Evaluation and Management of Women With BRCA1/2 Mutations

Evaluation and Management of Women With BRCA1/2 Mutations

ABSTRACT: Genetic counseling and testing for susceptibility to breast and ovarian cancer is often an integral component of management for women with a personal and/or family history of these malignancies. In this article, we will briefly review the function and genetic epidemiology of the two major susceptibility genes, BRCA1 and BRCA2. We will then address approaches to risk assessment for women at high risk with respect to the probability that they harbor a deleterious mutation in one of these genes, and the likelihood that they will develop cancer if such a mutation is identified. The process of genetic counseling and testing is discussed, including a summary of the potential benefits, limitations, and risks of testing as well as a summary of test result interpretation. We conclude with a review and appraisal of the various options for breast and ovarian cancer risk reduction and screening options for women with a BRCA1 or BRCA2 mutation.

It is estimated that between 5% and
10% of women with breast cancer
have an inherited mutation in a
cancer susceptibility gene.[1] Mutations
in the BRCA1 and BRCA2 genes
account for most of these cases. However,
BRCA1/2 mutations are most
likely to be identified in families with
multiple cases of ovarian and earlyonset
breast cancer.[2] The genetic
basis of cancer in families in which
multiple women have developed
breast cancer, even at an early age,
appears to be much more heterogeneous
given that many do not harbor
mutations in BRCA1 or BRCA2.[2]
For example, one study found that
among 237 families containing at least
four cases of female breast cancer,
only 65% were attributable to BRCA1
or BRCA2 mutations.[3]

While other hereditary cancer syndromes
also exist and should be considered
based on suggestive family
history constellations, together these
account for only a small proportion of
hereditary breast cancer. These syndromes,
including Li-Fraumeni,
Cowden, and Peutz-Jeghers, have distinct
clinical features and are reviewed
elsewhere.[4,5] Mutations in BRCA1,
BRCA2, and the genes associated with
the aforementioned syndromes all
confer substantially elevated risks of
breast and other cancers. But other
genes have been identified that appear
to confer more modest breast
cancer risks, including ATM and
CHK2, and their contribution to the
genetic epidemiology of familial and
hereditary breast cancer has yet to be
fully elucidated.[2]

Molecular and
Population Genetics

BRCA1 and BRCA2 function as
tumor-suppressor genes and fall under
the umbrella of "caretaker genes,"
given their role in DNA damage signaling
and repair, transcriptional regulation,
and cell-cycle regulation.[1]
The BRCA1 gene is located on chromosome
17q21 and spans 5.6 kilobases
of genomic DNA, comprising
1,863 amino acids.[1] BRCA2, on
chromosome 13q12 is much larger,
encompassing 10.2 kilobases and coding
for 3,418 amino acids.[1] Given
the large size of these genes, it is
perhaps not surprising that over 1,500
distinct mutations and variants have
been documented in each gene, including
five rarely occurring genomic rearrangements
in BRCA1 that are not detectable by sequencing.[6-8].

Some recurrent mutations have
been identified in specific geographic
or ethnic groups. Most notably, in
Ashkenazi Jewish individuals (descended
from central or eastern
Europe), two BRCA1 mutations
(187delAG, 5385insC) and one
BRCA2 mutation (6174delT) have
been identified with a population frequency
of 1 in 40 (compared to the
incidence in the general population of
up to 1 in 500).[5,9] It is relatively
rare for high-risk Jewish families to
harbor a mutation other than one of
these three.[10,11]

In the United States, virtually all
clinical testing is performed by the
commercial laboratory that holds the
gene patents, Myriad Genetic Laboratories.
As of February 2005, full
gene sequencing of BRCA1 and
BRCA2 costs approximately $3,000,
and includes analysis for the five
BRCA1 rearrangements. Testing for
the three recurrent mutations observed
in Ashkenazi Jews is $415, and single
mutation analysis is $350. Many insurance
companies will pay all or part
of the costs of BRCA1/2 testing, usually
on the basis of medical necessity
to the person requesting testing.

Risk Assessment

A three-generation pedigree, as
shown in Figure 1, is a convenient
form of recording family history to
determine whether an individual is at
high risk of cancer. Age at diagnosis,
current age, age and cause of death,
surgical procedures (including those
performed for benign conditions such
as removal of the ovaries and uterus),
precancerous conditions, and relevant
environmental exposures should also
be documented, as well as the ethnic/
racial background of the patient's
grandparents (eg, "Irish").

