Seminars in Oncology ] (2016) ]]]–]]]

Contents lists available at ScienceDirect

Seminars in Oncology
journal homepage: www.elsevier.com/locate/ysonc

Updates on breast cancer genetics: Clinical implications of detecting

syndromes of inherited increased susceptibility to breast cancer
Erin F. Cobaina,b, Kara J. Millirona,b, Sofia D. Merajvera,b,c,n
a
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
b
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
c
Department of Epidemiology, University of Michigan School of Public Health , Ann Arbor, MI

a r t i c l e in fo a b s t r a c t

Since the initial discovery that pathogenic germline alterations in BRCA 1/2 increase susceptibility to
Keywords: breast and ovarian cancer, many additional genes have now been discovered that also increase breast
Hereditary breast cancer cancer risk. Given that several more genes have now been implicated in hereditary breast cancer
Genetic testing syndromes, there is increased clinical use of multigene panel testing to evaluate patients with a
Panel testing suspected genetic predisposition to breast cancer. While this is most certainly a cost-effective approach,
Variant of uncertain significance broader testing strategies have resulted in a higher likelihood of identifying moderate-penetrance genes,
BRCA1/2 for which management guidelines regarding breast cancer risk reduction have not been firmly
TP53
established. In addition, the testing of more genes has led to increased detection of variants of uncertain
significance. We review the current knowledge regarding both high- and moderate-risk hereditary breast
cancer syndromes, as well as additional genes implicated in hereditary breast cancer for which there is
limited data. Furthermore, strategies for cancer risk reduction in mutation carriers as well as therapeutic
implications for those patients who harbor pathogenic germline alterations are discussed.
& 2016 Elsevier Inc. All rights reserved.

1. Introduction mutations [7]. Interestingly, whereas somatic de novo mutations

1.1. History of BRCA1 and BRCA2 gene mapping and discovery
In 1990, Mary-Claire King and colleagues reported genetic
linkage studies in families with early-onset breast cancer which
implicated a relatively narrow region in chromosome 17q [1]. The
previous year, Narod and colleagues had identified linkage in the
same region in families with breast and ovarian cancer [2]. These
seminal reports spurred a competitive race between several
international collaborations to isolate the BRCA1 gene, which was
finally cloned in 1994 [3] and mutations were identified in tumors
belonging to the linked kindreds [4]. BRCA1, and BRCA2 isolated in
1995 [5], are essential to the process of repairing double strand
breaks in DNA via homologous recombination [6]. In this form of
repair, the DNA is restored to its original sequence; however, when
this process is deficient, other forms of less conservative DNA
repair take place. One such mechanism is non-homologous end
joining, which simply joins two ends of broken DNA without using
a template sequencing, often resulting in the introduction of
n
Corresponding author. Sofia D. Merajver, Division of Hematology/Oncology,
Molecular Medicine & Genetics, Department of Internal Medicine, Room 7303
Cancer Center , 1500 E Medical Center Dr, Ann Arbor, MI, 48109.
E-mail address: smerajve@umich.edu (S.D. Merajver).
were identified in sporadic ovarian cancers [8] they were relatively
rare in breast cancers, suggesting that BRCA1 differed from
classic tumor suppressors such as WT1 or TP53 in its spectrum
of somatic changes. Finding germline mutations in families affected
with breast and ovarian cancer set the stage for the integration of
genetic counseling and predisposition testing into clinical care for
cancer risk management of high-risk patients and families [9].
1.2. Early efforts to incorporate genetic counseling and testing into
the clinic
The discovery of the breast cancer susceptibility genes BRCA1
and BRCA2 made predictive genetic testing possible. Academic
centers initially took the lead in offering integrated risk evalua-
tions, including counseling before and after genetic testing and
personalized risk management plans tailored to patients’ age,
health status, reproductive plans, and cultural background. Since
then, genetic risk assessment for breast cancer risk has been
integrated into clinical care in a number of different clinical
settings (primary care, obstetrics and gynecology, oncology, and
screening mammography) and the emergence of patient advocacy
groups and increasing interest about genetic medicine on the part
of patients and their providers has significantly increased referrals
for genetic risk evaluation.

http://dx.doi.org/10.1053/j.seminoncol.2016.10.001
0093-7754/& 2016 Elsevier Inc. All rights reserved.
2 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
2. Hereditary breast cancer syndromes
Most women who present with breast cancer do not have an
inherited predisposition to developing the disease. However, up to
20% of patients with a family history of breast cancer may harbor a
germline mutation associated with increased cancer risk [10].
Inherited susceptibility to developing breast cancer most com-
monly results from mutations in BRCA1 or BRCA2; however, addi-
tional genes have been implicated in genetic predisposition to
breast cancer. Below, these syndromes are classified into high-risk
and moderate-risk of developing breast cancer (Table 1).
2.1. High-risk syndromes
2.1.1. BRCA1- and BRCA2-associated hereditary breast cancer
Approximately 40% of hereditary breast and ovarian cancer (HBOC)
cases are associated with pathogenic germline alterations in BRCA1 or
BRCA2, which are inherited in an autosomal dominant fashion.
Families that harbor these pathogenic mutations are often character-
ized by multiple females affected by breast cancer at an early age
(premenopausal). While tumors associated with germline alterations
in BRCA1 or BRCA2 are more likely to be triple negative [11], other
histologic subtypes can be seen. Estimates of lifetime risk of develop-
ing breast cancer for patients with BRCA1 and BRCA2 mutations varies
across studies; however, pooled results suggest cumulative risk of
developing breast cancer by age 70 in BRCA1 mutations carriers is
approximately 65% compared to 45% in BRCA2 mutation carriers [12].
In addition to a higher lifetime risk of developing breast cancer with a
BRCA1 mutation, these patients also tend to have earlier onset of
disease, particularly before age of 50 [13–15]. BRCA1 and BRCA2
germline mutations are also found at higher frequency among certain
ethnic groups. For example, approximately 1 in 40 individuals of
Ashkenazi Jewish decent unselected for personal or family history of
malignancy carry one of three founder mutations: 187delAG or
5385insC in BRCA1 or 6174delT in BRCA2 [16]. Founder mutations in
BRCA1 and BRCA2 have also been reported in the Netherlands, Sweden,
Hungary, Iceland, Italy, France, South Africa, Pakistan, Asia, French
Canadians, Hispanics, and African Americans [12,17–21]. Men with
BRCA2 mutations have an approximately 7%–8% lifetime risk of
developing breast cancer (a risk comparable to women who are at
lower than average risk) versus 1% lifetime risk for those with BRCA1
mutations [22,23].
