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Current Status of Prophylactic Mastectomy

Current Status of Prophylactic Mastectomy

ABSTRACT: The management of women at high risk for breast cancer presents a clinical dilemma to the health-care provider as well as to the woman herself. Current options include surveillance, prophylactic surgery (mastectomy and/or oophorectomy), and/or chemoprevention. Prophylactic mastectomy, including bilateral prophylactic mastectomy in high-risk women or contralateral prophylactic mastectomy in women with primary breast cancer, has been a controversial clinical option. In this review, we address the efficacy of prophylactic mastectomy in reducing the risk of breast cancer in high-risk women, the use of this procedure, surgical complications, and its psychosocial impact. The decision to undergo prophylactic mastectomy is highly personal and must be preceded by an in-depth assessment of the woman’s risk of breast cancer, and a thorough discussion of the benefits of the procedure weighed against its potential surgical risks and psychological impact. It is also imperative that the woman be informed of alternative options for management, including chemoprevention, close surveillance, and prophylactic oophorectomy. [ONCOLOGY 16:1319-1332, 2002]

An accurate assessment of the risk of breast cancer is the
first step in planning future preventive strategies. Women at high risk of
breast cancer are those with known BRCA mutations or a strong family history
characterized by multiple relatives with breast cancer, early age at diagnosis,
and in some cases, ovarian cancer. These women currently have three management
options: cancer surveillance, prophylactic surgery (mastectomy and/or
oophorectomy), and/or chemoprevention. Prophylactic mastectomy includes
bilateral prophylactic mastectomy in a high-risk woman who has not had cancer
and contralateral prophylactic mastectomy, defined as mastectomy of the opposite
breast in a woman with a primary breast cancer. In this review, we discuss the
currently available literature on prophylactic mastectomy, its indications, and
role in breast cancer prevention.

Surgical Techniques

Surgical options for prophylactic mastectomy include
subcutaneous mastectomy or total mastectomy, usually followed by breast
reconstruction. Subcutaneous mastectomy is performed via an inframammary
incision through which the breast tissue is resected, sparing the nipple-areolar
complex.[1] Historically, subcutaneous mastectomy was performed more commonly
than total mastectomy, which removes the majority of the breast tissue along
with the nipple-areolar complex through an elliptical skin incision. Given
current nipple reconstruction techniques, total mastectomy is the preferred
prophylactic procedure today.[2] With both procedures, however, small amounts of
remaining breast tissue—which can develop into cancer—may be left behind in
the axilla, inframammary fold, and skin flaps.[3] This issue must be clearly
explained to the patient, because the risk of breast cancer, therefore, cannot
be completely eradicated with prophylactic mastectomy.

Historical Perspective

Prophylactic mastectomy has been performed for decades.
Historically, contralateral prophylactic mastectomy was advocated to reduce the
increased risk of a second primary breast cancer in women who had had a first
breast cancer. Bloodgood was the first to report on this strategy, in his 1921
discussion of the management of the remaining breast after radical removal of
the opposite breast for carcinoma.[4] With the availability of breast implants
for reconstruction, and the increasing awareness of familial breast cancer risk,
bilateral prophylactic mastectomy began to be more commonly performed in the
1960s and 1970s.

In 1989, Pennisi and Capozzi published data on 1,500 women
who had undergone subcutaneous mastectomy.[5] Patients were identified through
solicitations to the membership of the American Board of Plastic Surgery. A
total of 165 plastic surgeons contributed cases. A family history of breast
cancer (first-degree, second-degree, maternal, or paternal relatives) was noted
in 41% of involved patients. Of the 1,500 patients, 139 underwent a
contralateral subcutaneous prophylactic mastectomy after a modified radical
mastectomy of the opposite breast for primary breast cancer.

