Download Contralateral Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

VOLUME
22
䡠
NUMBER
12
䡠
JUNE
15
2004
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Contralateral Breast Cancer in BRCA1 and BRCA2
Mutation Carriers
Kelly Metcalfe, Henry T. Lynch, Parviz Ghadirian, Nadine Tung, Ivo Olivotto, Ellen Warner,
Olufunmilayo I. Olopade, Andrea Eisen, Barbara Weber, Jane McLennan, Ping Sun, William D. Foulkes,
and Steven A. Narod
From the Faculty of Nursing and the
Centre for Research on Women’s
Health, and Sunnybrook and Women’s
College Health Sciences Centre, University of Toronto; Toronto Sunnybrook
Regional Cancer Centre, Toronto; Epidemiology Research Unit, Centre Hospitalier de Université de Montreal
(CHUM); Program in Cancer Genetics,
McGill University, Montreal; British Columbia Cancer Agency, Vancouver;
Hamilton Regional Cancer Centre, Hamilton, Canada; Department of Preventive
Medicine and Public Health, Creighton
University School of Medicine, Omaha,
NE; Beth Israel Deaconess Medical
Center, Boston, MA; Department of
Medicine, University of Chicago, Chicago, IL; Departments of Medicine and
Genetics, Department of Hematology/
Oncology, University of Pennsylvania,
Philadelphia, PA; Cancer Risk Program,
UCSF Comprehensive Cancer Center,
San Francisco, CA.
Submitted April 3, 2003; accepted
March 24, 2004.
Authors’ disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Steven
Narod, MD, Centre for Research on
Women’s Health, Women’s College
Hospital, 790 Bay St, Room 750,
Toronto, Ontario, Canada M5G 1N8;
e-mail: [email protected].
© 2004 by American Society of Clinical
Oncology
0732-183X/04/2212-2328/$20.00
DOI: 10.1200/JCO.2004.04.033
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Purpose
To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers after diagnosis and to
determine which factors are predictive of the risk of a second primary breast cancer.
Patients and Methods
Patients included 491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2
mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer
until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.
Results
The actuarial risk of contralateral breast cancer was 29.5% at 10 years. Factors that were predictive of
a reduced risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR], 0.73; 95%
CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v ⱕ 49 years; HR, 0.63; 95% CI, 0.36 to
1.10); use of tamoxifen (HR, 0.59; 95% CI, 0.35 to 1.01); and history of oophorectomy (HR, 0.44;
95% CI, 0.21 to 0.91). The effect of oophorectomy was particularly strong in women first diagnosed
prior to age 49 years (HR, 0.24; 95% CI, 0.07 to 0.77). For women who did not have an
oophorectomy or take tamoxifen, the 10-year risk of contralateral cancer was 43.4% for BRCA1
carriers and 34.6% for BRCA2 carriers.
Conclusion
The risk of contralateral breast cancer in women with a BRCA mutation is approximately 40% at 10
years, and is reduced in women who take tamoxifen or who undergo an oophorectomy.
J Clin Oncol 22:2328-2335. © 2004 by American Society of Clinical Oncology
INTRODUCTION
Women who carry a germline mutation in
either the BRCA1 or BRCA2 gene face a high
lifetime risk of breast cancer,1 and, once diagnosed with breast cancer, face a high risk
of subsequently developing cancer in the
contralateral breast.2-7 As a result, women
may opt for contralateral mastectomy as a
preventive measure as part of their initial
treatment. It is not clear to what extent the
risk of contralateral breast cancer varies with
age, and if the risk is equivalent for carriers
of BRCA1 and BRCA2 mutations. Factors
that modify the risk of contralateral breast
cancer in BRCA carriers have not been studied prospectively. In a case-control study,8
we found that the risk of contralateral breast
cancer in BRCA carriers was reduced if the
woman had taken tamoxifen (hazard ratio
[HR], 0.50; 95% CI, 0.28 to 0.89), if she had
had an oophorectomy (HR, 0.42; 95% CI,
0.22 to 0.83), or if she had received chemotherapy (HR, 0.40; 95% CI, 0.26 to 0.60).
However, it was not possible to estimate the
actuarial risk for contralateral breast cancer
or to study the possible effect of age at diagnosis on contralateral breast cancer risk.
Here we present data from a large-scale prospective study designed to generate estimates
of the risk of contralateral breast cancer among
women with BRCA1 or BRCA2 mutations,
and to identify host- and treatment-related
factors that might modify the risk.