2.1.2. Li-Fraumeni syndrome
Li-Fraumeni Syndrome (LFS) is associated with germline alter-
ations in the tumor-suppressor gene TP53 and is inherited in an
Table 1
Summary of high- and moderate-penetrance genes implicated in genetic predisposition to breast cancer.
Germline alteration Lifetime breast cancer risk
BRCA1 65% (by age 70)
BRCA2 45% (by age 70)
TP53 50% (by age 60)
STK11 30%–50% (lifetime)
PTEN 85% (lifetime)
CDH1 60% (lifetime)
MSH1, MSH2, MLH1, Unknown
PMS2, EPCAM
CHEK2 20%–25% (lifetime)
PALB2 33% (by age 70 without family history), 58% (by N/A
age 70 with family history)
ATM 20% (lifetime)
autosomal dominant fashion. Individuals with this syndrome are
at very high risk of developing multiple malignancies in childhood
or early adulthood, including but not limited to: breast cancer,
sarcomas, brain cancer, leukemias, lung cancers, and adrenocort-
ical cancers [24,25]. For females, the risk of developing breast
cancer by the age of 60 is approximately 50% and the median age
at diagnosis is under 35 years [25–28]. Breast cancer arising in
women with a germline TP53 mutation is more likely to have
amplification of the human epidermal growth factor receptor 2
(HER2) [29]. In general, mastectomy is usually recommended for
surgical management of breast cancers in patients with LFS, as
radiation exposure can markedly increase the risk for developing a
secondary radiation-associated malignancy.
2.1.3. Peutz-Jeghers syndrome
Peutz-Jeghers Syndrome (PJS) results from germline alterations
in the STK11 gene and is inherited in an autosomal dominant
fashion. Patients with PJS often present with intestinal obstruc-
tions as a result of small bowel polyps; however, they also have
very elevated risks of gastrointestinal cancers [30], and women are
at increased risk for breast and ovarian cancer. Lifetime risk for
breast cancer is approximately 55% and median age at diagnosis is
in the late 30s [30,31]. Mucocutaneous pigmentation and or
gastrointestinal hamartomatous polyps are noted in 95% of indi-
viduals with PJS [30].
2.1.4. PTEN hamartoma tumor syndrome (Cowden syndrome)
PTEN hamartoma tumor syndrome (PTHS) results from germ-
line alterations in the tumor-suppressor gene PTEN. For patients
with this condition, the lifetime risk of developing breast cancer is
approximately 85% [32]. Most women are diagnosed with preme-
nopausal breast cancer [33] and these patients also have increased
risk of benign breast diseases such as fibroadenomas [34]. Women
with this syndrome also have an increased risk for endometrial
cancer. Men and women with a PTEN gene mutation also have an
increased risk for thyroid cancer (particularly follicular type), renal
cancer, and colon cancer. Additional non-cancer manifestations
include autism spectrum disorder, macrocephaly, hamartomas,
trichilemmomas, and plantar keratosis.
2.1.5. Hereditary diffuse gastric cancer syndrome
This syndrome is characterized by genetic susceptibility to
diffuse gastric cancer, associated with germline cadherin-1
(CDH1) mutations [35,36]; however, CDH1 mutations are also
associated with increased risk of lobular breast cancer in women,
Most common associated Other associated malignancies
breast cancer pathology
Triple Negative Ovarian, fallopian tube, primary peritoneal, pancreas, prostate
Triple-negative or estrogen Ovarian, melanoma, fallopian tube, primary peritoneal,
receptor–positive pancreas, prostate. stomach, gallbladder/biliary
Her2-amplified Sarcoma, CNS malignancies, adrenocortical carcinoma,
gastrointestinal, radiation-associated cancers
N/A Colorectal, stomach, small bowel, pancreas, ovarian, cervical,
Sertoli cell testicular
N/A Thyroid, endometrial, colorectal, renal
Invasive lobular carcinoma Stomach (diffuse)
N/A Colorectal, endometrial, ovary, stomach, small bowel,
hepatobiliary, CNS
Estrogen receptor–positive Colorectal (1100delC mutation), stomach, prostate, kidney,
thyroid, sarcoma
Pancreas
N/A Pancreas
 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
with a lifetime risk of developing breast cancer of approximately
60% [35–37]. Of note, germline CDH1 mutations have been
identified in patients with invasive lobular breast cancer in the
absence of diffuse gastric cancer, implying that development of
gastric cancer is not an obligatory component of the syndrome
[38]. While guidelines suggest that all patients with a confirmed
pathogenic CDH1 mutation be counseled regarding prophylactic
gastrectomy to mitigate risk of developing diffuse gastric cancer,
whether this recommendation should be modified for individuals
with no family history of gastric cancer remains controversial. It
should be noted, however, that individuals who present with
lobular breast cancer may harbor a de novo mutation, and lack
of family history does not necessarily indicate a low-penetrance
mutation [39,40].
2.1.6. Lynch syndrome
Lynch syndrome, otherwise known as hereditary nonpolyposis
colon cancer (HNPCC), results from germline alterations in genes
involving mismatch repair (MSH2, MLH1, MSH6, and PMS2) or a
mutation in the epithelial cell adhesion molecule (EPCAM) gene
[41,42]. While risks for colon, endometrial, ovarian and stomach
cancers are markedly increased, some studies have suggested risk
for female breast cancer may also be higher [41,43,44]; however,
the magnitude of risk may vary by the specific gene affected [45].
2.2. Moderate-risk syndromes
2.2.1. CHEK2
The checkpoint kinase 2 gene (CHEK2) is involved in DNA
damage repair via the Fanconi anemia (FA)–BRCA pathway [46].
There are many variants of CHEK2 that have been identified;
however, the 1100delC polymorphism has been associated with a
two- to threefold increased risk of breast cancer, particularly in
Caucasian women [47–50]. The lifetime risk of breast cancer is
approximately 20%–25% among CHEK2 mutations carriers who
have a positive family history of breast cancer [51,52]. When
compared with breast cancer patients that do not harbor a germ-
line alteration in CHEK2, mutation carriers are more likely to be
younger at diagnosis, have a family history of breast cancer, have
estrogen receptor–positive breast cancer, develop a second pri-
mary breast cancer, and appear to have higher risk of cancer-
specific death [50]. Male CHEK2 carriers also appear to have a
higher risk of developing male breast cancer [53]. Chek2 gene
mutations also cause an increased risk for thyroid cancer, colon
cancer, and perhaps ovarian cancer.
