This article appeared in Genome in January 2018.
At a routine eye appointment at a Geisinger ophthalmology clinic in Coal Township, Pennsylvania, Patrice Molesevich was invited to participate in a study. By contributing two extra tablespoons of blood whenever her doctor ordered bloodwork, she could help Geisinger researchers explore and understand human genetic variation and discover new disease-causing and disease-preventing genes, as well as new targets for future drug development.
The MyCode Community Health Initiative is Geisinger’s system-wide biobanking program that stores patients’ blood and other samples and links them to electronic health record data for research use. To date, more than 170,000 patients have signed up.
“I told them I’d love to participate. If it can help somebody down the road, that’d be great,” Molesevich, now 58, recalls. She never expected that the “somebody” would be her.
MyCode’s objective is research, but when researchers find that an individual has a gene mutation known to cause harm, they notify the person. In March 2016 — about a year after she had joined and all but forgotten about MyCode — Molesevich got a phone call from a genetic counselor who told her that she carried a BRCA2 gene variant that significantly increases breast-cancer risk.
Molesevich was no stranger to cancer. “Six or seven of my mother’s 13 siblings had different cancers. My brother died of pancreatic cancer, and my dad died of prostate cancer,” she says. But even with this family history, Molesevich didn’t meet the criteria for BRCA screening, which only apply to women with a personal or family history of breast, tubal, peritoneal or ovarian cancer. If it hadn’t been for her voluntary participation in a research study, Molesevich might have found out about her breast-cancer risk after it was too late. She was one of 37 MyCode participants who were contacted who did not know they had a BRCA mutation, and one of three participants who then discovered she had early-stage cancer.
Some 50 percent of BRCA1 and BRCA2 mutation carriers are missed by current screening guidelines. For this reason, the geneticist who first demonstrated that breast cancer was hereditary, Mary-Claire King, has called for all women to be offered testing at about age 30, regardless of family history. Critics, however, say evidence that the general population would be helped, and not harmed, by such testing is lacking.
Hereditary breast cancer and who gets screened
BRCA1 and BRCA2, tumor-suppressor genes, repair damaged DNA that could otherwise lead to certain cancers. Specific mutations in these genes can render the gene unable to do its job, thereby increasing a person’s risk for breast, ovarian, and other cancers. Men and women who carry these mutations have a 50 percent chance of passing them on to each of their children.
The average woman has about a 12 percent risk of getting breast cancer before she is 70 and a 1.3 percent lifetime ovarian-cancer risk. But women with a relevant BRCA1 mutation have a 55 to 65 percent breast-cancer risk and a 39 percent ovarian-cancer risk up to age 70. BRCA2 mutations raise risk for breast cancer before age 70 to 45 percent and for ovarian cancer to as much as 17 percent.
The U.S. Preventive Services Task Force (USPSTF) recommends BRCA testing only for women who have a relative who has had breast, ovarian, tubal, or peritoneal cancer and who meet other criteria that raise suspicion of a BRCA mutation. These would include, for example, a male relative who had breast cancer, a female relative who had breast cancer before age 30, or multiple relatives on the same side of the family who had breast or ovarian cancer.
Every woman at age 30
In a 2014 Journal of the american Medical Association op-ed, King and her co-authors, physicians Ephrat Levy-Lahad and Amnon Lahad, called for all women to be screened for BRCA mutations at age 30, regardless of family history.
“It’s crazy that we’re not identifying [mutation carriers] before they have cancer,” says Levy-Lahad, a medical geneticist and the director of the Medical Genetics Institute at Shaare Zedek Medical Center in Jerusalem. “The whole idea of genetic testing for adult disease susceptibility is to find that risk before you ever develop the disease.”
Thirty is a good age, King adds, “because then a woman who carries a BRCA1 or BRCA2 mutation has about a decade to decide what to do. A few years earlier or later is fine, but we do not test teens. Nothing in the life of a teen should change based on her BRCA genotype.” King is a professor of genome sciences and medical genetics at the University of Washington.
Gathering the evidence
Estimates of the risk that BRCA mutations add are based on cancer rates among female carriers who have a family history of women’s cancers. Little is known about the lifetime cancer risk of non-Jewish mutation carriers who don’t have a significant family history. Should they consider the same extreme preventive measures — preemptive bilateral mastectomy and oophorectomy (removal of breasts and ovaries) — as women whose mothers, grandmothers, and aunts have died of cancer?
“If there are multiple women in both branches of a carrier’s family who have lived into their older years without getting cancer or doing anything to prevent it, should I tell that person that her lifetime chance of getting cancer is up to 85 percent? I don’t think I can say that,” says Joy Larsen Haidle, a certified genetic counselor at North Memorial Health in Robbinsdale, Minnesota.
Levy-Lahad, King, and their colleagues say carriers of BRCA mutations all have elevated risk for breast cancer regardless of family history. They tested more than 8,000 healthy Ashkenazi Jewish men in Israel for the three BRCA mutations that account for 11 and 40 percent of breast and ovarian cancers in that population. About half of the 175 who tested positive came from families with a significant breast- and ovarian-cancer history. The other half did not. The men were representative of the Ashkenazi population at large in that just over 2 percent were mutation carriers and just under 10 percent had a mother who had had breast cancer. The men referred their female relatives for testing, which led to identification of 211 carriers. Examining the women’s personal medical histories, the researchers found that risk of developing breast or ovarian cancer by age 80 was 83 percent for BRCA1 carriers and 76 percent for BRCA2, regardless of family history.