2328
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BRCA Mutations and Contralateral Breast Cancer
PATIENTS AND METHODS
Study Subjects
Pedigrees of cancer families identified at 10 participating
cancer genetics clinics were reviewed. A family was considered to
be eligible for the study when a BRCA1 or a BRCA2 mutation was
documented in the family, and at least one case of invasive breast
cancer was recorded. Eligible study subjects included all women
from these families who were diagnosed with stage I or stage II
breast cancer at age 65 years or younger, between 1975 and 2000.
Living and deceased women were eligible, but those with a prior
diagnosis of cancer (including breast cancer) or those who resided
outside of North America were excluded. It was not necessary to be
a proven carrier of the mutation found in the family to be included
in the study; however, affected women who were known to be
noncarriers were excluded. All study procedures were approved by
the institutional review boards at each of the participating centers.
We identified a total of 1,139 breast cancer cases in 337
families. Of the total of 1,139 cases of breast cancer, 320 women
were excluded because the date of diagnosis indicated on the
pedigree was before 1975, and 50 women were excluded because
the age of diagnosis was older than 65 years. An additional 19
women were not carriers of the familial mutation and were therefore excluded. Ten women were excluded because they had a
diagnosis of other cancer before breast cancer, and 11 women were
excluded because they were treated outside of North America.
We were able to obtain identifying information for 587 of the
remaining 729 women (80.5%). An attempt was made to contact
each of these women or their respective next-of-kin to obtain
permission to review the medical records. Thirteen women (or
their next of kin) refused to provide consent for the release of their
medical records. The medical record was requested from the hospital where treatment was received for the remaining 574 women.
In 54 cases, the hospital was not able to locate the record or did not
forward the requested documents. The medical record was obtained for the remaining 520 women (91%).
After review of the medical records, an additional 29 women
were excluded. Of these, 22 women were excluded because tumor
stage was greater than 2, six women were excluded because the
tumor was noninvasive (ductal carcinoma in situ or lobular carcinoma in situ), and one woman was excluded because she refused
treatment. The remaining 491 women were included in the analysis. In summary, of the 1,139 breast cancers, 439 were ineligible,
and we were able to enroll 491 of the remaining 700 eligible cases
(70%). Ninety-two (18.7%) of the 491 women were deceased.
Study Protocol
The medical treatment records and pathology documents
were reviewed. We established whether the tumor was unilateral
(482 cases) or bilateral (nine cases) at initial diagnosis. We recorded tumor size (in centimeters), nodal status (positive or negative), and tumor grade (I to III). Where possible, we abstracted
information on both mitotic grade and nuclear grade. Estrogen
receptor status was recorded as positive, negative, or equivocal.
We recorded the use of chemotherapy (yes or no), tamoxifen (yes
or no), and radiotherapy (yes or no). We established whether or
not the patient had undergone a bilateral oophorectomy, and if so,
the date of the operation. We categorized the principal surgery as
either breast-conserving surgery (ie, lumpectomy), unilateral
mastectomy, or bilateral mastectomy. In some cases, the contralateral mastectomy and/or oophorectomy were performed several
years after the initial surgical treatment; the dates of these late
treatments were recorded. We reviewed the medical records of
deceased women to establish the cause of death. Because of the
relatively young ages of death of these women (mean age, 48.0
years; range, 31.5 to 84.1 years), the great majority of deaths in the
cohort were due to breast or ovarian cancer. We reviewed the dates
of diagnosis of all contralateral breast cancers reported in the
cohort. Only invasive contralateral cancers were included. Contralateral breast cancers were assumed to be new primary breast
cancers and not metastases of the original primary. No woman was
diagnosed with contralateral breast cancer after she was diagnosed
with distal metastases.
Statistical Analysis
A survival analysis was performed. We considered the
woman to be at risk for contralateral breast cancer from the date of
the first surgical procedure until either death from breast or ovarian cancer, death from another cause, or the date of last follow-up.
Initially, we compared the risk of contralateral breast cancer in
women who had and who did not have a contralateral mastectomy. In subsequent analyses, only women for whom the contralateral breast was intact were considered to be at risk for
contralateral breast cancer.
Survival curves were constructed and compared for subgroups of women defined by age (ⱕ 40 years; 41 to 50 years; ⱖ 51
years) and by mutation status (BRCA1 v BRCA2). We also compared the risk of contralateral breast cancer for subgroups defined
by each of the four treatments individually (ie, tamoxifen v no
tamoxifen, oophorectomy v no oophorectomy, and so on) and in
combination. Hazard ratios (HRs) were estimated using the Cox
proportional hazards model, implemented in SAS (SAS Institute,
Cary, NC). The HRs were adjusted for age, mutation status
(BRCA1 v BRCA2), and other treatments received.