2.2.2. PALB2
Partner and localizer of BRCA2 (PALB2) is a gene that is integral
in mediating the BRCA2 DNA damage response. Biallelic germline
mutations in PALB2 have been identified in a subset of patients
with of FA and monoallelic deleterious germline alterations in
PALB2 have been identified in approximately 2% of familial breast
cancer cases [54]. Carriers of PALB2 germline mutations have a risk
of developing breast cancer that is similar to patients with
pathogenic BRCA2 alterations [55,56], although risk for those
patients who also have a positive family history of breast cancer
may be higher [54].
2.2.3. ATM
Ataxia telangiectasia mutated (ATM) is involved in DNA repair.
While carriers of biallelic germline mutations develop the autoso-
mal recessive disorder ataxia-telangiectasia (AT) [57], monoallelic
germline mutations have been identified at increased frequency
among patients with various cancer types including pancreatic and
breast cancer, implicating it in cancer susceptibility. Females who
3
are heterozygous carriers of deleterious ATM gene mutations
appear to have a risk of breast cancer that is approximately
twofold higher than that of the general population [57–59]. ATM
germline mutations are relatively common in the general popula-
tion, with approximately 3% of Caucasians in the United States are
ATM heterozygotes [60].
2.3. Additional genes implicated in hereditary breast cancer
Several other genes have been identified that may increase the
risk of developing breast cancer; however, additional studies are
needed to better characterize their specific risk. These genes are
being more frequently identified in clinical practice, particularly
with the increase in use of multigene panel testing. Kurian and
colleagues noted in a study of 198 women referred for clinical
BRCA1/2 testing that approximately 11% of patients who tested
negative for mutations in BRCA1/2 tested positive for pathogenic
variants in other genes [61]. Below is a brief summary of the
available data regarding genes that have been implicated in
hereditary breast cancer.
2.3.1. BRCA1-associated RING domain protein (BARD1)
BARD1 shares strong structural homology with BRCA1, and has
been demonstrated to be involved with the cellular DNA repair
process [62]. Several studies have identified germline BARD1
mutations resulting in protein truncation in breast cancer families
that do not harbor germline alterations in BRCA1/2 [63–65]. As
these reported germline alterations occur at low frequency even in
high-risk populations, information regarding specific breast cancer
risk and penetrance is still lacking.
2.3.2. BRCA1 interacting protein C-terminal helicase 1 (BRIP1)
BRIP1 encodes a helicase-like protein that directly binds to
BRCA1 and is involved in homologous recombination [66]. Inher-
itance of two pathogenic germline alterations in BRIP1 has also
been demonstrated to be causative of FA [67]. Several studies have
reported that truncating germline BRIP1 mutations confer
increased susceptibility to breast cancer [68–71]; however, a
recently reported large study from Europe reported that genotyp-
ing from over 48,000 breast cancer cases and 43,000 controls
found the number of truncating variants of BRIP1 to be similar
between the two groups, suggesting that germline BRIP1 muta-
tions may not substantially increase breast cancer risk [72]. BRIP1
gene mutations may also cause an increased risk for developing
ovarian cancer, although the exact risk data is in flux.
2.3.3. Mre11 (MRN) complex (includes MRE11, RAD50, and NBS1
genes)
In response to DNA double strand breaks, the MRN complex
genes sense DNA damage and aid in the recruitment of the DNA
repair machinery [73]. In a study that mutation screened the MRN
genes in 1,313 early-onset breast cancer cases and 1,123 heathy
controls, germline alterations in the MRN genes occurred at higher
frequency in those with breast cancer, suggesting that these may
be intermediate-risk breast cancer susceptibility genes [74].
2.3.4. RAD51 paralogs (RAD 51 C and D)
The RAD51C and D genes encodes proteins that are essential for
homologous recombination repair. Similar to BRIP1 above, biallelic
inheritance of missence mutations in RAD51 can cause a FA-like
syndrome [75]. In a study reported by Meindl and colleagues, six
monoallelic pathogenic mutations were identified in RAD51C in
more than 1,000 German families with gynecologic malignancies,
suggesting that these mutations confer an increased risk for breast
and ovarian cancer [76]. RAD51D was first implicated as a potential
4 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
risk gene for the development of ovarian cancer [77]; however, its
correlation with breast cancer risk is less clear. A recent case report
featured identification of a pathogenic RAD51D germline mutation
in a young female with triple-negative breast cancer and family
history of male breast cancer [78].
2.3.5. MUTYH
The MUTYH gene is an important component of the DNA base
excision repair mechanism. Bi-allelic MUTYH mutation carriers have a
28-fold increase in colorectal cancer risk, while mono-allelic carriers
have a moderately increased colorectal cancer risk [79]. Mono-allelic
MUTYH mutations are relatively common (carrier rate is 1% in the
population) and it remains controversial whether or these confer an
increased risk of breast cancer, although studies have reported
increased risk in both bi-allelic [80] and mono-allelic [81] carriers.
Case control studies, however, have failed to demonstrate a clear
association between mono-allelic MUTYH carriers and increased
susceptibility to breast cancer [82].
3. Strategies for genetic testing for genetic predisposition to
breast cancer
3.1. Criteria for breast cancer genetic risk evaluation
Guidelines for genetic counseling and possible testing for
genetic predisposition to breast cancer have been established by
the National Comprehensive Cancer Network [83]. Key criteria in
these guidelines are summarized in Table 2.
3.2. Collection of family history in breast cancer risk evaluation
Family history is a complex tool for assessing disease risk that can
offer insight into the multifactorial risk for many conditions (especially
cancer) and can clarify a patient’s potential risk and can play an
important role in increasing uptake and effectiveness of preventative
services.
A detailed family history, comprising at least three generations, if
available, is a highly useful first step in cancer risk evaluation. If
possible, confirmation of cancer diagnosis should be made via medical
records or pathology reports. Information on gynecologic malignancies
affecting a family member can be especially unreliable, and obtaining
pathology confirmation becomes quite important in these cases to
prevent inaccurate risk calculations. Important components of family
history are summarized below in Table 3.
