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Prophylactic Surgery in Hereditary Breast/Ovarian Cancer Syndrome

Prophylactic Surgery in Hereditary Breast/Ovarian Cancer Syndrome

ABSTRACT: The hereditary breast/ovarian cancer syndrome is responsible for approximately 5% of all breast cancers and 10% of all ovarian cancers. Although this accounts for a small portion of these diseases, much attention has been focused on this syndrome because of the abundance of research in this area. The majority of the hereditary breast/ovarian syndrome can be attributed to germ-line mutations in the BRCA1 and BRCA2 genes. Reliable screening techniques for these mutations have been developed and are readily available in clinical practice. For patients who are thought to have the hereditary breast/ovarian cancer syndrome based on family history or genetic testing, options exist for either intensive screening or prophylactic surgery. This review will discuss the mechanisms by which mutations in the BRCA genes lead to the development of cancer, the limitations of currently available screening techniques, and the efficacy of prophylactic surgery. In general, prophylactic oophorectomy can be performed laparoscopically as an outpatient procedure, carrying as its main drawback the associated consequence of surgical menopause. Prophylactic mastectomy is quite effective in reducing the risk of breast cancer but is a more extensive surgical procedure and results in disfigurement. For any given patient, the best estimates of individual risk of breast or ovarian cancer should be weighed against the benefits of prophylactic surgery and the patient’s personal wishes.

Cancer is the second leading
cause of death behind heart disease,
and breast cancer is the
leading cancer diagnosis. In the year
2003, an estimated 212,600 new cases
of breast cancer will be diagnosed
and 40,200 deaths from the disease
will occur.[1] Ovarian cancer is the
fifth leading cause of cancer death
among women and has a higher case
fatality rate than breast cancer. In
2003, an estimated 25,400 new cases
of ovarian cancer will be diagnosed
and 14,300 individuals will die of the
disease.[1] For both breast and ovarian
cancer, incidence rates have increased
and death rates have decreased
in the past 20 years. Although overall
cancer death rates have increased from
18% to 23% over the past 20 years,
5-year survival rates have increased
more than 20% for breast and ovarian
cancer since the 1950s.

The lifetime risk of being diagnosed
with ovarian cancer is approximately
1.7%, and the median age at
diagnosis is 61 years. The lifetime
risk of being diagnosed with invasive
breast cancer is approximately 13.4%,
and the median age at diagnosis is 62
years.[2] Hereditary cancer is responsible
for approximately 5% of all
breast cancers and almost 10% of all
ovarian cancers. For ovarian cancer,
almost the entire genetic predisposition
is due to pathogenic mutations in
BRCA1 and BRCA2. For breast cancer,
a smaller proportion of hereditary
cases are attributable to mutations
in the BRCA genes.

This review will begin by discussing
the identification and function of
the BRCA1 and BRCA2 genes, as
they are responsible for the majority
of the hereditary breast/ovarian cancer
syndrome and readily available
mutation-detection assays exist. The
lifetime risks associated with specific
mutations will also be discussed. Data
supporting the efficacy of prophylactic
mastectomy and prophylactic
oophorectomy will be covered, as will
the incidence of regret surrounding
these procedures. Alternatives to prophylactic
surgery, including intensive
surveillance and chemoprevention,
and their limitations, will be addressed.
Ongoing clinical trials and areas of
future investigation will be mentioned
throughout.

BRCA GenesIdentification and Function
In 1990, linkage analysis revealed
a region on chromosome 17q21 that
was associated with an increased risk
of breast cancer.[3] Shortly thereafter,
families with both ovarian and
breast cancers were found to have linkage
disequilibrium at this locus.[4] In
1994, the specific gene that was
associated with the predisposition to
breast and ovarian cancer, BRCA1,
was cloned and sequenced.[5] The following
year, BRCA2, which mapped
to chromosome 13q12, was also
cloned.[6] The BRCA1 protein is
1,863 amino acids in length, 220 kD
in weight, and encoded by 24 exons.
The BRCA2 protein is even larger,
containing 3,418 amino acids, weighing
380 kD, and encoded by 27 exons.