Features of the family history that
are suggestive of a BRCA1/2 mutation
include the presence of (a) two or
more women on the same side of the
family diagnosed with breast cancer
prior to age 50, (b) breast and ovarian
cancer in the same woman, (c) breast
and ovarian cancer in two or more
relatives on the same side of the family,
and (d) male breast cancer, especially
with a family history of breast
and/or ovarian cancer. In addition,
Jewish women diagnosed with breast
cancer (especially premenopausally)
or ovarian cancer, even in the absence
of a family history of these cancers,
should be referred for genetic
counseling and consideration of genetic

Mutations in the genes are passed
down in an autosomal dominant fashion,
such that each child of a parent
with a BRCA1 or BRCA2 mutation
has a 50% chance of also testing positive.
Thus, it is important to assess
family history on both the paternal
and maternal side and to be aware
that transmission of the mutated gene
may occur through males. Specific
referral guidelines, which may be useful
in the identification of high-risk
patients, have been developed.[12,13]

Quantitative Assessments
Although a qualitative impression
of risk is useful for making determinations
about who may be referred
for genetic counseling, quantitative
assessments of carrier probability may
be useful for patients who are considering
BRCA1/2 testing, especially in
light of the potential expense. The
most easily referenced estimates are
empiric, based on the reported family
history of over 30,000 women tested
clinically through Myriad Genetic
Laboratories.[10,14] Data are organized
into two easy-to-read tables,
which may be downloaded onto palm
or handheld personal computers.

Probabilities of testing positive for
a BRCA1 or BRCA2 mutation are
provided based on whether or not the
patient is of Ashkenazi Jewish ancestry,
personal history of breast or ovarian
cancer, and family history of these
cancers by age at diagnosis of breast
cancer (ie, less than age 50 or not).
Important limitations of these data are
the lack of independent verification
of cancer diagnoses, and the fact that
family history beyond that observed in
first- and second-degree relatives may
not have been routinely recorded.

Other Risk Assessment Models
Other models for predicting
BRCA1/2 carrier probability have
been developed.[15] Thus far, only
the BRCAPRO model has been
subject to rigorous validation.[16]
This model, which is available at no
cost after completing a licensing
agreement, can be downloaded from
a comprehensive breast cancer
risk assessment package known as
CancerGene.[17] It relies on estimates
of BRCA1/2 mutation prevalence and
penetrance to apply Bayesian (a priori)
probabilities of carrier status. Because
a full-pedigree structure (of both affected
and unaffected individuals, including
all current ages, ages at
diagnosis, and death) is required, providing
rapid risk assessments at the
time of the initial patient inquiry may
not be feasible.

Each model has its own set of
strengths and limitations, and ease of
use within the clinic. However, one
critical caveat is that it is important
for clinicians to always consider the
limitations in pedigree-based risk assessment
such as small family size,
few females, limited family history
information, and death at young ages.
In addition, the decision to undergo
genetic testing may not always be
based merely on the likelihood of testing
positive, but on the patient's worry
about testing positive and the degree
of reassurance, if any, that may be
obtained as a result of pursuing testing.
As discussed below, it is valuable
to elicit these concerns during the
course of genetic counseling.

Genetic Counseling and Testing

Although healthy individuals are
often likely to seek out genetic counseling
for the purposes of being tested
themselves, it is ideal to initiate
BRCA1/2 testing in the relative who
is most likely to test positive on the
basis of a personal history of ovarian
cancer or early-onset breast cancer.
In Figure 1, the proband (indicated by
an arrow) is not the family member
who is most likely to test positive,
given that she was diagnosed with
breast cancer after menopause. However,
because there are no other living
affected relatives available to test,
it is still preferable to test her before
testing healthy relatives concerned
about their risk.

Possible Outcomes of Testing
There are three possible outcomes
of BRCA1/2 testing.[18] Again referring
to Figure 1, it is possible that the
proband will test positive for a deleterious
mutation in the BRCA1 or
BRCA2 gene. In that instance, there
may be medical implications for her
(as discussed later) and relatives such
as her daughters and son (not pictured).
Given that her maternal histo-
ry is noncontributory, she would be
counseled that her paternal relatives
have a 50% chance of carrying the
mutated gene (or 25% if they are children
of her paternal uncles). Testing
for these individuals would involve
analysis only for the deleterious mutation.
If they test negative for the
familial mutation, they could be counseled
that a true negative result means
that their risk of developing cancer is
thought to be equivalent to that of the
general population, although personal
risk factors and the cancer history
of the other side of their family would
also need to be assessed.

