REVIEWS

BRCA mutations in the management

of breast cancer: the state of the art
Steven A. Narod
Abstract | Genetic testing for BRCA1 and BRCA2 mutations is gaining acceptance in clinical oncology worldwide
and may help target unaffected high-risk women for prevention and for close surveillance. Annual screening
with MRI seems to be an effective surveillance strategy, but the long term follow-up of women with small MRI-
detected breast cancers is necessary to establish its ultimate value. Women with cancer and a BRCA mutation
may benefit from tailored treatments, such as cisplatin or olaparib. The treatment goals for a woman with a
BRCA-associated breast cancer should be to prevent recurrence of the initial cancer and to prevent second
primary breast and ovarian cancers. Mutations in BRCA1 and BRCA2 are presented throughout the world and
it is important that the benefits of genetic testing and of targeted therapies be extended to women who live
outside of North America and Western Europe.
Narod, S. A. Nat. Rev. Clin. Oncol. 7, 702–707 (2010); published online 19 October 2010; doi:10.1038/nrclinonc.2010.166

Introduction
The discovery of the BRCA1 gene in 19941 was quickly fol-
lowed by the discovery of BRCA2 in 1995.2 Shortly there-
after, genetic testing for breast cancer susceptibility was
introduced into clinical practice and testing is now widely
available in North America and in Europe. The hope is that
if a mutation can be identified before diagnosis, breast and
ovarian cancer can be prevented. BRCA mutation carriers
may be offered intensified surveillance so that breast cancer
may be diagnosed before metastatic spread. Furthermore,
the optimum treatment of women with breast (or ovarian)
cancer and a BRCA1 or BRCA2 mutation may be differ-
ent from that of non-carriers. However, the directed treat-
ment of women with hereditary breast cancer requires that
genetic testing be available at the time of diagnosis. These
topics will be discussed in this Review.
Screening for mutations
Genetic sequencing—whom to test?
Genetic testing is expensive and in most countries it is
rationed; thus, a lot of effort has been expended on decid-
ing upon whom to test. Relevant issues involved in decision
making include the cost of a test and the prior probability
of a woman having a positive test result. The probability of
a BRCA mutation being present is a function of the age
of the woman and her disease status, as well as her ethnic
group and her family history (Box 1).
Founder mutations
Genetic testing is greatly simplified and relatively inexpen-
sive in populations where founder mutations are present.
Womens College
Research Institute,
In these populations, a relatively small number of specific
790 Bay Street, BRCA1 or BRCA2 mutations account for the majority of all
Toronto, ON M5G 1N8,
Canada.
steven.narod@ Competing interests
wchospital.ca The author declares no competing interests.
mutations in that population. For example, two mutations
in BRCA1 (185delAG and 5382insC) and one mutation in
BRCA2 (6174delT) account for the vast majority of BRCA
mutations (>90%) in the Ashkenazi Jewish population.3
Thus, it is reasonable to test all Ashkenazi women with
breast or ovarian cancer for the three founder mutations.4,5
Moreover, in 2010, Metcalfe et al.6 suggested that this
recommendation be extended to include the Jewish popu-
lation at large. Other populations with important founder
mutations include ethnic isolates such as the Dutch7 and
French–Canadians.8 A common set of founder mutations
is present in Eastern Europe—encompassing Poland,9
Russia,10 Belarus11 and the Baltic states12,13—reflecting
their common Slavic ancestry. Founder mutations have
also been seen in island populations such as Iceland,14
Greenland,15 Cyprus16 and the Bahamas.17 A number of
founder mutations have been identified in patients from
several South American countries,18,19 but few studies have
been carried out in these populations. Founder muta-
tions seem to be less important in the UK, Western and
Southern Europe, Asia and Africa.
