REVIEW ARTICLE

Clinical Cancer Genetics Part 2

Breast
Jondavid Pollock, MD, PhD* and James S. Welsh, MS, MD, FACROwz

Abstract: Since the discovery of proven genetic mutations which

predispose people to breast cancer along with the routine availability of
genetic testing for such mutations, a number of issues have surfaced
regarding potential methods of breast cancer diagnosis, surveillance,
treatment, and risk reduction. Many of these issues pertain to the
practice of radiation oncology and can affect decisions on management. This article aims to describe some of the more salient features of
individuals at high genetic risk for breast developing cancer along with
aspects of their tumor biology, clinical natural history, and how the
radiation oncologist may address these challenges.
Key Words: cancer genetics, breast cancer, radiation oncology

(Am J Clin Oncol 2014;37:8689)

dentified in 1990, the BRCA1 and BRCA2 genes have been a

subject of discussion and controversy in tumor boards
throughout the educated world. BRCA1 is mapped to chromosome 17q and BRCA2 to chromosome 13q with various
potential roles including tumor suppression, transcriptional
activation, centrosome duplication, and embryogenesis among
others.1,2 BRCA1 has an important role in double-strand DNA
break repair, specifically the homologous recombination mechanism. Along with other tumor suppressors, DNA-damage
sensors and signal transducers, BRCA1 is a component of the
large multisubunit protein complex known as the BRCA1-associated genome surveillance complex or BASC. In addition to
breast cancer, mutations in the BRCA1 gene also increase the
risk of ovarian, cervical, uterine, fallopian tube, prostate, colon, and pancreas cancers. In contrast, heterozygous carriers of
deleterious mutations in BRCA2 are at risk of breast cancer and
also lead to an increased risk of cancers of the ovaries, stomach, prostate, pancreas, as well as malignant melanoma and
cholangiocarcinoma. Men with BRCA1 mutations generally
are not at increased risk of developing breast cancer (in contrast to male BRCA2 mutation carriers who are at an approximate 5% lifetime risk of breast cancer). As breast cancer
in males is rare, when it occurs, concern about an underlying BRCA2 mutation is reasonable. The risk of breast cancer
in women carrying deleterious BRCA2 mutations are similar
to the risk of BRCA1 carriers; however, the chances of

From the *Department of Radiation Oncology, Schiffler Cancer Center,

Wheeling, WV; wDepartments of Radiology and Neurosurgery, Louisiana State University Health Sciences Center-Shreveport; and
zDepartment of Radiation Oncology, Willis-Knighton Hospital,
Shreveport, LA.
The authors declare no conflicts of interest.
Reprints: James S. Welsh, MS, MD, FACRO, Department of Radiology
and Neurosurgery, Louisiana State University Health Sciences CenterShreveport, 1501 Kings Highway, Shreveport, LA 71130. E-mail:
jameswelsh@charter.net.
Copyright r 2012 by Lippincott Williams & Wilkins
ISSN: 0277-3732/14/3701-0086
DOI: 10.1097/COC.0b013e31823fe657

86 | www.amjclinicaloncology.com

developing ovarian cancer is lower in BRCA2 mutation carriers. With either gene, the loss of function results in impaired
cellular defense against DNA damage. BRCA1/2 gene mutations have been shown to result in hypersensitivity to DNAdamaging agents including ionizing radiation, thus the concern
regarding the use of radiation therapy in these patients. Individuals with homozygous BRCA2 gene mutations have a
type of Fanconi anemia, a classic radiation hypersensitivity
syndrome. In addition to hypofunctioning bone marrow leading to anemia, patients with Fanconi anemia are prone to
various malignancies, including leukemias and solid tumors,
particularly of the head, neck, skin, and reproductive organs.
The prevalence of a gene mutation or number of cases at
any given time in the population can be difficult to estimate as
any newly diagnosed breast cancer patient, by definition, become a high-risk individual. In patients younger than 35 years
of age, there is a 6% prevalence of a BRCA1 mutation. In
women older than age 45 years and whom a family history has
been identified, the prevalence of a BRCA1 mutation is 7%. In
women who report a family history of breast cancer, and in
whom genetic testing did not demonstrate a BRCA mutation,
the lifetime risk of breast cancer is 6% if 1 relative is affected,
and 13% if 2 are affected. In a large meta-analysis of 53,000
breast cancer patients and 100,000 controls, 13% versus 7%
reported a family history of the disease, respectively.3
Because the majority of patients who develop breast
cancer do not have a proven germline mutation in BRCA genes
yet maintain a strong family history of the disease regardless,
the term private familial mutation has been adopted to refer
to individuals with an apparent genetic predisposition to the
disease, unrelated to the BRCA genes. In order to identify the
potential risk for developing breast cancer a family pedigree is
of benefit, and is utilized regularly by genetic counselors and
physicians. Estimates of a 4-fold increase in the risk of developing breast cancer have been raised in patients with a
strong family history (2 or more relatives who have breast
cancer at younger than 50 y of age or 3 or more at any age).4
This equates to a 20% lifetime risk of breast cancer by age 58
and 40% by age 75.