The two proteins normally reside
in the nucleus and participate in multiple
cellular functions. BRCA1 has
two unique motifs-a RING finger
domain near the N-terminus and a
BRCT domain near the C-terminus
(Figure 1). The RING finger may facilitate
both protein-protein and protein-
DNA interactions. The RING
finger motif interacts with a similar
region in the BRCA1-associated
RING domain (BARD1) protein. Two
BRCT motifs participate in cell-cycle
regulation and DNA repair. BRCA2
has no recognizable protein motifs but
does have a BRC repeat region that
physically interacts with the RAD51
protein. The interaction between
BRCA1, BRCA2, and RAD51 appears
to be central to the global function of
DNA repair.

BRCA1 and BRCA2 also have other
roles in the maintainenance of genomic
integrity. Evidence stems from
many sources, including the embryonic

lethality of mice that are deficient
in functional BRCA1 protein. In
addition, the proteins are important to
the proper conduct of meiosis and regulation
of the cell cycle, specifically
at the G1/S and G2/M checkpoints.
The specific contributions of these
genes to DNA repair of double-strand
breaks include participation in homologous
recombination, which may be
required to repair certain errors generated
during S-phase sister chromatid
exchange. Defective transcriptioncoupled
repair of oxidative DNA
damage has also been demonstrated
in BRCA1- and BRCA2-mutated
cells.[7] In addition to as yet undiscovered
functions in chromosomal
stability, these gene products are
thought to regulate transcription and
potentially participate in protein
ubiquitination.

Loss of Heterozygosity
The role of BRCA1 and BRCA2
as tumor-suppressor genes is supported
by their ability to inhibit progression
through the cell cycle after DNA
damage, and the loss of this function
is oncogenic. A mutation in a single
allele of any tumor-suppressor gene
generally increases the risk of developing
certain types of tumors-in this
case, breast, ovarian, and other associated
malignancies. This ability is
supported by studies of loss of heterozygosity,
which show that biallelic
mutations in tumor specimens result
in functional inactivation of the corresponding
protein.

Originally proposed by Alfred G.
Knudson in 1971 as the "two-hit hypothesis"
and well delineated in colon
cancer, loss of heterozygosity is
the manifestation of the "second hit"
in individuals who already harbor a
germ-line mutation.[8] Although in
actuality more than two genetic mutations
are required for oncogenesis
(probably about six or seven), the early
accumulation of important mutations
increases the likelihood of
developing additional mutations,
which may occur at a more rapid rate.
In most BRCA-related breast and ovarian
tumors reported to date, both alleles
are mutated when analyzed using
molecular techniques. A central region
within exon 11 of BRCA2 is
thought to contain an ovarian cancer
cluster region, as a mutation within
these 1,150 nucleotides has been reported
to increase the risk of ovarian
cancer almost fourfold over mutations
found elsewhere in this gene.[9,10]

Mutation Frequency
and Penetrance

Both the frequency of BRCA1 and
BRCA2 mutations and their penetrance
(proportion of individuals with
the germ-line mutation who actually
get the disease-in this case, breast or
ovarian cancer) are highly variable
depending on the population studied.
A common theme to be remembered
throughout the rest of this discussion
is that the risks to an individual reflect
that person's family history and
ethnic background in addition to the
results of genetic testing. All BRCA
mutations do not confer the same risk
of cancer.

  • Frequency-In the general population,
    the frequency of carrying a
    germ-line mutation in BRCA1 or
    BRCA2 is approximately 0.1%. In
    certain ethnic groups, the frequency
    of mutations is much higher because
    of the founder effect, in which a particular
    population (and genetic mutation)
    can trace its roots back to a small
    group of ancestors that originated from
    a common geographic location. In the
    Ashkenazi Jewish population-perhaps
    the best studied group in this
    regard-whose origins are from
    Central and Eastern Europe, three
    common mutations (185delAG and
    5382insC in BRCA1, and 6174delT
    in BRCA2) occur in approximately
    1 of every 40 Ashkenazim. Other
    founder mutations have been identified
    in French-Canadians and people
    from Iceland, Sweden, the Netherlands,
    and certain parts of North
    Africa.