In contrast to full gene sequencing, testing for founder
mutations can be done at relatively low cost. In some cases
(for example, in Ashkenazi Jewish women or women from
the Bahamas) the founder mutations are common and the
probability of a breast cancer patient having a mutation
exceeds 10%,4,20 but in other populations the frequency
of founder mutations is not higher than expected (for
example, 5–6% of Polish or French–Canadian premeno-
pausal patients with breast cancer carry a BRCA muta-
tion8,21). However, where founder alleles are present and
represent the majority of mutations in a population, the
background genetic diversity will be less than that of an
ethnically mixed population and the prevalence of non-
founder mutations is likely to be relatively low. In practical

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© 2010 Macmillan Publishers Limited. All rights reserved

terms, the criteria for testing a patient from a population
with a founder mutation should be less stringent than for
an ethnically mixed population. By contrast, for full gene
sequencing, the criteria should probably be more stringent
than otherwise. For example, in our clinic we offer genetic
testing for three founder mutations to all Ashkenazi breast
cancer patients based on a low cost of testing (approxi-
mately CAD$100) and a high prevalence of mutations
(12%).4 However, if a founder mutation is not present, we
are reluctant to invest additional resources in search of
a rare non-founder mutation, unless the family history
is remarkable.
The 14% mutation prevalence in women with a non-
mucinous invasive ovarian cancer indicates that it is ratio-
nal to recommend genetic testing in this cancer type.22 For
patients with breast cancer, both age-of-onset and recep-
tor status are important predictors of a mutation. The
majority of BRCA1 mutation-associated breast cancers
are triple-negative (estrogen receptor-negative, proges-
terone receptor-negative, HER2-negative),23 but only
about 10% of early-onset triple-negative breast cancers
are BRCA1-positive.24,25 Age-of-onset alone is a relatively
weak criterion for genetic testing, but the predictive value
of age-of-onset is improved if the triple-negative pheno-
type is used to stratify cases.26,27 Hence it is rational to offer
genetic testing to all women diagnosed as having triple-
negative breast cancer before the age of 50, whereas for
estrogen-receptor positive cases, in the absence of a family
history, the upper age limit for testing unselected cases
should be 30–35 years.
The identification of mutation carriers before the
development of cancer is desirable as preventative measures
can be taken at an early stage. However, the prior prob-
ability of a mutation being present is higher in an affected
woman of a given age, than in an unaffected woman of the
same age; thus, paradoxically, it is often easier to qualify
for testing after a diagnosis of cancer than before. In the
absence of a personal history of cancer, genetic testing
is based on a family history of early-onset breast cancers
(age <50 years) and ovarian cancers (at any age). Typically,
a family with two early-onset breast cancers or ovarian
cancers would qualify for testing.
International variation
Genetic testing has been available in Canada, the USA and
the UK since 1996. The extent to which genetic testing
is employed varies globally and remains rare outside of
North America and Western Europe. The international
variation is largely due to market forces and the extent
to which genetic testing is an insured service. However,
other important factors include the availability of genetic
counseling, the presence of testing facilities and physi-
cian awareness and referral networks. In the past decade,
genetic testing has been introduced in Eastern Europe
and some latin American countries, largely due to the
presence of founder mutations in these populations.
The use of the various preventive practices (described
in detail below) varies widely between countries.28 For
example, in North America, patients with cancer are much
more likely than their European counterparts to undergo
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FoCuS on bREASt CAnCER
Key points
■ Genetic testing for BRCA1 and BRCA2 is facilitated by the presence of one or
more founder mutations in a population
■ Ideally, prevention of hereditary breast cancer should encompass the entire
period of risk
■ Preventive oophorectomy reduces the risks of both breast and ovarian cancer
■ Tamoxifen is currently the only drug approved for breast cancer prevention in
premenopausal women
■ The treatment of patients with breast cancer who have a BRCA1 or BRCA2
mutation should target the recurrence of the initial cancer and prevention of
second primary cancers
■ Rapid genetic testing at the point of breast cancer diagnosis may influence
treatment plan, in particular with regard to the use of novel agents, such as
cisplatin and olaparib
Box 1 | Factors that predict a BRCA1 or BRCA2 mutation
■ Ethnic group (for example, Ashkenazi Jewish)
■ Young age (<50 years) of onset of breast cancer
(especially for triple-negative disease)
■ Invasive ovarian cancer (any age)
■ Family history of breast or ovarian cancer
bilateral mastectomy as part of the initial treatment.28
In both Europe and North America, rates of preventive
oophorectomy are high (approximately 60%), but tamox-
ifen chemoprevention is infrequent in both regions.28 The
Netherlands is notable for a very high uptake of preven-
tive mastectomy among gene carriers.29 Genetic testing
services have now been established in Japan and South
America, but to date, little information has emerged from
these regions regarding the frequencies of preventive and
treatment options.
