Breast cancer genetic screening may bring uncertainty

New technologies, and a little help from the U.S. Supreme Court, have made it possible for large numbers of women to find out whether they carry genetic mutations that increase their risk of breast cancer – a development warmly welcomed by experts in the field.

But the availability and relative affordability of multigene-panel tests also can lead to anxiety and confusion about what course of action to choose, because the risk associated with many of those genes remains unknown.

“Genetic testing holds a lot of potential and a whole lot of uncertainty,” said Beth Peshkin, a professor of oncology and senior genetic counselor at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington.

“The more genes we test, the more variants we’re likely to find,” Peshkin explained. “A recent study found that about 40 percent of people who underwent panel testing had variants, or genetic changes, that we don’t know how to interpret.”

In 2013, the Supreme Court invalidated Myriad Genetics’ patents on the two major genes that predispose women to breast and ovarian cancer, ruling that human genes cannot be patented.

Since then, several companies have begun testing for mutations in those genes, BRCA1 and BRCA2, which are responsible for about 80 percent of hereditary breast cancer cases; and the genes have been incorporated into panels that use so-called next-generation sequencing to test for multiple genes simultaneously.

The problem arises because some of the mutations detected in those panels are relatively rare and scientists do not yet know how much additional risk they confer, if any.

In August, the New England Journal of Medicine published a study showing that certain mutations in a gene called PALB2 were associated with a lifetime risk of between 33 percent (for carriers with no family history of breast cancer) and 58 percent (for those with a strong family history). That’s similar to the risk associated with a BRCA2 mutation, but lower than that for BRCA1.

The average lifetime risk for an American woman is about 12 percent. The vast majority of breast cancer cases are not linked to any known hereditary factor.

“Investigators from 14 centers around the world pooled data from all of their families with PALB2 mutations,” said Dr. Jane Churpek, co-director of the Comprehensive Cancer Risk and Prevention Program at University of Chicago Medicine. “So, for the first time, we had a large enough series to get an estimate (of risk) for carriers of mutations in this gene. The hope is we’ll see similar efforts for each gene on these panels.”

When actress Angelina Jolie announced last year that she carried a BRCA1 mutation, her choice was relatively straightforward. She decided to have a preventive double mastectomy after her mother died of ovarian cancer and Jolie learned she herself had up to an 87 percent chance of getting the disease.

Some breast cancer experts noted that the “Angelina Jolie effect” – the dramatic upsurge in testing for breast cancer genes that followed her story – was a good thing. It raised awareness of a problem about which something could be done. A study presented in early September at a meeting of the American Society of Clinical Oncology found that referrals for genetic testing at one large medical center doubled in the six months following Jolie’s announcement.

But BRCA1 is a well-studied gene for which there is good evidence of the associated risk. Although there can be many different mutations in that gene, and they don’t all confer the same risk, researchers have investigated most of them and have a pretty good idea how they affect a person’s chances of getting breast cancer.

“Over a million women have been tested for BRCA,” Peshkin said. “Very few variants (of unknown significance) remain.”

Geneticist Mary-Claire King, who discovered BRCA1, stirred controversy recently by calling for all American women older than 30 to be tested for BRCA1 and BRCA2. (Current guidelines for healthy women say only those with a family history should be referred for genetic counseling and testing.)

But King added that women should be told only about mutations that are associated with known cancer risk.

Many of the newer gene mutations have not been studied in enough carriers for scientists to be able to quantify the risk associated with them. So learning she has one of those mutations would almost certainly cause a woman concern and anxiety, but it wouldn’t provide enough information for her to make an informed decision about how to proceed.

Only by knowing the likelihood that someone who carries a given mutation will actually develop breast cancer can a doctor help a patient decide if it’s appropriate to take certain risk-reduction steps. Those may include:

• More intensive screening (typically, an annual MRI in addition to mammography).

• Chemoprevention (taking a drug that blocks the effect of estrogen on the breasts).

• Prophylactic salpingo-oophorectomy (surgical removal of the fallopian tubes and ovaries).

• Mastectomy (surgical removal of the breasts).

“It’s going to take a national, or international, effort to learn how to interpret variants that are rare, or found only in individual families,” Peshkin said.

Such efforts already are underway. A number of labs and medical centers, including Georgetown, the University of Chicago and Memorial Sloan Kettering in New York, are participating in a new registry to collect genetic information and outcomes data on patients who undergo multigene-panel testing and consent to be followed.

The registry will focus on the kind of genes for which cancer risk is uncertain and no clinical management guidelines are currently available.

Even after the level of risk is known, however, good genetic counseling is needed, Churpek explained, because that estimate may be affected by other things, including lifestyle factors, other genetic factors, family cancer history and country of residence. “It’s why those of us who practice cancer risk make sure testing is done by someone who knows how to interpret the results,” she said.

Churpek stressed that genetic testing is only one component of estimating someone’s cancer risk. “We take into account personal factors – such as age at first period and first childbirth – as well as the family history,” she said. “If genetic testing does not identify a mutation, but there is a strong family history of breast cancer, we take care of that woman differently.”

That was the case for Kelly McCarthy and Kristen Maurer of Crown Point, Indiana, twin sisters who were both diagnosed with breast cancer at age 32, shortly before their mother died of colon cancer. McCarthy, a nurse, had a very aggressive tumor; Maurer’s was less aggressive and less advanced.

Genetic testing showed no BRCA mutation and no conclusive breast cancer risk in any other gene on the panel. Nevertheless, both women opted for double mastectomies.

“It was a peace-of-mind situation,” said Maurer, now 35, who works in enrollment services at Indiana Wesleyan University and has two young daughters. “I didn’t want it to ever come back.”