    While these figures and others can
    guide initial estimates of frequency, a
    greater likelihood of harboring a mutation
    has been associated with individuals
    who display the cancer
    phenotype. Among Ashkenazi Jewish
    patients with ovarian or peritoneal
    cancer, the probability of carrying a
    pathogenic BRCA1/2 mutation is approximately
    40%.[11,12] Among
    Jewish patients with breast cancer,
    the mutation frequency is close to
    10%.[13,14] These results have been
    reproduced in populations throughout
    the world, including Poland, Turkey,
    Israel, and India. The mutation
    frequency is markedly lower among
    patients with fallopian tube cancer and
    is extremely low for non-Jewish patients
    with breast cancer.

    Table 1 provides a comprehensive
    summary of mutation frequencies for
    selected malignancies seen in women.[
    10-32] In studies of patients with
    strong family histories, the frequency
    of mutations is even higher than in
    patients with only a personal history
    of breast or ovarian cancer.

  • Penetrance-The penetrance of
    mutations for breast and ovarian cancer
    varies widely and is subject to
    methodologic biases. By and large,
    the estimates are only applicable to
    founder mutations, because-with the
    exception of one Icelandic mutation-
    no robust penetrance estimates are
    available. For breast cancer, the lifetime
    risk of developing a BRCAassociated
    breast cancer ranges from
    35% to 75%.[14,33-36] The higher
    estimates originate from studies of
    breast cancer risk assessment programs
    rather than series of incident
    cases. The actual penetrance of breast
    cancer associated with a BRCA
    mutation is likely to range from 50%
    to 70%, which is four- to sixfold
    greater than the risk in the general
    population.

    For breast cancer, the penetrance
    of BRCA1 is almost twice that of
    BRCA2 (Figure 2). BRCA-associated
    breast cancers have a poorer prognosis,
    being less differentiated, with
    fewer estrogen receptors, a higher frequency
    of lymph node metastases, and
    a shorter disease-free survival.[13,37]
    This association seems to be more
    common in BRCA1-associated breast
    cancers than in BRCA2-associated
    breast cancers.

    Penetrance estimates for ovarian
    cancer vary as much as do those for
    breast cancer. The lifetime risk of
    developing ovarian cancer among
    BRCA mutation carriers has been
    reported to range from 15% to
    60%.[10,34,38,39] More recent studies
    put this estimate at 20% to 40%,
    which is 10 to 20 times greater than
    the frequency of ovarian cancer in
    the general population.[35,40] These
    estimates are also higher for individuals
    in families with a history of multiple
    early-onset breast or ovarian
    cancers.

    In contradistinction to breast cancer,
    BRCA-associated ovarian cancer
    appears to have a more favorable
    prognosis, with affected individuals
    achieving a longer overall and disease-
    free survival.[12] This may be a
    consequence of greater sensitivity to
    standard chemotherapy regimens reflected
    by the greater cellular proliferation
    found in BRCA-associated
    tumors than in sporadic tumors.[41]
    BRCA1-associated ovarian tumors
    manifest approximately 10 years earlier
    than sporadic tumors, and
    BRCA2-associated tumors manifest
    at approximately the same age as
    sporadic tumors. The risk of ovarian
    cancer associated with BRCA1 mutations
    is greater than that associated
    with BRCA2 mutations. To date, very
    few genetic modifiers of hereditary
    breast or ovarian cancer have been
    identified.[42-45]

BRCA Mutations
and Other Cancers

Mutations in the BRCA genes are
also associated with increased risks
of cancers of the fallopian tube, peritoneum,
prostate, and pancreas, as well
as melanoma.[35,46,47] Other cancers
have been associated with these
genes in certain studies, but those findings
have not been confirmed and are,
therefore, not generally accepted. The
magnitude of increased risk for other
cancers is not nearly as great as that
for breast and ovarian cancer; however,
there is a statistically significant
association between BRCA2 mutations
and male breast cancer, which
accounts for approximately 1,500 cases
per year in the United States.[9]

Prophylactic Mastectomy

Prophylactic, or risk-reducing,
mastectomy may be performed in patients
at increased risk for breast cancer.
The two groups of patients who
are usually candidates for this procedure
are (1) those with a genetic predisposition
to breast cancer due to
a known germ-line mutation in
BRCA1/2 or a strong family history
of breast and/or ovarian cancer and
(2) those with a personal history of
unilateral breast cancer. The first
group of patients would undergo a
bilateral prophylactic mastectomy,
and the second group, a contralateral
prophylactic mastectomy.