Cance screening—selecting the best method
Screening for breast cancer in BRCA1 and BRCA2 muta-
tion carriers should ideally include an annual MRI
examination. Studies have consistently shown MRI to be
more sensitive than mammography.30–32 In a prospective,
non-randomized, study, the incidence of advanced breast
cancer (2 cm or more or node-positive) was reduced by
70% in the 6-year follow-up period in women with a BRCA
mutation who underwent regular MRI examination, com-
pared with those who had conventional mammography.33
To achieve maximal benefit, MRI screening should be con-
ducted annually in women aged 25–65 years, or a total of
40 examinations should be carried out. This method of
screening is an expensive commitment; each MRI exami-
nation costs between US$1,000 and $3,000. In addition,
long-term health implications of 40 doses of gadolinium
have not been evaluated. Moreover, the benefit of MRI
probably does not persist much beyond 2 years after the
last screening examination. Mammography is a much
less expensive alternative to MRI, but in cohort studies of
BRCA mutation carriers who were screened by mammo-
graphy alone, the rate of interval cancers was unacceptably
high, that is, in some cases the majority of breast cancers
were found between screens by the patient herself.34–37
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Hereditary breast cancer
After a diagnosis of breast cancer in one breast, a woman
with a BRCA1 or BRCA2 mutation experiences a high risk
of contralateral breast cancer. The 10-year risk of contra-
lateral breast cancer has been estimated to be between 20%
and 30%.38–41 Factors that predict the risk of contralateral
breast cancer include an early age of diagnosis of the first
breast cancer and a family history of early-onset breast
cancers in first-degree relatives.38–41
natural history of hereditary breast cancer
Most breast cancers in women with a BRCA1 mutation are
diagnosed at a young age (typically between ages 30 and
50 years) and are triple-negative.26 To a large extent, the
natural history of cancer in women carrying BRCA muta-
tions is similar to that of young women with triple-negative
breast cancer. The salient features of triple-negative cancers
include a propensity to early distant recurrence (com-
monly within 1–3 years) and an attenuated relationship
between tumor size, lymph-node status and survival.42 In
an historical cohort study from Israel, Rennert and col-
leagues found that overall, the 10-year survival of women
with a BRCA1 mutation (49%) or a BRCA2 mutation (48%)
was similar to that of non-carriers (51%), but tumor size
did not predict survival in the BRCA1-positive cohort.43
Women with small cancers (<2 cm) had relatively poor
outcomes and women with large cancers (>2 cm) did com-
paratively well. There are few comparable data for BRCA2
mutation carriers.
Primary prevention of hereditary breast cancer
Consideration of strategies for primary prevention in terms
of their potential for reducing the lifetime risk of cancer
could be very useful. The lifetime risk of breast cancer is
about 70% for a BRCA1 mutation carrier and about 60%
for a BRCA2 mutation carrier.44 The risk of ovarian cancer
in BRCA1 and BRCA2 mutation carriers is around 40%
and 20%, respectively.44 Strategies for cancer prevention
should be evaluated in terms of the magnitude and dura-
tion of the protective effect. Prevention strategies can be
divided into those that offer transient protection and those
that offer lifelong protection. For example, a 5-year course
of tamoxifen might offer an unaffected woman protection
against breast cancer for 15 years—including the 5 years
on therapy and 10 years thereafter. However, the BRCA1
mutation carrier faces a significantly elevated risk of breast
cancer from the age of 25 to 70 years (a 45-year period);
therefore, a single course of tamoxifen cannot be expected
to offer lifetime protection in this group.