A third outcome of testing arises
when no risk-conferring mutation in
BRCA1 or BRCA2 is identified in the
proband. This result is uninformative
because it does not rule out the possibility
that the proband still may have
an inherited susceptibility to breast
cancer, either due to a mutation that
could not be detected by conventional
methods or to a mutation in another
gene. The probability of the former is
estimated to be up to 15%.[8] In Figure
1, given the patient's later age at
diagnosis, it is also possible that she
may have developed sporadic breast
cancer in a family that does in fact
harbor a BRCA1 or BRCA2 mutation.
Another type of uninformative
result arises when a genetic variant or
DNA change is identified that cannot
be classified as deleterious or benign.
In such instances, healthy relatives
should not be tested for the variant for
clinical purposes, as it does not serve
to clarify their cancer risk. Counseling
about cancer risk in "uninformative
families" is complex and should
be tailored to the specific history noted
in the family.[18]

Counseling and Consent
The genetic counseling and informed
consent process should include
a thorough discussion encompassing
risk assessment, psychosocial assessment,
and a review of test result inter-
pretation, management guidelines, and
family implications.[19] In addition,
patients should consider the potential
benefits, limitations, and risks associated
with genetic testing. Fortunately,
most studies have shown that at least
in the context of genetic counseling
and testing obtained in research settings,
there do not appear to be significant
adverse psychosocial effects
among women who learn their results.[
20] However, this does not diminish
the potentially life-altering
impact of genetic testing for an individual
woman and her family, who
may be faced with difficult decisions
about screening and prevention as well
as the various emotional responses to
living with an increased cancer risk
and the possible implications to future

Cancer RisksBreast and Ovarian Cancer
Cancer risks associated with mutations
in BRCA1 and BRCA2 are quite
variable depending on the population
studied (Table 1).[3,21-31] Estimates
from high-risk, registry-based kindreds
and clinic-based populations
have tended to yield the highest
cancer risks of breast and ovarian cancer.
For example, studies in such
groups have found that the lifetime
breast cancer risks in BRCA1 and
BRCA2 carriers range from 73% to
87%.[21,22] The lifetime risk of
ovarian cancer in BRCA1 carriers is
approximately 40%, and in BRCA2
carriers, 25%.[3,21,22]

Although data from unselected individuals
(ie, those not studied on the
basis of a strong family history of
these malignancies) have revealed
much lower estimates than those quoted
above, a recent pooled analysis of
data from 22 studies involving 8,139
index cases from unselected families
demonstrated that the average risk of
breast cancer was 65% in BRCA1 carriers
and 45% in BRCA2 carriers.[23]
The average cumulative risk of ovarian
cancer was 39% and 11% in BRCA1
and BRCA2 carriers, respectively.[23]

A novel approach to deriving cancer
risk in carriers was undertaken by
the New York Breast Cancer Study
Group.[24] Instead of using "likelihood"
approaches to estimating mutation
status of relatives, BRCA1/2
testing was actually performed in relatives
of unselected Jewish breast cancer
patients with positive BRCA1/2
test results. The 71% cumulative risk
of breast cancer to age 70 that they
identified in carriers is comparable to
that found in the highest-risk kindreds,
as is the risk of ovarian cancer in
BRCA1 carriers (46%).[24] The
BRCA2 risk was lower, at 12% by
age 70, although it increased to 23%
by age 80.[24]

There do appear to be differences
in age-specific risks for breast and
ovarian cancer between BRCA1 and
BRCA2 carriers. Overall, the risk of
breast and ovarian cancer among
women under age 50 is lower in
BRCA2 carriers than in BRCA1 carriers,
but at all ages in both groups,
the risk is significantly increased over
that of the general population.[3,23]
That said, ovarian cancer rarely occurs
in women under age 30. Risk for
this cancer begins to rise appreciably
after age 35, throughout the 40s, and
after age 50.[23]

Second Malignancies
After Breast Cancer

It is well established that BRCA1/2
carriers who have had unilateral breast
cancer are at elevated risk of developing
contralateral primary breast cancers.
Studies have shown that the
lifetime risk of such occurrences is between
40% and 65%, with the risk at
10 years postdiagnosis being as high as
30%.[21,22,25-27] By comparison,
sporadic breast cancer patients face a
20-year cumulative risk of contralateral
breast cancer of up to 20%.[28]

With respect to the risk of metachronous
ipsilateral breast cancer in
carriers, the largest studies performed
to date demonstrate that the 10-year
actuarial risk is roughly between 11%
and 14%, which is similar to the risk
for young breast cancer patients without
an identified inherited susceptibility.[
27] Continued investigation in
large cohorts over an extended period
of time will be important to further
clarify these risks and determine the
incidence of late events.