Subsequently, six women (0.4%) developed breast cancer,
leading the authors to conclude that the procedure provided effective
prophylaxis. However, some of the limitations regarding this study included a
possible bias toward inclusion of patients with a favorable outcome, lack of
definition of the patients’ risk of breast cancer, a high
"lost-to-follow-up" rate of 30%, and inclusion of women with a history
of cancer in the opposite breast.[5]

In 1997, the Cancer Genetics Studies Consortium, organized by
the National Human Genome Research Institute, published a consensus statement on
the optimal care of individuals carrying mutations in the BRCA1 and BRCA2
genes.[6] Regarding prophylactic mastectomy, their recommendation stated,

There is insufficient evidence to recommend for or against prophylactic
mastectomy as a measure for reducing breast cancer risk. Individuals should be
counseled that this is an option available to them. Those considering
prophylactic mastectomy should be counseled that cancer has been documented to
occur after the procedure; its efficacy in reducing risk is uncertain.[6]

Indeed, case reports had detailed the recurrence of breast
cancer in residual breast tissue following both total and subcutaneous
prophylactic mastectomy.[7-9] Several studies of the efficacy of the procedure
(see below) have been published since this consensus statement.

Efficacy of Prophylactic Mastectomy

Bilateral Prophylactic Mastectomy

Mayo Clinic Study—In an effort to quantify the risk
reduction associated with prophylactic mastectomy, Hartmann and colleagues at
the Mayo Clinic performed a retrospective cohort analysis of 639 women with a
family history of breast cancer who had undergone prophylactic mastectomy
between 1960 and 1993.[10] Women were assigned retrospectively to either a
moderate-risk group (425 women) or high-risk group (214 women) based on the
extent of their family history of breast cancer. Follow-up was available for 99%
of the cohort for a minimum of 2 years; median follow-up was 14 years (9,095
person-years).

The investigators compared the total number of breast cancers
observed among study participants with the total number predicted by the Gail
model (for the moderate-risk group) and by a nested sister control study (for
the high-risk group). The Gail model predicted that 37.4 women in the
moderate-risk group would develop breast cancer by the median follow-up of 14
years. However, only four of these women developed the disease, representing an
89.5% reduction (P < .00001) in incidence following prophylactic mastectomy.
The Gail model also predicted that 10.4 women in the moderate-risk group would
die of breast cancer, but, in fact, no deaths from breast cancer occurred in
these women.

With regard to the high-risk group, 3 of the 214 women
developed breast cancer after prophylactic mastectomy. From their sisters’
experiences, 30 breast cancers were predicted in these high-risk women (see
Table 1).[10] Thus, prophylactic mastectomy was associated with a 90% reduction
in the risk of breast cancer in high-risk women. Similarly, compared with the
expected number of breast cancer deaths in the probands, prophylactic mastectomy
in the high-risk group resulted in an 81% to 94% reduction in breast cancer
mortality.

Dutch Study—A recent prospective Dutch study evaluated
139 BRCA1 or BRCA2 carriers followed at the Rotterdam Family Cancer Clinic; none
had a history of breast cancer.[11] A total of 76 of these women elected to
undergo prophylactic mastectomy, and 63 remained under careful surveillance. At
a mean follow-up of 2.9 ± 1.4 years, no cases of breast cancer were observed in
the prophylactic mastectomy group, compared to eight cases in the surveillance
group (hazard ratio: 0; 95% confidence interval [CI]: 0-0.36).

Of the eight cases, four were interval cancers diagnosed
between scheduled screening tests. Four of the cancers involved axillary lymph
nodes, and seven were estrogen-receptor and progesterone-receptor negative. The
interval from initiation of surveillance to diagnosis of cancer ranged from 2 to
42 months. These investigators concluded that in women with a BRCA1 or BRCA2
mutation, at 3 years of follow-up, prophylactic bilateral total mastectomy
reduced the incidence of breast cancer (relative risk reduction: 100%, absolute
risk reduction: 12.7%).

Contralateral Prophylactic Mastectomy

Contralateral breast cancers occur at a rate of approximately
0.5% to 1.0% per year of follow-up after a primary breast cancer in women at
average risk.[12] In women with a family history of breast cancer, Harris et al
described a 35% risk of contralateral breast cancer by 16 years after the first
breast cancer diagnosis.[13] However, in carriers of a BRCA1 or BRCA2 mutation,
the contralateral breast cancer rate is higher, ranging from 12% at 5 years in
BRCA2 carriers, to 20% to 31% at 5 years in BRCA1 carriers[14] and Ashkenazi
BRCA1 or BRCA2 carriers.[15]

Data on the efficacy of contralateral prophylactic mastectomy
have been relatively sparse. However, two recent studies have addressed this
issue.