Table 2
NCCN criteria for HBOC risk evaluation.
Risk evaluation for HBOC should be performed in patients who meet one or more of the following criteria:
1. Female breast cancer diagnosed r 50 years of age
2. Triple-negative breast cancer diagnosed at age r 60 years
3. Invasive ovarian, fallopian tube, or primary peritoneal cancer
4. Male breast cance
5. Any HBOC-associated cancers, regardless of age at diagnosis, and of Ashkenazi Jewish Ancestry
6. Two or more primary breast cancers
Risk evaluation should be performed in patients with breast cancer and first-, second-, or third-degree relatives with any of the following:
1. Breast cancer diagnosed at age r50 years in one or more relatives
2. Invasive ovarian, fallopian tube, or primary peritoneal cancer in one or more relatives
3. Breast, prostate, and/or pancreatic cancer diagnosed at any age in two or more relatives
3.3. Options for genetic testing (single gene versus multigene panel
testing)
The use of genetic testing in suspected HBOC has expanded
well beyond evaluating for mutations in BRCA1/2 since these tests
became commercially available in the 1990s. Next-generation
sequencing technologies (NGS) have made it possible to sequence
multiple genes simultaneously at a cost that is often lower
compared to Sanger sequencing for single genes. Currently, many
patients undergoing evaluation for HBOC ultimately have multi-
gene panel testing. Selection of patients appropriate for single
gene (ie, BRCA 1/2 sequencing only) versus multigene panel testing
in suspected HBOC is currently a topic of debate within the field.
Many laboratories are marketing multigene panel testing as a
“more is better” approach; however, paucity of data regarding
cancer risks and lack of specific management recommendations
for carriers of moderate penetrance genes has introduced numer-
ous challenges when counseling patients [84]. Furthermore,
increased identification of variants of undetermined significance
(VUS) can increase anxiety among patients.
It is important to consider, however, the potential advantages of
multigene panel tests. Aside from being cost-effective, panel tests
are particularly helpful if there are features in the family history
suggestive of multiple hereditary cancer syndromes. For example,
for patients diagnosed with breast cancer at age o 40, the differ-
ential diagnosis includes TP53 or PTEN mutations, as well as BRCA1
and BRCA2. Genetic testing laboratories offer a wide variety of
cancer gene panel tests; while some include only selected high-
risk/highly penetrant genes, others offer expanded gene lists that
includes dozens of genes associated moderate cancer risk, for
which clinical implications and management recommendations
remain uncertain [85]. The decision whether to use a comprehen-
sive versus more targeted gene panel should consider each
patient’s personal and family history, as well as the clinical impact
of findings of alterations in moderate/low-penetrance genes and/
or variants of uncertain significance.
3.4. Variants of undetermined significance in breast cancer risk genes
Complete gene sequencing can identify changes in the
sequence of a gene that are known to be pathogenic, as well as
variants of unknown or uncertain significance (VUS), for which the
effect of the sequence change on gene function is not known.
When a VUS is found during a test for inherited susceptibility to
cancer, the diagnosis of a hereditary cancer syndrome often cannot
 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
Table 3
Important components of family history (including relatives at least to third degree)
Individual data Notes
Identification First and last name for patient, but no identifiers for relatives should be recorded to preserve privacy of the family members
Current age Current age of patient and family members, with a date stamp of when this was recorded so that the family history information can be
updated
Age of death If exact age is not known, approximations of age of death (eg, 50s) is appropriate
Cause of death Unknown cause of death should always be noted
Ethnicity/race Will inform risk assessment
Biological sex
Twin/multiple births Identical/Fraternal status must be noted
Biological parents identified Allows for pedigree construction
Consanguinity
Adoptive status
Other genetic disorders Requires documentation of diagnosis type, age of diagnosis, and age of death (if appropriate)
Relevant genetic/genomic In following of HIPPA rules
test
Certainty of data Noted by provider
Adapted from Feero and colleagues [108].
be confirmed or excluded, and patients should be counseled
accordingly about their own risks as well as potential risks for
their family members. When a VUS genetic test result is identified,
there are several additional pieces of data that can help assess the
likelihood that the VUS is associated with an increased risk for
cancer, including the following:
(1) Does the VUS track with cancer in the family? If yes, then
this is additional information that the VUS may be associated
with an increased risk for developing cancer, if not, than this is
additional information that the VUS may not be associated
with an increased risk for developing cancer.
(2) Is the VUS seen in both individuals with cancer and without
cancer? If yes, then the VUS may not be associated with an
increased risk for developing cancer.
(3) Has the VUS been seen in association with a known gene
mutation in a gene that causes an increased risk for
developing cancer? If yes, then the VUS may not be associated
with an increased risk for developing cancer.
(4) Is the area of the gene where the VUS is located in an area of
the gene that appears to be important for all species? If yes,
then the VUS may be associated with an increased risk for
developing cancer.
(5) Is the gene change anticipated to affect how the gene
functions in the body? If yes, then the VUS may be associated
with an increased risk for developing cancer.
(6) Is there a loss of the normal gene in tumor analysis? If yes,
then the VUS may be associated with an increased risk for
developing cancer.
(7) Does the protein seem to function normally in laboratory
studies? If yes, then the VUS may not be associated with an
increased risk for developing cancer.
There are many databases in the public domain that collect
information on VUS. These include but are not limited to the Breast
Information Core (BIC), ClinVar, Prospective Registry of Multiplex
Testing (PROMPT), International Agency of Cancer Research (IARC),
International Society for Inherited Gastrointestinal Tumours
(InSight), and Mismatch Repair Genes Variant Database [86].
4. Implications of genetic diagnosis for treatment of breast
cancer
Identification of a pathogenic germline BRCA1/2 mutation, or
pathogenic mutation of other genes involved in the DNA repair
5
process, may have therapeutic implications for the patient.
Although not approved by the US Food and Drug Administration
(FDA) for treatment of breast cancer, studies of inhibitors of poly
adenosine diphosphate-ribose polymerase (PARP) have shown
promise in the treatment of patients with metastatic BRCA1/2-
associated breast cancer [87–90]. For example, in a study by Tutt
and colleagues, it was demonstrated that olaparib administered to
women with advanced BRCA1/2-associated breast cancer resulted
in an overall response rate of 41% and progression-free survival of
5.7 months [87]. Of note, olaparib does not appear to have activity
in breast cancer outside of BRCA1/2 mutation carriers; this is in
contrast to epithelial ovarian cancers, which appear to respond to
PARP inhibition independent of germline BRCA1/2 status [89].