For women with early-stage breast
cancer who have a good long-term
prognosis, there is concern not only
about the risk of a second breast cancer
but also the risk of ovarian cancer. As
expected, these patients have a very
high 10-year actuarial risk of ovarian
cancer after their diagnosis, which is
approximately 13% in BRCA1 carriers
and 7% in BRCA2 carriers.[29] In the
cohort of stage I breast cancer patients
studied by Metcalfe et al, 25% of their
mortality over 10 years was attributed
to ovarian cancer.[29] Therefore, management
strategies in breast cancer
patients need to emphasize the importance
of aggressively addressing
their risk of ovarian cancer.

Other Cancers
The most substantial risks of cancer
conferred by mutations in BRCA1
and BRCA2 are for breast and ovarian
cancer. However, female mutation
carriers should be informed that there
are medical implications to at-risk
male relatives with respect to prostate
cancer and breast cancer.[30] Although
the implications for screening
are not clear, the risk of prostate cancer
appears to be most significant in
BRCA1 and BRCA2 carriers under
age 65; however, the absolute risk is
difficult to pinpoint.[30]

In addition, other cancers have
been reported to occur in excess, with
overall low absolute rates (ie, less than
10%). For example, both BRCA1 and
BRCA2 carriers have an increased risk
of pancreatic cancer, whereas risks of
melanoma, stomach cancer, and
possibly other cancers appear to
be elevated in BRCA2 carriers
only.[21,25,30] Of note, by order of
magnitude, the risk of fallopian tube
cancer in BRCA1 and BRCA2 carriers
is also quite significant (relative
risk of 120, translating to a cumulative
risk of 3%),[21] although pathologically,
these cancers are very
similar to ovarian cancers. Most studies
have not shown an excess risk of
colon cancer in carriers. Ongoing research
will clarify the tumor spectrum
associated with BRCA1/2

In the decade or so since the cloning
of BRCA1 and BRCA2, an abundance
of data have been published
about cancer risk in BRCA1/2 carriers.
While there are certainly some
disparities in the estimated cancer
risks, in many instances the confidence
intervals within studies may be
wide, and between studies, may overlap
significantly. Patients should be
informed about how cancer risks are
derived and that precision in risk estimates
is not possible. It is clear, however,
that relative to the general
population, BRCA1/2 carriers face
significantly elevated risks of breast
and ovarian cancer that need to be
addressed through appropriate and aggressive
management strategies.

Risk ModifiersGenetic Factors
One potential explanation for the
wide variability in cancer risks among
mutation carriers is the effect of individual
risk modifiers on penetrance. It
is possible that specific mutations in
BRCA1 or BRCA2 may have a different
effect on risk based on their effect
on the protein product or the location
of the mutation within the gene.[32]
For example, women with a mutation
in the ovarian cancer cluster region (nucleotides
3059-4075 and 6503-6629)
of the BRCA2 gene appear to have a
higher risk of ovarian cancer and a
diminished risk of breast cancer compared
to women with mutations in other
parts of the gene.[33,34]

Variations in other genes are also
important considerations. For instance,
polymorphisms in genes that
are related to the metabolism of sex
hormones or DNA repair, such as the
androgen receptor gene, AIB1,
RAD51, and HRAS1, may affect risk
in carriers, although the data are too
preliminary to be utilized for tailored
risk assessments in carriers.[32]

Nongenetic Factors
Reproductive, environmental, and
lifestyle factors may also affect risk
in carriers. Rapid proliferation of
breast epithelial cells occurs during
puberty and pregnancy, which may
result in the loss of somatic BRCA1
or BRCA2 alleles.[35] Thus, it is of
interest to determine what impact reproductive
factors such as parity, pregnancy,
and breast-feeding have on
cancer risk among carriers, especially
given the tendency for high-risk women
to develop premenopausal breast
cancer. A neither strong nor consistent
association of these risk factors with
risk has emerged. Data are variable as
to the effect of age at first full-term
pregnancy, with some studies indicating
no association and others suggesting
a protective effect of late age
at first full-term pregnancy.[36,37]

Interestingly, data have shown that
tubal ligation reduces the risk of ovarian
cancer in BRCA1 but not BRCA2
carriers, and that this effect is magnified
in carriers who also used oral
contraceptives.[32] The specific mechanism
by which tubal ligation may reduce
risk has not been elucidated.
Additionally, it is important to note that
many of the studies examining the
significance of cancer risk modifiers
in mutation carriers are limited by
small sample size and thus must be
viewed as preliminary in nature.