“I think we’ve got the evidence [to support universal screening] for the Jewish population,” says Ranjit Manchanda, a gynecological oncologist at the Centre for Experimental Cancer Medicine at Barts Cancer Institute in London. “But we haven’t yet generated the equivalent evidence for the general population.”
An added complication when it comes to applying the Israeli study results to the U.S. population is that BRCA-driven cancers in Ashkenazi Jewish people are caused by one of three mutations that one in 40 people of Ashkenazi Jewish background carry. Mutation-driven breast and gynecological cancers in the U.S. are driven by thousands of possible mutations found in one in 300 women.
But, Levy-Lahad argues, “There’s no reason to think that other deleterious BRCA mutations would behave differently from the so-called Jewish mutations. Women who have mutations but who in fact are not at risk are very rare.”
On the flipside, little is known about risk among women with a significant family history who don’t carry a mutation in BRCA1 or BRCA2. There are many other genes that may be responsible for an inherited cancer predisposition. In addition, other factors, including environmental and lifestyle choices, could cause multiple members of a family to develop cancer. “If you have a big family with a strong history of cancer, and your gene test is negative, risk reduction might still be something to consider based on the family history,” says Haidle.
Many experts acknowledge that population-wide screening for BRCA and other known harmful gene variants is on the horizon. But it can be dangerous to implement new guidelines before gathering the data on potential risks. Take, for example, the controversial prostate-specific antigen test, which may have lowered cancer death rates but has increased unnecessary biopsies and treatments that can cause infection, impotence, and incontinence.
“The history of medicine is fraught with things that seemed like good ideas but proved to be far more complex. The time to find that out is before you do a full-scale implementation,” says Jim Evans, a professor of genetics at the University of North Carolina School of Medicine.
A massive undertaking
Population-wide BRCA screening would require improvements in healthcare infrastructure and, if not a larger workforce, a more efficient one. We would need electronic health records that are interoperable across health systems to prevent duplicate testing every time a woman changes doctors.
The genetic counseling workforce, as it currently operates, couldn’t bear the burden of universal screening. USPSTF recommends face-to-face genetic counseling both before and after BRCA screening. But studies, as well as initiatives testing the waters of population-based screening, show such counseling might not be necessary.
A randomized controlled trial of 936 Ashkenazi Jewish adults in London found no difference in understanding, risk perception, or uptake in testing among those who received traditional face-to-face pretest counseling and those who watched an educational DVD before testing.
HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, offers free testing for BRCA gene mutations and several others known to increase breast- and ovarian-cancer risk to women and men age 30 and older through its Information is Power initiative. Only participants who test positive for a mutation or have a very substantial family cancer history that warrants hypervigilance regardless of carrier status receive one-to-one genetic counseling.
“We’ve had over 2,000 people tested,” says Kelly East, a genetic counselor for Hudson-Alpha. “We would love to have personal conversations with all of them before and after testing, but that’s not feasible. We utilize more scalable methods of communication with everyone and focus on cases where personal communication is most warranted.”
Paying the price
If every U.S. woman over 30 were to be screened, it could cost billions. Add to that, more frequent mammograms, additional MRIs, and preventive surgeries, and the cost becomes even more daunting.
Expensive, sure, but is it cost-effective?
BRCA tests are now available for less than $250. If universal screening uncovers one carrier for every 400 women tested, it would probably help prevent four breast cancers and two ovarian cancers for every 10,000 women screened and increase their life expectancy by 2.1 days. The cost of those extra days? About $53,000 per year of perfect health.
But maybe patients and the healthcare system could get even more bang for their healthcare buck. Eventually, when genetic testing becomes a part of routine care, as experts on both sides of this proposal believe it will, public health experts expect to see screening for more than just two genes.
“Because of scientific, ethical, and logistical issues, it’s difficult to justify population screening that focuses on one or two genes,” says Muin Khoury, the director of the Center for Disease Control and Prevention’s Office of Public Health Genomics. Khoury suggests that future population-based screening could target multiple genes, including BRCA mutations, Lynch syndrome (a genetic predisposition to colorectal and uterine cancers) mutations, and mutations that cause familial hypercholesterolemia (a genetic predisposition for naturally high cholesterol). “These three conditions together affect about two million people,” he says. A rigorous scientific evaluation will be needed before implementing such a program.
Choosing to know
When BRCA carriers learn their status, they face tough choices. Women may choose more frequent mammograms, supplemented by breast MRIs in between, which can lead to false positives and unnecessary biopsies; preventive medication that can cause serious side effects; or prophylactic removal of the breasts and ovaries.
If BRCA testing were to become a part of routine preventive care for all women once they reach age 30, “Is this information that all women [would] want?” asks Beverly Levine, a research fellow in public health sciences at Wake Forest School of Medicine in Winston-Salem, North Carolina. “I think it’s presumptuous to assume that. Women might not be at the stage that they are ready to act on the results given to them.”
But Manchanda believes that basing guidelines on whether women are ready for the information is a “paternalistic approach. No one is forcing anyone to get a test, but the opportunity to make an informed choice of whether to get tested or not should be available.” Manchanda’s research has found that women and men who learn their BRCA status via population-based screening have the same quality of life and suffer no more psychological distress than those who are referred for testing based on family history.
Molesevich, for her part, was happy to get the information during that unexpected phone call. “It wasn’t like I was frantic or hysterical. I was relieved that something genetic was found before cancer was found.”
Molesevich chose to have routine breast MRIs and more frequent mammograms. Her first MRI, a month after she learned she was a BRCA carrier, detected early-stage breast cancer. She opted to have a bilateral mastectomy. Today, cancer-free, Molesevich tells everyone how they can be screened at Geisinger, too. “It saved my life.”