The two types of commonly performed
prophylactic mastectomies are
subcutaneous and total. A subcutaneous
mastectomy is usually performed
through an inframammary incision
and involves complete removal of the
breast tissue, leaving the overlying
skin, nipple-areolar complex, and axillary
lymph nodes undisturbed. In this
procedure, a small amount of residual
breast tissue may be left adherent to
the skin, in the inframammary fold,
or in the axilla. A total mastectomy is
usually performed through an elliptical
incision and involves removal of
much of the skin and the entire nipple-
areolar complex, with the axillary
lymph nodes again left undisturbed.

In both cases, a small amount of
residual tissue is likely to be left behind,
rendering the procedure less than
100% effective in preventing subsequent
breast cancer. Breast reconstruction
can be performed either
immediately after surgery or as an
interval procedure.

Clinical Trials
Two large studies of the efficacy
of prophylactic mastectomy have been
reported in the past several years. The
first, by Hartmann et al,[48] retrospectively
reported on 214 patients
considered to be at high risk for breast
cancer based on family history alone.
After a median follow-up of 14 years,
three breast cancers (1.4%) were diagnosed
in this group of patients.
Compared to their sisters, 39% of
whom developed breast cancer, incidence
was reduced by approximately
90%. These authors subsequently
genotyped 176 of these patients for
BRCA1/2 mutations and found 26
with germ-line mutations.[49] None
of these 26 patients developed breast
cancer over a median follow-up of 13
years; six incidental breast cancers
were found at the time of prophylactic
mastectomy.

The second study was conducted
in 139 women with pathogenic BRCA
mutations followed prospectively.[50]
Patients who chose to undergo prophylactic
mastectomy were compared
to those who remained under regular
surveillance. After a mean follow-up
of 3 years, no cases of breast cancer
developed in the prophylactic mastectomy
group and eight developed in
the surveillance group. The 5-year
incidence of breast cancer in the surveillance
group was 17%. No incidental
breast cancers were noted at
the time of prophylactic mastectomy.
These two studies, taken together, suggest
that prophylactic mastectomy is
highly effective in preventing breast
cancer in high-risk patients.

  • Prophylactic Contralateral Mastectomy-
    The largest study of women
    undergoing prophylactic contralateral
    mastectomy was conducted by the
    Mayo Clinic. In this study, 745 patients
    were followed for a median of
    10 years after prophylactic contralateral
    mastectomy.[51] A total of eight
    women developed contralateral breast
    cancer, for a reduction in risk of approximately
    95% based on the expected
    rate of contralateral breast
    cancer in patients with a personal and
    family history of breast cancer.

    In a case-control study from City
    of Hope, 64 patients who underwent
    prophylactic contralateral mastectomy
    were matched for multiple pathologic
    and clinical variables almost 3
    to 1 with controls.[52] In the prophylactic
    contralateral mastectomy group,
    three incident breast cancers were
    found at the time of surgery, but no
    subsequent cancers occurred at a mean
    follow-up of 6.8 years. In the control
    group, 36 contralateral breast cancers
    were identified.

    Despite a marked reduction in contralateral
    breast cancers among patients
    who underwent a prophylactic
    contralateral mastectomy, the improvement
    in 15-year overall survival
    was not statistically significant (64%
    vs 48%, P = .26).[52] This is attributable
    to the high rate of metastatic disease
    from the primary breast cancer.
    It appears that an improvement in
    overall survival may be realized by
    patients with early-stage breast cancer
    who undergo prophylactic contralateral
    mastectomy, because their
    risk of metastatic disease is proportionately
    lower than their risk of contralateral
    breast cancer. Despite the
    lack of improvement in overall survival,
    the City of Hope study did show
    an improvement in disease-free survival
    at 15 years.

    It is clear from both studies that
    prophylactic contralateral mastectomy
    can dramatically reduce the risk
    of contralateral breast cancer in patients
    with unilateral disease. Whether
    or not this will have a significant
    impact on patients with early-stage
    disease will require further study.

Sentinel Lymph Node Biopsy
The role of sentinel lymph node
biopsy at the time of prophylactic
mastectomy is under investigation.
The reason a sentinel lymph node biopsy
is performed at the time of prophylactic
mastectomy is to prevent
the need for subsequent axillary dissection
in patients found to have occult
cancers at the time of surgery.

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