  • Hormones-Studies suggest that
    exogenous hormones may also affect
    risk. Although data in the general population
    and in women with a family
    history of ovarian cancer have demonstrated
    that birth control pills reduce
    the risk of ovarian cancer, two
    large studies in mutation carriers
    reached opposite conclusions about
    this issue.[32] With respect to breast
    cancer risk, one large case-control
    study found an elevated risk of breast
    cancer in BRCA1 carriers who used
    the pill prior to 1975, before age 30
    years, or for more than 5 years.[38]
    No elevation in risk of breast cancer
    was observed for BRCA2 carriers.[38]
    Thus, mutation carriers who are considering
    initiating use of oral contraceptives
    must consider the limitations
    in data about the effect on breast and
    ovarian cancer risk, and must also
    weigh the other potential benefits and
    risks associated with such use.

    Another hormone of interest is
    tamoxifen, an antiestrogenic drug used
    in the adjuvant treatment of estrogenreceptor-
    positive breast cancer and
    as a chemopreventive agent in highrisk
    women. A large retrospective
    case-control study demonstrated that,
    similar to the effect observed in sporadic
    breast cancer patients, tamoxifen
    reduced the risk of contralateral
    breast cancer in BRCA1 and BRCA2
    carriers overall by 50%, with a greater
    effect seen in the former (62% vs
    37%).[39] This difference is especially
    interesting given that BRCA1 carriers
    tend to develop estrogen-receptor-
    negative breast cancers.[40]

    Indeed, analysis of 19 BRCA1/2
    mutation-positive participants in the
    National Surgical Adjuvant Breast
    and Bowel Project prevention trial
    (NSABP-P1) who developed breast
    cancer after randomization to tamoxifen
    or placebo showed that tamoxifen
    reduced the incidence in BRCA2,
    but not BRCA1, carriers.[41] However,
    the small sample size and lack
    of statistical significance of these results
    reduces the generalizability of
    these findings to clinical practice.
    More data are needed to adequately
    assess the effectiveness of tamoxifen
    in mutation carriers as a preventive
    measure to reduce the incidence of
    first or second breast cancers.

    One observation that is consistent
    with tamoxifen's efficacy in reducing
    the risk of breast cancer is the finding
    that oophorectomy in carriers less than
    age 50 (ie, premenopausal) has an
    effect of similar magnitude. For example,
    a retrospective study of 99
    BRCA1/2 carriers followed for a median
    of 8.8 years revealed that
    oophorectomy in premenopausal
    women reduced their risk of breast
    cancer by 53%.[42] Among women
    who have had breast cancer, the effect
    of oophorectomy on the risk of
    second breast cancers appears to be

    In addition, tamoxifen and oophorectomy
    appear to have synergistic effects,
    given that BRCA1/2-positive
    breast cancer patients who completed
    both interventions had lower risks of
    second primary breast cancers than
    women who underwent one or the
    other treatment.[26,39] However, as
    discussed later, the primary indication
    for oophorectomy is to reduce
    the risk of ovarian cancer, but the
    compelling evidence for its role in
    breast cancer risk management is reason to reinforce to carriers the benefit
    of obtaining this surgery prior to
    menopause, so that maximum benefits
    can be realized.

  • Diet and Exercise-Many BRCA1/2
    mutation carriers inquire about the effect
    of diet and exercise on breast
    cancer risk. Although there is an association
    between alcohol intake and
    breast cancer risk in the general population,
    there are no data about this or
    other dietary factors in carriers.[43]
    However, it has been postulated that
    given the genes' role in DNA repair,
    studies of drugs or nutritional supplements
    that reduce oxidative damage
    may be of interest.[32] One study
    showed that higher levels of physical
    activity during adolescence and having
    a normal weight at age 21 were associated
    with a delayed onset of breast cancer.[
    24] This area of modifiable risk
    factors, as with the others discussed
    above, will require further investigation
    before such information can be
    adequately considered in risk estimates
    or management guidelines. Nonetheless,
    given the other known health benefits
    of physical exercise, for example,
    it is reasonable to encourage women to
    pursue this activity.


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