Women with pathogenic mutations in the tumor suppressor genes BRCA1 and BRCA2 (BRCA1/2) have a greatly increased lifetime risk for developing breast and ovarian cancer, as high as 84% and 39%, respectively, and they often develop breast cancer at younger ages than most other women. Knowledge of BRCA1/2 status can help women make decisions about prophylactic mastectomy or oophorectomy, both of which have been shown to reduce risk of cancer and of overall mortality. The U.S. Preventive Services Task Force (USPSTF), National Comprehensive Cancer Network, and many clinicians recommend that women with a family history of breast, ovarian, and certain other cancers consider BRCA1/2 testing, while those diagnosed with breast cancer at especially early ages may qualify for BRCA1/2 testing even if they don’t have a suspicious family history. However, a prominent researcher who first established the BRCA1/2–breast and ovarian cancer link has called for testing all U.S. women at age 30, prompting debate about whether widespread testing would be cost-effective and feasible (Proc Natl Acad Sci U S A 2014;111:14205–10).

Mary-Claire King, PhD—a professor of genomic sciences and of medicine at the University of Washington in Seattle—based her stance on her findings in 8,222 Israeli Ashkenazi Jewish men tested for three pathogenic BRCA1/2 mutations known to commonly cause breast and ovarian cancers in Ashkenazi Jewish women. Subsequent testing of female relatives revealed that the mutations were equally common in both sexes. Fifty percent of families that harbored the mutations had no history of cancer that would have prompted testing (JAMA2014;312:1091–2).

Population screening would identify women who wouldn’t be offered testing based on their family history, King and her team wrote, adding that clinicians don’t always follow the USPSTF guidelines. Widespread testing “enables mutation carriers to be identified independent of physician referral or family involvement,” they maintained.


Researchers from UCLA have argued that the scenario suggested by King would be too costly and inefficient in the U.S., principally because of a dramatically lower prevalence of pathogenic BRCA1/2 mutations here. About one in 40 Ashkenazi Jews has a pathogenic mutation, versus a more modest prevalence of one in 400 among the general population. Population screening would prevent just four breast cancers and two ovarian cancers for every 10,000 women screened, according to the researchers’ analysis (JAMA Oncol 2015;1:1217–8).

For 99.75% of women screened, a negative genetic test result confers no gain in life expectancy, does not eliminate the need for regular mammograms, and may provide false reassurance, they noted.

In the time since the UCLA researchers conducted their analysis, BRCA1/2 test prices have dropped owing to the U.S. Supreme Court having invalidated most gene patents. This has enabled multiple labs to offer the test, creating price competition. One lab, Color Genomics, even offers a 19-gene test, including BRCA1/2, for $249.

While that price is unusually low, costs are dropping at a rate that could make BRCA1/2 testing common in 5 years, said Steven Katz, MD, MPH, a professor of medicine, health management, and policy at the University of Michigan in Ann Arbor.

Cheaper tests aside, one of the UCLA authors pointed to several other costs associated with universal BRCA1/2 testing. These include genetic counseling, appointments with surgeons and gynecologists to discuss possible reconstructive surgery and fertility options, and the procedures themselves, said Elisa Long, PhD, an assistant professor at the UCLA Anderson School of Management. Long, who is a breast cancer survivor with a deleterious BRCA1/2 mutation, added that few studies have addressed how women act on test results.

Costs and benefits are important considerations under the Wilson and Jungner criteria usually used in population screening decisions, noted Tuya Pal, MD, a clinical geneticist at the Moffitt Cancer Center in Tampa, Florida and an associate professor of cancer biology at the University of South Florida. These criteria call for considering the cost of finding those who need treatment in relation to possible expenditures on medical care as a whole. “We would need a national discussion about whether [population-based BRCA1/2 screening] is worth pursuing.”

“Medicine is all about targeting those at high risk in a way that gets the biggest bang for the buck,” Katz added. With the overall low prevalence of pathogenic BRCA1/2 mutations in American women, population screening will not enhance life expectancy and quality of life for a large proportion of the population, he contended.

Geneticists Weigh In

Geneticists and genetic counselors say the goal of population-based BRCA1/2 screening is worthy, but implementing wide-scale testing would be more difficult here than in Israel, which has a high concentration of Ashkenazi Jews with well-defined pathogenic mutations. The U.S. is more diverse racially and ethnically, so its population will have many more types of BRCA1/2 mutations than the three included in King’s study. Meanwhile, many variants’ pathogenicity isn’t well-established, said Bruce Korf, MD, PhD, chair of genetics at the University of Alabama at Birmingham (UAB) and past president of the American College of Medical Genetics and Genomics.

“Knowing how to handle variants of unknown significance is a particular challenge,” Korf noted, adding that the proportion of individuals with a pathogenic variant who will actually develop clinical symptoms is unknown for many BRCA1/2 mutations and can vary by race and ethnicity. “With a diverse U.S. general population, you have to decide which pathogenic mutations to include,” he explained.

Among the fast-growing population of U.S. Hispanics descended from various Latin American countries, there is great diversity that could make choosing particular variants difficult. A recent review paper suggested that in Latin American countries there is significant variation both in rates of BRCA1/2 mutations and prevalence of specific ones. The authors proposed different testing strategies for particular countries.

Pal, whose own research found that young black women in Florida diagnosed with invasive breast cancer have higher BRCA1/2 mutation frequency than previously appreciated, emphasized that discussions related to universal screening should focus on the population as a whole rather than particular ethnic groups. 

Screening and Counseling: Hand-in-Hand

Regardless of any screening paradigm that might be adopted, counseling would be key. Each woman must understand that a negative BRCA1/2 test result doesn’t mean she absolutely does not harbor a disease-causing genetic variant in one of those two genes or potentially in other cancer predisposition genes, said Meagan Farmer, MS, director of cancer genetic counseling at UAB. “A negative BRCA test result doesn’t negate the need for mammograms. Women with family histories of breast cancer may qualify for advanced breast cancer surveillance, such as earlier breast imaging or breast magnetic resonance imaging in addition to mammograms, even after a negative BRCA test result,”she added.

Before any population screening, the country must have adequate infrastructure, genetics professionals emphasized. Right now, there is a shortage of both geneticists and genetic counselors in many parts of the U.S., according to Farmer. Meanwhile, Long asked who would handle the conversations about risks associated with BRCA1/2 and other potentially pathogenic variants. “Do you have primary care doctors step in? They might not be familiar with BRCA or have enough time to counsel patients.”

Any plans to improve screening infrastructure also should consider the needs of women with less access to follow-up care and ability to pay for it, Pal added. Those women are disproportionately nonwhite. She also pointed out that while the federal Affordable Care Act generally covers preventive care, including BRCA1/2 testing, insurers have varying personal and family history criteria for coverage. While the federal Genetic Information Non-Discrimination Act makes illegal genetic discrimination in health insurance and employment, it does not protect against such discrimination in life and disability insurance. 

Questions related to population BRCA1/2 testing may be a preview for the day when most patients get some form of genomic sequencing as part of preventive care, Korf said. “As we learn more about genetic risk factors for common diseases with actionable prevention methods, consideration of wide-scale population screening will become more and more important. Decisions to initiate screening need to be based on rational, evidence-based studies of cost-effectiveness, infrastructure readiness, and consideration of social issues.”

Deborah Levenson is a freelance writer based in College Park, Maryland. +Email: [email protected]