There are numerous ongoing clinical trials looking at the use of
PARP inhibitors the neoadjuvant, adjuvant and metastatic treat-
ment settings for patients with pathogenic germline alterations in
BRCA1/2. The American Society of Clinical Oncology (ASCO) Tar-
geted Agent Profiling and Utilization Registry (TAPUR) study is a
prospective, non-randomized trial that aims to describe the safety
and efficacy of commercially available, targeted anti-cancer drugs
prescribed for treatment of patients with advanced cancer that
have a potentially actionable genomic variant revealed by a
genomic test. Under this protocol, patients with either germline
or somatic bi-allelic loss of BRCA1/2 or ATM identified in a
metastatic tumor sample are eligible to receive a PARP inhibitor
as therapy.
5. Management strategies for cancer risk reduction
Strategies for breast cancer risk reduction for individuals at
high–moderate risk of developing breast cancer include surveil-
lance, risk-reducing surgery, chemoprevention, and to some
extent, lifestyle modifications. Below, these options are reviewed
in detail with regard to potential magnitude of benefit in specific
mutation carriers as well as potential impact on patient quality
of life.
5.1. Risk-reducing surgery
National Comprehensive Cancer Network (NCCN) guidelines
recommend that prophylactic mastectomy be offered to all
patients who carry a germline BRCA1 or BRCA2 mutation, as both
retrospective and prospective studies have demonstrated that the
incidence of breast cancer can be reduced by as much as 90% in
those that undergo surgery [91–98]. It should be noted that for
6 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
Table 4
NCCN guidelines: breast cancer screening in BRCA1/2 mutation carriers
Periodic self-breast examination beginning at age 18
Clinical breast examination every 6–12 months beginning at age 25
Annual mammography beginning at age 30 (or individualized if earliest onset of cancer in the family is under age 25)
Annual breast magnetic resonance imaging beginning at age 25
Discussion of ovarian cancer screening in those whom have not undergone BSO to include concurrent transvaginal ultrasound and CA-125 measurement every 6 months
beginning at age 30 (or 5–10 years prior to the age of first diagnosis of ovarian cancer in the family)
those patients who choose to have surgery, a bilateral total
mastectomy or skin-sparing mastectomy is recommended as
opposed to a subcutaneous mastectomy. The latter surgical
approach leaves behind glandular tissue which can subsequently
develop into breast cancer [92,99].
NCCN guidelines also recommend that bilateral salpingo-
oophorectomy (BSO) be offered to BRCA mutation carriers once
they have completed childbearing, and is generally performed
between the ages of 35–40. In BRCA mutation carriers, BSO
has been demonstrated to reduce the risk of ovarian cancer and
breast cancer, as well as mortality [97,100,101]. Following BSO,
there is a theoretical concern that reduction in breast cancer risk
could be negated by the use of hormone replacement therapy
(HRT) in patients that are symptomatic following surgery.
Several studies have demonstrated, however, that this is not the
case [97,102]. Given this, it is reasonable to offer women who are
symptomatic following BSO HRT to mitigate these symptoms,
particularly in those that have also undergone prophylactic
mastectomy.
5.2. Surveillance strategies
For those women who harbor a BRCA1 or BRCA2 mutation and
do not pursue risk-reducing surgeries, breast cancer surveillance
should be offered and screening for ovarian cancer can be
considered. The highlights of the NCCN guidelines regarding breast
cancer screening in BRCA mutations carriers are listed in Table 4
[83].
5.3. Chemoprevention
For BRCA1 or BRCA2 mutation carriers who decline prophylactic
surgery, the use of chemoprevention agents can be considered;
however, data are limited regarding the effectiveness of selective
estrogen receptor modulators (ie, tamoxifen or raloxifene) for
preventing breast cancer in patients with BRCA1 or BRCA2 muta-
tions. The most robust evidence for use of tamoxifen in this setting
comes from a subset analysis of National Surgical Adjuvant Breast
and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1
trial). In this study, use of tamoxifen in BRCA2 mutations carriers
decreased the risk of developing breast cancer by 62%; however,
risk of breast cancer was not reduced in BRCA1 mutation carriers
[103]. This study was limited by small numbers; however, the
difference in risk reduction observed between BRCA1 and BRCA2
mutation carriers may be attributable to the higher incidence of
estrogen receptor–positive breast cancers in the BRCA2 group.
While aromatase inhibitors and raloxifene have been demon-
strated to decrease the risk of developing breast cancer in other
high-risk populations, there are no studies that have looked at the
potential use of these agents in patients with BRCA1 or BRCA2
mutations.
Use of oral contraceptives (OCPs), primarily for reduction in risk
of developing ovarian cancer, can be considered in those BRCA
mutation carriers who decline BSO. While studies have demon-
strated a benefit for this purpose [104,105], there has been a trend
observed toward increased risk of breast cancer in those to
use OCPs.
5.4. Breast cancer risk reduction strategies for other gene mutation
carriers
Strategies to reduce the risk of developing breast cancer in
patients with germline mutations in other high-penetrance cancer
predisposition genes associated with lifetime breast cancer risks of
4 40% (TP53, PTEN, STK11, CDH1) are similar to those described
above for BRCA mutation carriers; however, management of those
patients with genetic mutations associated with more moderate
cancer risk (CHEK2, PALB2 and ATM) is more complex. In general,
breast cancer surveillance recommendations are similar to those
made for carriers of highly penetrant genes; however, some
guidelines bodies, such as the United Kingdom’s National Health
Service, have recommended that patients with germline ATM
mutations try to minimize exposure to radiation, and undergo
surveillance with annual breast magnetic resonance imaging
beginning at age 25 in addition to mammography every 18 months
from ages 40–49, followed by every 3 years after age 50 [106].
Decisions regarding risk reduction surgery (such as prophylactic
mastectomy) must be highly individualized in these patients,
taking into account the patient’s family history of breast cancer
in addition to their mutation status. In addition, patients with
CHEK2 mutations may be candidates for chemoprevention with
tamoxifen, as they are considered to be more likely to develop
estrogen receptor–positive breast cancers.
