes are called cancer-predisposition genes. In some cases, a cancer-predisposition gene is inherited, or passed along from generation to generation. Several dozen cancer-predisposition genes have been identified, and about 5 to 10% of all cancers result directly from those that are inherited from a parent.
For example, BRCA1 and BRCA2 are inherited cancer predisposition genes. Mutations on these genes increase the risk for developing certain cancers.
The term penetrance is used to describe how many people carrying a mutation or cancer predisposition gene will eventually develop cancer. If everyone who inherits a mutation develops cancer, that mutation is said to have complete penetrance. If some people don’t, it’s incomplete or reduced penetrance. If most people with an inherited mutation develop cancer, that mutation has high penetrance. For example, pathogenic variations on the BRCA1 and BRCA2 genes are high-penetrance gene mutations. Other gene mutations are in categories considered to be moderate- or low-penetrance.
CARRIER researchers reviewed data from about 27,000 women with breast cancer and about 26,000 women without it. Data came from epidemiologic studies that included the ACS Cancer Prevention Studies, CPS-II and CPS-3.
In a recently published study, they reported these findings. Accounting for PRS information in general may provide more personalized estimates of a woman’s risk for developing breast cancer. Specifically, including the PRS:
The authors say that future research is needed to establish just how PRS and rare variants in cancer predisposition genes can help doctors manage a woman’s personal risks for developing breast cancer.
Several American Cancer Society (ACS) epidemiologists participated in the study, including Alpa V. Patel, PhD, and Lauren Teras, PhD, as well as former ACS researchers Mia Gaudet, PhD, and Eric Jacobs, PhD. Some of the many other contributors included ACS grantee Julie Palmer, PhD, and former ACS grantees Jeffrey N. Weitzel, MD, and Fergus Couch, PhD, (senior author).
Why Does It Matter? The more breast cancer specialists can classify the risk of developing breast cancer, the more personalized guidance can be given to women regarding how they can manage lifestyle breast cancer risks and develop a screening plan. For example, a personal approach may affect the age a woman starts getting regularly screened and whether she would benefit from screening with both breast magnetic resonance imaging (MRI) in addition to or instead of mammography.
Taking a personalized approach to risk assessment and screening can help breast cancer to be found early when it might be easier to treat. This approach can also help reduce the chance of false positive screening test results that lead to more testing that is unnecessary. Knowing more details about a breast tumor through a personalized approach can also help a diagnosis of breast cancer be treated more effectively.