Peralta et al Study—Peralta et al studied the efficacy
of contralateral prophylactic mastectomy in a retrospective analysis of 64
patients with a personal history of breast cancer who underwent this procedure,
compared with 182 controls who did not.[16] The end points were contralateral
breast cancer rate, disease-free survival, and overall survival. The groups were
matched by age, stage, surgery, chemotherapy, and hormonal therapy.

In the contralateral prophylactic mastectomy group, three
incidental contralateral breast cancers (4.5%) were found at the time of
prophylactic mastectomy, but none occurred subsequently; 36 contralateral breast
cancers occurred in the control group (P = .005). The mean follow-up was 6.8
years (range: 0.3-23.6 years). Overall survival at 15 years was 64% (95% CI:
45%-78%) in the contralateral prophylactic mastectomy group vs 49% (95% CI:
39%-58%) in the control group (P = .26). The researchers concluded that
contralateral prophylactic mastectomy prevented contralateral breast cancer and
that the potential benefit was greatest when the risk of contralateral breast
cancer was highest.[16]

McDonnell et al Study—McDonnell et al followed 745 women
(388 premenopausal, 357 postmenopausal) with a first breast cancer and a family
history of breast and/or ovarian cancer who underwent contralateral prophylactic
mastectomy at the Mayo Clinic between 1960 and 1993.[17] Using life tables for
contralateral breast cancers (referred to as the Anderson model),[18,19] the
investigators considered current age, age at first breast cancer, and type of
family history (which is based only on breast cancer events in the family and
requires one of three types of pedigree—parent-affected, sibling-affected,
second-degree relative-affected). With these data, they predicted the number of
contralateral breast cancers in this cohort had patients not undergone
contralateral prophylactic mastectomy. The median length of follow-up was 10
years, with a minimum follow-up of 2 years for 98% of the cohort.

Eight women developed contralateral breast cancer. Six events
were observed in the premenopausal group of 388 women compared with 106.2
predicted, representing a risk reduction of 94.4% (95% CI: 87.7%-97.9%). In
the postmenopausal group of 357 subjects, two events were observed compared with
50.3 predicted, representing a 96% risk reduction (95% CI: 85.6%-99.5%). The
incidence of contralateral breast cancer, therefore, appears significantly
reduced after contralateral prophylactic mastectomy in women with a personal and
family history of breast cancer.[17]

Schrag et al Study—Schrag et al performed a decision
analysis using a Markov model to predict years of life gained through various
prevention strategies in BRCA1 or BRCA2 carriers.[20] They estimated the
probabilities of developing contralateral breast cancer and ovarian cancer,
dying from these cancers, and dying from primary breast cancer, based on
published studies. They also calculated reductions in the incidence and
mortality of cancer resulting from prophylactic surgeries and/or tamoxifen.

Using hypothetical breast cancer patients with BRCA1 or BRCA2
mutations who faced secondary cancer prevention strategies, they assessed the
effect of contralateral prophylactic mastectomy, bilateral prophylactic
oophorectomy, and 5 years of tamoxifen therapy on their life expectancy.
Based on the assumed penetrance of BRCA mutations, compared to surveillance
alone, 30-year-old, early-stage breast cancer patients with BRCA mutations gain
0.4 to 1.3 years of life expectancy with tamoxifen therapy, 0.2 to 1.8 years
with prophylactic oophorectomy, and 0.6 to 2.1 years with contralateral
prophylactic mastectomy. The magnitude of the gain was highest for women with
high-penetrance mutations.[20]

Thus, contralateral prophylactic mastectomy provides a
potential benefit for patients at high risk of contralateral breast cancer, with
chemoprevention and close surveillance being important alternatives. It is
essential to provide each patient with appropriate counseling regarding the risk
of recurrence of her primary breast cancer, the risk of contralateral breast
cancer, and the efficacy of contralateral prophylactic mastectomy (and its
cosmetic outcomes), in order to optimize the ultimate outcome, including patient
satisfaction.

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