6. Conclusions
The demand for clinical evaluations of individuals for genetic
susceptibility to breast cancer is increasing. Amidst changes in
technology and the advent of more data on the significance of gene
variants, ASCO provides guidelines for genetic evaluation for
cancer susceptibility, highlighting the challenges of multigene
panel testing, the need to ensure quality assurance in genetic
testing laboratories, promote education among oncology profes-
sionals that are ordering, interpreting and discussing genetic
testing results with patients, and providing access to cancer
genetics services [107].
Pre- and post-genetic test counseling by healthcare providers
with genetics expertise leads to proven improvements in
patients’ knowledge about genetics, increased satisfaction with
decision-making about risk management options, and risk appro-
priate access to screening. There is a significant disparity in access
to specialized genetic counseling for HBOC yndromes by tradi-
tionally underserved populations based on ethnicity and socio-
economic status. Such disparities ought to be high priority
concerns in public health in the United States. Risk management
plans for increased cancer susceptibility are dynamic strategies
that should be revisited intermittently throughout the lifespan and
as the person ages. The rapid advances in science and technology
provide excellent new tools that need to be harnessed for the
benefit of society, for improving cancer outcomes and decreasing
 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
cancer incidence, through the provision of specialized services to
individuals at increased risk in an equitable and cost-effective
manner.
Conflicts of interest
None
References
[1] Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast
cancer to chromosome 17q21. Science 1990;250(4988):1684–9.
[2] Narod SA, Sobol H, Schuffenecker I, Ezekowitz RA, Lenoir GM. Early detection
of hereditary medullary thyroid cancer with polymorphic DNA probes.
Groupe d'Etude des Tumeurs a Calcitonine. Henry Ford Hosp Med J
1989;37(3-4):106–8.
[3] Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast
and ovarian cancer susceptibility gene BRCA1. Science 1994;266(5182):
66–71.
[4] Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary
breast and ovarian carcinomas. Science 1994;266(5182):120–2.
[5] Tavtigian SV, Simard J, Rommens J, et al. The complete BRCA2 gene and
mutations in chromosome 13q-linked kindreds. Nat Genet 1996;12(3):
333–7.
[6] Venkitaraman AR. Cancer suppression by the chromosome custodians,
BRCA1 and BRCA2. Science 2014;343(6178):1470–5.
[7] Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature
2012;481(7381):287–94.
[8] Merajver SD, Pham TM, Caduff RF, et al. Somatic mutations in the BRCA1
gene in sporadic ovarian tumours. Nat Genet 1995;9(4):439–43.
[9] Hoskins KF, Stopfer JE, Calzone KA, et al. Assessment and counseling for
women with a family history of breast cancer. A guide for clinicians. JAMA
1995;273(7):577–85.
[10] Olopade OI, Grushko TA, Nanda R, Huo D. Advances in breast cancer:
pathways to personalized medicine. Clin Cancer Res 2008;14(24):7988–99.
[11] Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer
susceptibility genes among a large triple-negative breast cancer cohort
unselected for family history of breast cancer. J Clin Oncol 2015;33
(4):304–11.
[12] Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian
cancer associated with BRCA1 or BRCA2 mutations detected in case Series
unselected for family history: a combined analysis of 22 studies. Am J Hum
Genet 2003;72(5):1117–30.
[13] Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance
analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast
Cancer Linkage Consortium. Am J Hum Genet 1998;62(3):676–89.
[14] van der Kolk DM, de Bock GH, Leegte BK, et al. Penetrance of breast cancer,
ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families:
high cancer incidence at older age. Breast Cancer Res Treat 2010;124(3):
643–51.
[15] Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al. Presymptomatic DNA
testing and prophylactic surgery in families with a BRCA1 or BRCA2
mutation. Lancet 2000;355(9220):2015–20.
[16] Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population
frequencies for common mutations in BRCA1 and BRCA2. Nat Genet
1996;14(2):185–7.
[17] Ferla R, Calo V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes.
Ann Oncol 2007;18(Suppl 6):vi93–8.
[18] Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum
Genet 1997;60(5):1013–20.
[19] Begg CB, Haile RW, Borg A, et al. Variation of breast cancer risk among
BRCA1/2 carriers. JAMA 2008;299(2):194–201.
[20] Wang F, Fang Q, Ge Z, Yu N, Xu S, Fan X. Common BRCA1 and BRCA2
mutations in breast cancer families: a meta-analysis from systematic review.
Mol Biol Rep 2012;39(3):2109–18.
[21] Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrange-
ments in BRCA1 and BRCA2. Cancer 2012;118(21):5210–6.
[22] Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male
BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2007;99(23):1811–4.
[23] Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F. Risk of
breast cancer in male BRCA2 carriers. J Med Genet 2010;47(10):710–1.
[24] Malkin D. Li-Fraumeni syndrome. Genes Cancer 2011;2(4):475–84.
[25] Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multiple primary cancers
in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;90(8):
606–11.
[26] Lammens CR, Bleiker EM, Aaronson NK, et al. Regular surveillance for Li-
Fraumeni Syndrome: advice, adherence and perceived benefits. Fam Cancer
2010;9(4):647–54.
[27] Masciari S, Dillon DA, Rath M, et al. Breast cancer phenotype in women with
TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast
Cancer Res Treat 2012;133(3):1125–30.
7
[28] Olivier M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes:
correlation between tumor type, family structure, and TP53 genotype.
Cancer Res 2003;63(20):6643–50.
[29] Wilson JR, Bateman AC, Hanson H, et al. A novel HER2-positive breast cancer
phenotype arising from germline TP53 mutations. J Med Genet 2010;47
(11):771–4.
[30] Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a
systematic review and recommendations for management. Gut 2010;59
(7):975–86.
[31] Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in
familial Peutz-Jeghers syndrome. Gastroenterology 2000;119(6):1447–53.
[32] Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer
risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18
(2):400–7.
[33] Starink TM, van der Veen JP, Arwert F, et al. The Cowden syndrome: a clinical
and genetic study in 21 patients. Clin Genet 1986;29(3):222–33.
[34] Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden
syndrome and the PTEN hamartoma tumor syndrome: systematic review
and revised diagnostic criteria. J Natl Cancer Inst 2013;105(21):1607–16.
[35] Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric
cancer: updated consensus guidelines for clinical management and direc-
tions for future research. Journal of medical genetics 2010;47(7):436–44.
