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.
availability and relative affordability of multigene-panel
tests can also lead to anxiety and confusion about what course
of action to choose, because the risk associated with many of
those genes remains unknown.
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.
more genes we test, the more variants we’re likely to
find," explained Peshkin. "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
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.
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
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.
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.
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.
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
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.
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.
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.
a million women have been tested for BRCA," said Peshkin.
"Very few variants (of unknown significance)
Mary-Claire King, who discovered BRCA1, stirred controversy
recently by calling for all American woman over 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.)
added that women should be told only about mutations that are
associated with known cancer risk.
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.
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:
intensive screening (typically, an annual MRI in addition to
(taking a drug that blocks the effect of estrogen on the
salpingo-oophorectomy (surgical removal of the fallopian tubes
and ovaries) and
(surgical removal of the breasts).
going to take a national, or international, effort to learn
how to interpret variants that are rare, or found only in
individual families," said Peshkin.
efforts are already 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
registry will focus on the kind of genes for which cancer risk
is uncertain and no clinical management guidelines are
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.
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."
the case for Kelly McCarthy and Kristen Maurer of Crown Point,
Ind., 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.
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.
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