Tamoxifen has been associated with a 70% reduction
in contralateral breast cancer in both BRCA1 and BRCA2
mutation carriers45 and it is reasonable to assume that it
should be effective in primary prevention as well. One
small study of 288 breast cancer cases, published in 2001,
found that tamoxifen was not associated with a reduc-
tion in the risk of first primary breast cancer in BRCA1
mutation carriers, but a risk reduction was seen in BRCA2
mutation carriers (62% reduction in breast cancer inci-
dence).46 No further studies have been published on
primary prevention with tamoxifen. To a large extent,
704 | DECEMBER 2010 | voluME 7
© 2010 Macmillan Publishers Limited. All rights reserved
this is because, outside of clinical trials, few unaffected
high-risk women have elected to take tamoxifen. Metcalfe
and colleagues estimated that only 6% of unaffected BRCA
mutation carriers with intact breasts choose to take tamox-
ifen for chemoprevention.28 These women often cite con-
cerns about potential side effects as the reason for this
choice. An alternate to tamoxifen for postmenopausal
women (including women who have undergone preven-
tive oophorectomy) is raloxifene, but data on raloxifene
in BRCA mutation carriers have not been published. In
the 2010 update of the Study of Tamoxifen and Raloxifene
(STAR) trial, the protective effect of tamoxifen exceeded
that of raloxifene by approximately 25%.47 little is known
about the potential benefit of tamoxifen or raloxifene in
women after oophorectomy. The majority of BRCA muta-
tion carriers in North America will undergo an oophorec-
tomy within 1 year of finding out their mutation status.48 In
one small study of BRCA1 and BRCA2 mutation carriers,
a past history of tamoxifen treatment was a risk factor for
endometrial cancer.49 The utility of tamoxifen for prevent-
ing distant recurrence specifically in women with BRCA1
mutation-associated breast cancer has not been evaluated
in any of the (few) studies that have examined clinical
outcomes in patients with hereditary breast cancer.
Oophorectomy is associated with reductions in the
risks of both ovarian and breast cancer in BRCA muta-
tion carriers.50–52 Approximately half of breast cancers
occur in BRCA1 mutation carriers before the age of 40
and, therefore, the earlier the oophorectomy, the greater
the potential for prevention. If oophorectomy is per-
formed after the age of 50 there is probably no benefit
for breast cancer risk. In a case-control study by Eisen
et al.,50 an oophorectomy before the age of 40 was associ-
ated with a reduction in the risk of breast cancer of 64% in
women with a BRCA1 mutation and 31% in women with
a BRCA2 mutation. Similar estimates were generated in a
meta-analysis by Rebbeck and colleagues.51 To what extent
the effect of oophorectomy on breast cancer risk dimin-
ishes with time since oophorectomy is not yet known.
Eisen et al.50 observed no protective effect for an oopho-
rectomy performed at least 15 years before diagnosis.
Some women are reluctant to undergo oophorectomy at
the age of 35 because of a desire to preserve fertility and
most are concerned about the acute effects of surgical
menopause. Several of the symptoms of menopause can
be mitigated by hormone replacement therapy, but the
quality-of-life does not return to presurgical levels.53 Two
studies reported that hormone replacement therapy did
not increase the subsequent risk of breast cancer in BRCA
mutation carriers.54,55 Evidence indicates that hormone
replacement may increase the risk of ovarian cancer in
the general population,56 but this association has not been
established in BRCA mutation carriers.
Owing to the limitations of tamoxifen, oophorectomy
and MRI screening described in this Review, many women
opt for preventive mastectomy. Cohorts of women with
preventive mastectomy have been followed in Europe and
North America.29,57,58 These studies indicate that the pro-
tection offered by bilateral total mastectomy approaches
100%, and the protection is permanent.29,57,58
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Secondary prevention of contralateral cancer
Several studies have reported that the risk of contralateral
breast cancer was reduced in women who had an oopho-
rectomy. Metcalfe et al. (unpublished work) estimated
the risk of contralateral breast cancer in 810 women
with a BRCA mutation or with a BRCA mutation in the
family. Among women diagnosed with the first breast
cancer below the age of 40 and with two ovaries intact,
the 15-year risk of contralateral breast cancer was 58%.
Oophorectomy was associated with a 52% reduction in
the risk of contralateral breast cancer.
In North America, about half of BRCA1 mutation car-
riers with breast cancer are treated with bilateral mastec-
tomy, but this practice is relatively rare in Europe.28 To date,
no study has documented a reduction in mortality from
cancer attributable to contralateral mastectomy. However,
if the goal of contralateral mastectomy is to reduce the
number of deaths from contralateral breast cancer, it may
take at least 20 years of follow-up to document a reduction
in mortality.
Treatment of hereditary breast cancer
In choosing treatment for a BRCA-positive woman
with breast cancer, several factors should be taken into
consideration, including the risk of recurrence and the
risks of contralateral breast cancer and ovarian cancer.
Theoretically, women with impaired DNA repair ability
might experience more adverse effects from radiotherapy
and/or chemotherapy than women without a BRCA muta-
tion, but this outcome has not yet been observed.59–62 Thus,
the choice of a treatment should be based on evidence of
its effectiveness.