[36] Guilford P, Humar B, Blair V. Hereditary diffuse gastric cancer: translation of
CDH1 germline mutations into clinical practice. Gastric Cancer 2010;13
(1):1–10.
[37] Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer
syndrome: CDH1 mutations and beyond. JAMA Oncol 2015;1(1):23–32.
[38] Xie ZM, Li LS, Laquet C, Penault-Llorca F, Uhrhammer N, Xie XM, Bignon YJ.
Germline mutations of the E-cadherin gene in families with inherited
invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer
2011;117(14):3112–7.
[39] Shah MA, Salo-Mullen E, Stadler Z, et al. De novo CDH1 mutation in a family
presenting with early-onset diffuse gastric cancer. Clin Genet 2012;82
(3):283–7.
[40] Sugimoto S, Yamada H, Takahashi M, et al. Early-onset diffuse gastric cancer
associated with a de novo large genomic deletion of CDH1 gene. Gastric
Cancer 2014;17(4):745–9, http://dx.doi.org/10.1007/s10120-013-0278-2.
[41] Walsh MD, Buchanan DD, Cummings MC, et al. Lynch syndrome-associated
breast cancers: clinicopathologic characteristics of a case series from the
colon cancer family registry. Clin Cancer Res 2010;16(7):2214–24.
[42] Shulman LP. Hereditary breast and ovarian cancer (HBOC): clinical features
and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome,
and Li-Fraumeni syndrome. Obstet Gynecol Clin North Am 2010;37
(1):109–33.
[43] Buerki N, Gautier L, Kovac M, et al. Evidence for breast cancer as an integral
part of Lynch syndrome. Genes Chromosomes Cancer 2012;51(1):83–91.
[44] Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for
carriers and noncarriers from families with a DNA mismatch repair gene
mutation: a prospective cohort study. J Clin Oncol 2012;30(9):958–64.
[45] Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a
systematic review. Breast Cancer Res 2013;15(2):R27.
[46] Moldovan GL, D'Andrea AD. How the fanconi anemia pathway guards the
genome. Annu Rev Genet 2009;43:223–49.
[47] Naslund-Koch C, Nordestgaard BG, Bojesen SE. Increased risk for other
cancers in addition to breast cancer for CHEK2*1100delC heterozygotes
estimated from the Copenhagen General Population Study. J Clin Oncol
2016;34(11):1208–16.
[48] Schmidt MK, Tollenaar RA, de Kemp SR, et al. Breast cancer survival and
tumor characteristics in premenopausal women carrying the CHEK2*1100-
delC germline mutation. J Clin Oncol 2007;25(1):64–9.
[49] Guenard F, Pedneault CS, Ouellette G, et al. Evaluation of the contribution of
the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-
BRCA1/2 French Canadian families with high risk of breast cancer. Genet Test
Mol Biomarkers 2010;14(4):515–26.
[50] Weischer M, Nordestgaard BG, Pharoah P, et al. CHEK2*1100delC hetero-
zygosity in women with breast cancer associated with early death, breast
cancer-specific death, and increased risk of a second breast cancer. J Clin
Oncol 2012;30(35):4308–16.
[51] Narod SA. Testing for CHEK2 in the cancer genetics clinic: ready for prime
time? Clin Genet 2010;78(1):1–7.
[52] Cybulski C, Wokolorczyk D, Jakubowska A, et al. Risk of breast cancer in
women with a CHEK2 mutation with and without a family history of breast
cancer. J Clin Oncol 2011;29(28):3747–52.
[53] Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance
susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of
BRCA1 or BRCA2 mutations. Nat Genet 2002;31(1):55–9.
[54] Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with
mutations in PALB2. N Engl J Med 2014;371(6):497–506.
[55] Catucci I, Milgrom R, Kushnir A, et al. Germline mutations in BRIP1 and
PALB2 in Jewish high cancer risk families. Fam Cancer 2012;11(3):483–91.
[56] Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi
anemia. Cancer Res 2010;70(19):7353–9.
[57] Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-
telangiectasia are breast cancer susceptibility alleles. Nat Genet 2006;38
(8):873–5.
8 E.F. Cobain et al. / Seminars in Oncology ] (2016) ]]]–]]]
[58] Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in
heterozygous ATM mutation carriers. J Natl Cancer Inst 2005;97(11):813–22.
[59] Paglia LL, Lauge A, Weber J, et al. ATM germline mutations in women with
familial breast cancer and a relative with haematological malignancy. Breast
Cancer Res Treat 2010;119(2):443–52.
[60] Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT.
The incidence and gene frequency of ataxia-telangiectasia in the United
States. Am J Hum Genet 1986;39(5):573–83.
[61] Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene
sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014;32
(19):2001–9.
[62] Wu LC, Wang ZW, Tsan JT, et al. Identification of a RING protein that can
interact in vivo with the BRCA1 gene product. Nat Genet 1996;14(4):430–40.
[63] Thai TH, Du F, Tsan JT, et al. Mutations in the BRCA1-associated RING domain
(BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol
Genet 1998;7(2):195–202.
[64] Ghimenti C, Sensi E, Presciuttini S, et al. Germline mutations of the BRCA1-
associated ring domain (BARD1) gene in breast and breast/ovarian families
negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer
2002;33(3):235–42.
[65] De Brakeleer S, De Greve J, Loris R, et al. Cancer predisposing missense and
protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer
families. Hum Mutat 2010;31(3):E1175–85.
[66] Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein,
interacts directly with BRCA1 and contributes to its DNA repair function. Cell
2001;105(1):149–60.
[67] Levitus M, Waisfisz Q, Godthelp BC, et al. The DNA helicase BRIP1 is defective
in Fanconi anemia complementation group. J Nat Genet 2005;37(9):934–5.
[68] Frank B, Hemminki K, Meindl A, et al. BRIP1 (BACH1) variants and familial
breast cancer risk: a case-control study. BMC Cancer 2007;7:83.
[69] Wong MW, Nordfors C, Mossman D, et al. BRIP1, PALB2, and RAD51C
mutation analysis reveals their relative importance as genetic susceptibility
factors for breast cancer. Breast Cancer Res Treat 2011;127(3):853–9.
[70] Guenard F, Labrie Y, Ouellette G, et al. Mutational analysis of the breast
cancer susceptibility gene BRIP1 /BACH1/FANCJ in high-risk non-BRCA1/
BRCA2 breast cancer families. J Hum Genet 2008;53(7):579–91.