TUMOR-RELATED AND PATIENT-RELATED

FEATURES
There are specific patient-related and tumor-related characteristics more commonly identified in those with a BRCA1/2
mutation. In terms of patient-related features, and based on a
Creighton University series, BRCA mutation carriers tend to be
younger than the sporadic cases (median, 40.3 vs. 42.0 y), there
is a greater likelihood of male breast cancers, and there is a
significant increase in the number of contralateral breast cancers (2.7% to 3.5% vs. 0.75%/y).5 With the exception of age at
diagnosis, other patient-related characteristics, such as number
of pregnancies and hormone therapy appear unrelated to carrier
status.6

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Volume 37, Number 1, February 2014

Tumor-related characteristics are even better defined.

Breast cancers identified in BRCA1 carriers are more commonly high grade, estrogen receptor negative, progesterone
receptor negative, and basal type (triple negative ie, negative
for ER, PR, and HER2 overexpression). On the other hand,
BRCA2 carriers often are even more likely to be estrogen receptor positive than sporadic controls. Given the relative
constancy in age-related hormone receptor status, in older
patients with hormone receptor-negative tumors one may
consider a BRCA1 gene mutation, whereas in much younger
patients with hormone receptor-positive status a BRCA2
mutation may be considered.7
In an effort to control for the hormone milieu which is
often altered by pharmacologic or surgical intervention, a regression analysis was used to evaluate the role of tamoxifen,
aromatase inhibitors, and surgical ovarian ablation on the
molecular profile (ie, ER/PR positive vs. negative) of the
presenting contralateral breast cancer in BRCA mutation carriers. The hormonal milieu was found to be unrelated to the
molecular profile of the contralateral tumor, leading the authors to conclude that breast cancers that occur related to a
gene mutation are derived from a similar precursor expressing
similar genetic variations, and altering the systemic hormonal
milieu with pharmacologic or surgical intervention is unlikely
to alter the profile of a new tumor.8 Clearly demonstrated is
the concordance between an ipsilateral and contralateral breast
cancer in gene carriers, from molecular profile to histopathologic morphology.

RECURRENCE PATTERNS
Theories abound when considering whether carriers respond to conventional therapies, yet empirical data to date
suggest that the BRCA1 and 2 mutation does not significantly
increase the risk of an in-breast recurrence after appropriate
breast-conserving therapy, nor does it worsen cause-specific
survival. A large French retrospective series evaluated gene
carrier outcomes in patients undergoing breast conservation.5
Importantly, patients with a strong family history, but without a
genetic mutation, were also identified and followed. Patients
underwent adequate tylectomies followed by 4500 to 6600 cGy
delivered to the breast, with some patients receiving a tumor
volume boost. The authors observed no difference in the inbreast tumor control between carriers, sporadic patients, or
those with a strong family history but without a gene mutation,
though there was a shorter disease-free interval observed in the
high-risk groups, in terms of in-breast recurrence (30 mo for
gene carriers, 35 mo for strong family history, and 50 mo for
sporadic patients). An important and repeatedly observed
finding was the significant increase in the risk of contralateral
breast cancer development at 9 years of follow-up in those with
the gene mutation (37%) compared with those with a strong
family history alone (18%) and the sporadic group (7%).
A second large multi-institutional series reviewed 160
gene mutation carriers who had developed stage 1 or 2 breast
cancer, and who were followed for a median of 8 years after
breast-conserving surgery and appropriate adjuvant radiation
therapy, with or without systemic therapy pending their risk
stratification. The gene carriers were cohort matched 1:3 to
sporadic controls estimated at a <5% risk of having a gene
mutation. An actuarial 15-year in-breast tumor recurrence rate
was comparable between the gene carriers (24%) and sporadic
controls (17%).9 This report shows the higher grade and ER/
PR receptor-negative influence on those carrying mutations
in BRCA1. Unlike the French study, the disease-free interval
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Clinical Cancer Genetics

regarding in-breast failures was longer in the gene carriers,

perhaps related to a more frequent use of systemic chemotherapy in the American experience (no data for comparison
provided). Interestingly, recurrences were more frequently observed in a distant quadrant in the gene carriers (60% vs. 29%),
and this pattern may have implications in terms of considering
partial breast irradiation in BRCA mutation carriers.