To a large extent, the response to treatment of BRCA1
mutation-associated cancers is related to the underlying
genetic defect, which may differ from other cancers with a
similar histological appearance. On the basis of preclinical
models, it was predicted that BRCA1 mutation-associated
breast cancers would be resistant to taxanes and sensitive
to DNA damaging agents, such as mitomycin C and cis-
platin.63–69 To date, few clinical trials have been conducted
on the hereditary subgroup and several reports are based on
observational trials. Robson and colleagues studied an
Ashkenazi Jewish cohort with early-stage breast cancers.70
The researchers found that women with a BRCA1 mutation
who did not receive chemotherapy had a worse outcome
than women with non-hereditary breast cancers of similar
size, but the adverse effect of mutation status on prognosis
was nullified if chemotherapy was given. Similarly, an
enhanced benefit of chemotherapy for BRCA1 mutation
carriers was seen in the study by Rennert et al.43 In 2008
Byrski and colleagues reported early results of a study of
neoadjuvant chemotherapy, showing that BRCA1 mutation
carriers were less likely to respond to taxanes (complete
or partial response) than were women without a BRCA1
mutation.71 In a follow-up study published in 2010, Byrski
et al.72 found that BRCA1 mutation carriers were highly
sensitive to neoadjuvant cisplatin chemotherapy. Of 12
women who were given cisplatin, 10 (83%) experienced
a pathologic complete response, compared with 13 of 76
women (17%) who received an anthracycline-containing
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FoCuS on bREASt CAnCER
regimen. It is not yet clear if the responsiveness of breast
cancer patients to cisplatin relates more to the triple-
negative phenotype or to the BRCA mutation status per se.
However, the degree of response to cisplatin among BRCA1
mutation carriers seems to exceed that of non-carrier
women with triple-negative cancer. In 2010, Silver et al.73
reported that four of 26 women with non-BRCA1 triple-
negative breast cancer had a pathologic complete response
after cisplatin treatment. In the same study, both women
with a BRCA1 mutation and triple-negative breast cancer
had a complete response. Clearly, more data on the use of
cisplatin in BRCA1 mutation carriers and other patients
from studies using multiple clinical end points are needed
before specific clinical recommendations can be made.
In the past 5 years, there has been much optimism
expressed in anticipation of a new class of drugs called
poly (ADP-ribose) polymerase (PARP) inhibitors.74
Members of this class of drugs have shown effectiveness
against BRCA1-positive and BRCA2-positive breast cancer
cells in preclinical models and phase II studies.74,75 PARP
is involved in the repair of single-strand DNA breaks
and inhibition of the enzyme results in an impairment
of DNA repair and an augmentation in the number of
double-strand DNA breaks. This phenotype is particu-
larly detrimental to cells with no intact BRCA1 or BRCA2
protein (such as breast cancer cells in mutation carriers,
which have undergone loss of heterozygosity) and results
in cell death. Single agent olaparib (a PARP inhibitor)
has shown effectiveness in treating metastatic hereditary
breast cancer,76,77 and it is hoped that this drug, or others
in its class, will be used to potentiate the effect of other
chemotherapies, such as cisplatin.
Conclusions
Increasing evidence indicates that knowledge of the
BRCA1 and BRCA2 mutation status will enable a patient
and her health care provider to make informed decisions
about cancer prevention, screening and treatment. To date,
compelling evidence has been noted regarding the sur-
gical prevention of hereditary breast and ovarian cancer,
through preventive mastectomy and oophorectomy. The
benefit of annual MRI screening has been suggested by a
number of studies, but has not yet been shown to reduce
mortality. Further studies need to be done on chemo-
prevention and on individualized therapy for women with
breast cancer and a BRCA1 or BRCA2 mutation.
Review criteria
The articles cited in this Review represent, from
the author’s point of view, the most important and
representative articles of their type published in
the English literature between 1994 and 2010 and
accessible through PubMed. Search terms include
“BRCA1”, “BRCA2”, “breast cancer”, “screening” and
“management”. No additional websites were searched.
The author regrets that, due to space limitations, not
all pertinent articles were included in this Review.
Several unpublished results (and in press articles) were
communicated here with permission from the authors.
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