[71] Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi
anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.
Nat Genet 2006;38(11):1239–41.
[72] Easton DF, Lesueur F, Decker B, et al. No evidence that protein truncating
variants in BRIP1 are associated with breast cancer risk: implications for
gene panel testing. J Med Genet 2016;53(5):298–309, http://dx.doi.org/
10.1136/jmedgenet-2015-103529 PubMed PMID: 26921362; PubMed Central
PMCID: PMCPMC4938802.
[73] Lavin MF. ATM and the Mre11 complex combine to recognize and signal DNA
double-strand breaks. Oncogene 2007;26(56):7749–58.
[74] Damiola F, Pertesi M, Oliver J, et al. Rare key functional domain missense
substitutions in MRE11A, RAD50, and NBN contribute to breast cancer
susceptibility: results from a Breast Cancer Family Registry case-control
mutation-screening study. Breast Cancer Res 2014;16(3):R58.
[75] Vaz F, Hanenberg H, Schuster B, et al. Mutation of the RAD51C gene in a
Fanconi anemia-like disorder. Nat Genet 2010;42(5):406–9.
[76] Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and
ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility
gene. Nat Genet 2010;42(5):410–4.
[77] Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer
susceptibility to ovarian cancer. Nat Genet 2011;43(9):879–82.
[78] Baker JL, Schwab RB, Wallace AM, Madlensky L. Breast cancer in a RAD51D
mutation carrier: case report and review of the literature. Clin Breast Cancer
2015;15(1):e71–5.
[79] Theodoratou E, Campbell H, Tenesa A, et al. A large-scale meta-analysis to
refine colorectal cancer risk estimates associated with MUTYH variants. Br J
Cancer 2010;103(12):1875–84.
[80] Nielsen M, Franken PF, Reinards TH, et al. Multiplicity in polyp count and
extracolonic manifestations in 40 Dutch patients with MYH associated
polyposis coli (MAP). J Med Genet 2005;42(9):e54.
[81] Wasielewski M, Out AA, Vermeulen J, et al. Increased MUTYH mutation
frequency among Dutch families with breast cancer and colorectal cancer.
Breast Cancer Res Treat 2010;124(3):635–41.
[82] Out AA, Wasielewski M, Huijts PE, et al. MUTYH gene variants and breast
cancer in a Dutch case-control study. Breast Cancer Res Treat 2012;134
(1):219–27.
[83] Network NCC. Version 2.2016 [Available from: https://www.nccn.org/profes
sionals/physician_gls/pdf/genetics_screening.pdf. Accessed [July 22, 2016].
[84] Domchek SM. Evolution of genetic testing for inherited susceptibility to
breast cancer. J Clin Oncol 2015;33(4):295–6.
[85] Doherty J, Bonadies DC, Matloff ET. Testing for hereditary breast cancer:
panel or targeted testing? Experience from a clinical cancer genetics
practice. J Genet Couns 2015;24(4):683–7.
[86] Domchek S, Weber BL. Genetic variants of uncertain significance: flies in the
ointment. J Clin Oncol 2008;26(1):16–7.
[87] Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase
inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced
breast cancer: a proof-of-concept trial. Lancet 2010;376(9737):235–44.
[88] Tutt ARM, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in
BRCA-deficient advanced breast cancer. J Clin Oncol 2009;27(18s): Abstract
CRA501.
[89] Gelmon KA, Herte HW, Robidoux A, et al. Can we define tumors that will
respond to PARP inhibitors? A phase II correlative study of olaparib in
advanced serous ovarian cancer and triple-negative breast cancer. J Clin
Oncol 2010;28(15s).
[90] Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor
veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin
Oncol 2010;28(15s):abstract 3002.
[91] Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after
prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2
mutation. N Engl J Med 2001;345(3):159–64.
[92] Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy
reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE
Study Group. J Clin Oncol 2004;22(6):1055–62.
[93] Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic
mastectomy in women with a family history of breast cancer. N Engl J Med
1999;340(2):77–84.
[94] Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic
mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst
2001;93(21):1633–7.
[95] Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Pro-
phylactic mastectomy in BRCA1/2 mutation carriers and women at risk of
hereditary breast cancer: long-term experiences at the Rotterdam Family
Cancer Clinic. Ann Surg Oncol 2007;14(12):3335–44.
[96] Geiger AM, Yu O, Herrinton LJ, et al. A population-based study of bilateral
prophylactic mastectomy efficacy in women at elevated risk for breast cancer
in community practices. Arch Intern Med 2005;165(5):516–20.
[97] Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing
surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
JAMA 2010;304(9):967–75.
[98] Ingham SL, Sperrin M, Baildam A, et al. Risk-reducing surgery increases
survival in BRCA1/2 mutation carriers unaffected at time of family referral.
Breast Cancer Res Treat 2013;142(3):611–8.
[99] Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of
risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol
2006;24(28):4642–60.
[100] Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in
carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346(21):1616–22.
[101] Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oopho-
rectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346
(21):1609–15.
[102] Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone
replacement therapy on breast cancer risk reduction after bilateral prophy-
lactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE
Study Group. J Clin Oncol 2005;23(31):7804–10.
[103] King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence
among women with inherited mutations in BRCA1 and BRCA2: National
Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer
Prevention Trial. JAMA 2001;286(18):2251–6.
[104] Iodice S, Barile M, Rotmensz N, et al. Oral contraceptive use and breast or
ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer
2010;46(12):2275–84.
[105] Moorman PG, Havrilesky LJ, Gierisch JM, et al. Oral contraceptives and risk of
ovarian cancer and breast cancer among high-risk women: a systematic
review and meta-analysis. J Clin Oncol 2013;31(33):4188–98.
[106] Programme NBCS. NHSBSP Publication no., December 2012. Available from:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/
file/439601/nhsbsp68.pdf. Accessed [July 22, 2016].
[107] Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology
Policy Statement update: genetic and genomic testing for cancer suscepti-
bility. J Clin Oncol 2015;33(31):3660–7.
[108] Feero WG, Bigley MB, Brinner KM. Family Health History Multi-Stakeholder
Workgroup of the American Health Information Community. New standards
and enhanced utility for family health history information in the electronic
health record: an update from the American Health Information Commun-
ity's Family Health History Multi-Stakeholder Workgroup. J Am Med Inform
Assoc 2008;15(6):723–8.