RISK-REDUCTION INTERVENTIONS
The 3 most commonly discussed and studied risk-reduction interventions in the management of hereditary breast and
ovarian cancers are pharmacologic hormonal manipulation,
oophorectomy, and mastectomy. Taken individually or collectively, these interventions are considered risk reducing,
though not risk preventing as there is a well-documented incidence of breast cancer after mastectomy and primary peritoneal carcinoma after oophorectomy. Furthermore, although
clearly beneficial in specific high-risk populations, risk reduction has not yet been associated with improvements in
overall survival or even cause-specific survival; the latter most
metric most certainly appears improved by risk reduction
though there is a paucity of data demonstrating it.
Pharmacologic hormonal manipulation with tamoxifen has
been studied as a risk-reduction measure in high-risk patients.
On the basis of mathematical models, chemoprevention with
antihormonal agents such as tamoxifen appears to be effective
with estimates ranging from 1.6 to 2.2 years of life gained by
a young woman with a proven gene mutation.10 Unfortunately,
a review of the empirical data on the subject is less encouraging
and is reasonably criticized due to the lack of any control.11 The
data on aromatase inhibitors as a chemopreventive measure are
theoretical only, though at least 3 prospective trials are presently
studying the potential benefit of Aromasin with Celebrex,
Aromasin alone, and Arimidex alone.12
Risk-reducing surgery, on the other hand, has enjoyed a
more convincing benefit than has pharmacologic intervention.
Bilateral salpingo-oophorectomy (BSO) has been shown to
significantly reduce the development of breast cancer in highrisk patients, as well as to reduce the likelihood of a recurrence
or new malignancy in patients with a diagnosis of breast
cancer. In patients with a proven mutation who self-selected
BSO versus observation, the surgery reduced BRCA1-associated ovarian cancer by 85% and BRCA2-associated breast
cancer by 72%. Curiously however, the surgery did not reduce
the risk of BRCA1-associated breast cancer or BRCA2-associated ovarian cancer.13 Given the high prevalence of hormone
receptor-negative breast cancers seen in BRCA1 gene carriers,
the lack of a BSO effect in this population is not unexpected.
Prophylactic mastectomy, either in response to a diagnosis of breast cancer or as a method to reduce the de novo
development of the disease, has been shown to be effective.
Indeed, almost all studies to date have demonstrated a 90%
risk reduction in patients undergoing a mastectomy in either
setting14,15 and the current controversy regards the volume of
tissue to be removed; advocates for skin-sparing and nipplesparing procedures have recently reported not only adequate
risk reduction when the procedure is performed prophylactically, but also good local control in patients who undergo the
procedure as a treatment for known disease, albeit with limited
follow-up of 13.5 months.16 In a large retrospective matched
control analysis of 483 carriers from North America and
Europe, with 6 years of follow-up, 49% of patients developed
breast cancer in the observation arm versus 2% in the mastectomy arm, with both patients who failed in the surgical arm
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American Journal of Clinical Oncology

undergoing a limited subcutaneous mastectomy.15 In a practical vein, a small retrospective analysis reviewed the extent of
surgery required in a prophylactic procedure, and the authors
concluded that a sentinel node mapping was not beneficial,
though patients younger than 60 years of age with lobular
carcinoma in situ identified at mastectomy may have a measurable risk of nodal metastases.17 In a psychosocial model
evaluating who undergoes risk-reduction surgery, the authors
found that 23% of carriers will undergo a mastectomy,
51% will undergo a BSO, and those most likely to have both
surgeries are the women who have already had one form or
another.18

NATIONAL COOPERATIVE CANCER NETWORK

GUIDELINES
National Cooperative Cancer Network guidelines (volume
1: 2009) recommend pause in consideration of breast-conserving therapy in patients presenting with a known BRCA1/2
mutation. Indeed, the expert panel suggests that a known mutation should be considered a relative contraindication to breast
radiotherapy, similar to patients presenting with systemic lupus
erythematosis, scleroderma, tumor size >5 cm, and a positive
surgical margin. The panel goes onto state that the known
mutation is associated with higher risks of in-breast recurrence
in carriers. There is clear evidence supporting the claim that
known gene carriers harbor a significantly higher risk of the
development of contralateral breast cancer, though the empirical data does not support the contention that there is a
statistically higher risk of in-breast recurrence after adequate
surgery and radiotherapy.5,9 A numerically higher risk of an inbreast recurrence in known carriers is no different in significance than is the known higher incidence of local failure in
any patients undergoing breast-conserving therapy versus
mastectomy, nor is it any different than recently reported series
demonstrating improved in-breast tumor control after partial
breast irradiation versus standard whole-breast treatment.19,20
In none of the comparison groups (known carriers who undergo
breast conservation and adjuvant radiotherapy, breast conservation versus mastectomy for early-stage disease, partial vs.
whole-breast radiotherapy) has a numerical difference in local
control translated into a difference in overall or cause-specific
survival.

