Using Genomics in Precision Prevention of Breast Cancer

Breast cancer is the most common cancer in women in the United States. It is estimated that 3%-5% of breast cancer cases are hereditary, most often involving mutations in BRCA1 and BRCA2 genes. Such mutations confer high lifetime risk of breast and ovarian cancer. The United States Preventive Services Task Force has issued specific recommendations for genetic counseling and testing for women based on family health history. For women at high risk, available interventions include surgery, enhanced surveillance, and medication use. Most breast cancer cases, however, are caused by a combination of genetic and environmental factors. Many gene variants (polygenes) individually confer only a slight increased risk for breast cancer. Collectively, these genes lead to a normal distribution of risk in the population. So far, we have not figured out how to use these variants in clinical practice and population screening.

In the past month, two very large studies have made remarkable progress in quantifying levels of breast cancer genetic risk, both for hereditary cancer (associated with BRCA1/2 mutations) and the more common breast cancer cases (associated with polygenes). In the first study of more than 31,000 women with BRCA1/2 mutations from 55 centers in 33 countries on 6 continents, researchers estimated the magnitude of risk for breast and ovarian cancer based on mutation type, function, and position. They found that different BRCA1/2 mutations are associated with significantly different risks of breast and ovarian cancer depending on where the mutations occur within the genes. For example, mutations located near the ends of the BRCA1 coding sequence were associated with a greater risk for breast cancer, while mutations located near the middle confered a higher risk of ovarian cancer. Of course, we have known about BRCA1/2 genes for more than 2 decades. These findings add to the knowledge that has already been gained from looking at the many types of mutations found in affected patients and their families over more than 2 decades. The new data, if appropriately validated, will have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations. Ultimately as Dr Francis Collins writes, “our hope is not only to spare women with BRCA1/2 who are at low risk of cancer from needless surgery, but to use this newfound knowledge to develop drugs and other less-invasive strategies for cancer prevention in high-risk women.”

In the second study of more than 33,000 breast cancer cases and 33,000 control women, researchers assessed the value of using 77 breast cancer-associated common variants for breast cancer risk stratification (rare variants such as BRCA1/2 mutations were not included in this study). They constructed a genetic risk score based on the combinations of variants. Women in the highest 1% of the genetic risk score had a three-fold increased risk of developing breast cancer compared with women in the middle range. They estimated that the lifetime risk of breast cancer for women in the lowest and highest quintiles of the risk score were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. The authors concluded that the observed level of risk discrimination could inform targeted screening and prevention strategies. In addition, further stratification of risk may be achieved by combining genetic risks with lifestyle/environmental factors (that were not measured in this study).  Until recently, we had known that multiple common susceptibility variants may be combined to identify women at different levels of breast cancer risk but population data were not available. The findings of this study, if further validated can lead to a general genetic risk assessment strategy for all women and not only those that harbor BRCA1/2 mutations.

Commenting on 25 years of breast cancer risk estimation, Mitchell Gail, the architect of the “Gail model” discussed the importance of quantifying absolute risk, namely the probability that a woman with specific risk factors will develop breast cancer over a defined age interval, as was done in the second study. Breast cancer is a common cancer for which screening preventive intervention has been developed (mammography) and recommended for women between 50-74 years by the US Preventive Services Task Force. However, for women aged 40-49 years, the US Preventive Services Task Force (USPSTF) determined that “The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient’s values regarding specific benefits and harms.” Although age is the most important risk factor, many women in their forties can have higher or lower level of risk based on other factors including genetic risk scores.

Nevertheless, evaluating the inclusion of genetic risk assessment scores in recommendations on breast cancer screening is not straightforward. Steve Narod writes in his recent commentary: “If genomewide association studies were the first step towards precision medicine and the development of the model is the second step, then the third step is to show that the personal risk score is useful. Who should be tested and who will pay?” For example, in the event that a woman’s genetic risk score places her in the top percentile, should we offer her more frequent and earlier screening, or more intensive screening (e.g., with MRI). The option for risk-reducing medications is also available. Nevertheless, there is still no direct evidence on whether or not stratified screening and prevention using genetic risk score will lead to overall net benefit vs harms for individual women and the population at large. In the United Kingdom, several workshops have examined scientific, ethical and logistical aspects of stratified population screening for breast cancer based on polygenic susceptibility. The promise of genetic stratification was recognized with the combination of age and genetic risk profile theoretically providing a more efficient screening program compared to age alone. However, they also recognized that key scientific, ethical and practice issues need to be addressed before genetic stratification for breast cancer can be implemented in practice.

In conclusion, data from two recent large population studies provide more precise estimates of breast cancer risk in women with high risk mutations in BRCA1/2 genes, and in all women based on their polygenic risk profile. These types of studies can influence clinical preventive services with additional evaluation of the utility of this information in reducing the burden of breast cancer morbidity and mortality. In the meantime, family history will continue to serve as a valuable low-tech tool in the stratification of breast cancer risk for screening and prevention. Beyond breast cancer, the large scale epidemiologic investigations of genetic risk will usher in a new era of precision prevention for many diseases in the years to come.