THEORETICAL RISK OF RADIATION THERAPY

AND BRCA1/2 GENE MUTATION CARRIERS
Based on empirical evidence, there is an absence of a
clear and significant decrement in in-breast tumor control after
breast-conserving surgery and radiotherapy in known carriers.
However, there is a sound theoretical concern that radiation
exposure may increase the likelihood of second malignancy
development in carriers. The primary determinant of radiation
sensitivity relates to the efficiency of DNA double-strand
break repair and numerous genetic factors determine radiation
sensitivity. Indeed, cells deficient in BRCA1/2 appear to be
radiation sensitive and this is accompanied by a defect in
homologous recombination. This pathway of DNA repair
is thought to occur in late S and G2 in the cell cycle.21
In a recent Dutch study of radiation effect in known
carriers, the authors compared 51 carriers of DDRP mutations
(DNA-damage repair pathway), specifically with a BRCA1/2
mutation or a mutation in the CHEK2 or ATM genes, with 196
noncarriers. The majority (68%) was irradiated postmastectomy and the authors estimated that 1% to 10% of the dose
delivered was received by the contralateral breast, though their

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method of estimate was not provided. The median dose delivered to the contralateral breast was 132 to 140 cGy and
patients were followed for a median of 5 years. By multivariate
analysis, correcting for age at diagnosis and time interval since
diagnosis, the results suggested that known mutation carriers
had a 2-fold increased risk of developing a contralateral breast
cancer when they received radiotherapy versus carriers who
did not receive postmastectomy radiotherapy (24% vs. 12%).22
In a second publication evaluating radiation exposure and
an apparent increased risk of secondary malignancies and gene
mutation status, the authors concluded that gene carriers who
undergo diagnostic mammography before 34 years of age
potentially develop malignant disease outweighing the benefit
of early detection. Based on a complex mathematical model
derived from pedigree studies, women aged 25 to 29 who
undergo standard mammographic survey annually for 5 years
will have a 0.26% risk of developing a radiation-induced breast
cancer; women aged 30 to 34 will have a 0.20% of cancer
development and those aged 34 to 39 will have a 0.13% of
radiation-induced clinical breast cancer. The scientists assumed
that there was a 15% to 20% mortality reduction attributed to
appropriate mammographic survey, and summarized by indicating there was no benefit to screening gene carriers younger
than 29, perhaps a slight benefit in those older than 29 years of
age, with a real benefit in woman older than 34.23 This recommendation sounds similar to the proclamations of various
screening groups regarding patients at low risk for developing
breast cancer.

CONCLUSIONS
Breast cancer patients with either a strong family history
or a proven genetic mutation experience a significantly higher
risk of developing a contralateral breast cancer. This risk can
be substantially reduced, though not entirely eliminated, by
risk-reduction surgery such as bilateral mastectomy. Chemoprevention may have some benefit in reducing BRCA2, hormone milieu-associated contralateral breast cancers, though
the benefit of hormonal manipulation by pharmacologic or
surgical means such as BSO has less proven benefit in BRCA1associated cancers. There are some data suggesting that partial
breast irradiation may be less effective in patients with a BRCA
mutation given the greater likelihood of an in-breast local recurrence in another quadrant, though there is no current empirical evidence demonstrating its ineffectiveness in this
patient population. Regardless of failure rates, there is a lack of
data demonstrating a survival decrement in gene carriers who
choose breast conservation.24 However, recent data should prompt
pause when considering adjuvant radiotherapy in known mutation
carriers because of a possible increased risk of a contralateral,
radiation-induced second malignancy. In the absence of significant patient motivation toward breast conservation, the presence of a proven deleterious mutation should prompt discussion
encouraging bilateral mastectomies. Although improved screening tools such as breast magnetic resonance imaging may have
an impact on earlier diagnosis of contralateral disease, greater
experience with this modality is necessary before clinicians
can reliably assure patients of the safety of breast conservation.

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