RESULTS
There were 491 women who were treated for stage I or II
breast cancer between 1975 and 2000. There were 327
women from families with a BRCA1 mutation, and 152
women from families with a BRCA2 mutation. Twelve
women carried a mutation in both genes. The characteristics of the 491 women with breast cancer included in the
analysis are presented in Table 1, the characteristics of their
tumors are detailed in Table 2, and the treatments they
received are presented in Table 3.
The majority of the subjects were treated with breastconserving surgery (39%) or with unilateral mastectomy
(52%), but 44 women (9%) were initially treated with a
bilateral mastectomy. One hundred six women had a contralateral preventive mastectomy at various times after the
initial surgery (range, 1 month to 14 years). However, three
women had had their contralateral breast removed before
their first diagnosis of invasive breast cancer (two because of
ductal carcinoma in situ, and one because of fibrocystic
disease). These three women were observed for contralateral breast cancer after their diagnosis of invasive cancer,
and were included with the women who had bilateral mastectomies. Of the nine women with bilateral synchronous
2329
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Metcalfe et al
Table 1. Characteristics of 491 Study Subjects
Table 2. Characteristics of 491 Breast Cancers in the Study
Characteristic
Patients
Characteristic
Year of birth
Year
Range
Age of diagnosis, years
Mean
Range
Age of diagnosis, years
⬍ 30
30-40
40-50
⬎ 50
Mutation
BRCA1
BRCA2
Both
Place of residence
Canada
United States
Genetic testing
Yes, positive
Not done
Vital status
Living
Deceased
No.
%
1947
1916-1971
42.1
24-65
28
190
180
93
5.7
38.7
36.7
18.9
327
152
12
66.6
31.0
2.4
191
300
38.9
61.1
411
80
83.7
16.3
399
92
81.3
18.7
breast cancer, seven had bilateral mastectomy, and two had
bilateral breast-conserving surgery. These nine women
were not at risk for contralateral breast cancer and are
excluded from the following analyses. There were 209
women who had an oophorectomy, either for treatment of
breast cancer, for the prevention of ovarian cancer, or for
another reason. The exact indication for the oophorectomy
was not known.
After a mean follow-up period of 9.2 years, one contralateral breast cancer (in the chest wall) occurred among
the 146 women treated with bilateral, prior, or delayed
contralateral mastectomy. In contrast, there were 97 contralateral breast cancers diagnosed among the 336 women
who retained the contralateral breast (HR, 0.03; P ⫽ .0005).
Because the observed risk of contralateral breast cancer
following mastectomy was so low, the following analyses are
restricted to the 336 women for whom the contralateral
breast was intact.
The mean interval between the diagnosis of the first
breast cancer and the diagnosis of the contralateral breast
cancer was 5.5 years (range, 0.1 to 16.2 years). The 5-year
actuarial risk of contralateral breast cancer was 16.9% (95%
CI, 10.5% to 23.3%), and the 10-year risk of breast cancer
was 29.5% (95% CI, 20.6% to 38.3%). The risk of contralateral breast cancer was estimated for patient subgroups defined by age, gene (BRCA1 v BRCA2), and by treatment
received (surgery, chemotherapy, tamoxifen, ovarian abla2330
Stage
I
II
Size, cm
0-2
2-5
Grade
I
II
III
Unknown
ER status
Positive
Negative
Equivocal
Unknown
Lymph node status
Positive
Negative
Laterality
Unilateral
Bilateral
Histology
Medullary
Ductal
Lobular
Other
Unknown
No.
%
231
260
47.0
53.0
324
167
66.0
34.0
13
93
214
171
2.6
18.9
43.6
34.8
146
213
12
120
29.7
43.4
2.4
24.4
160
331
32.6
67.4
482
9
98.2
1.8
43
410
16
19
3
8.8
83.5
3.3
3.9
0.6
NOTE. In the case of the nine women with synchronous bilateral
tumors, only the first of the tumors that was recorded in the database is
included here.
Abbreviation: ER, estrogen receptor.
tion). The univariate and multivariate HRs associated with
each of these factors are presented in Table 4. The 10-year
risk was slightly, but not significantly, higher for women
with BRCA1 mutations (32%) than for women with BRCA2
mutations (24.5%; Fig 1). The risk was also slightly higher
for women younger than 50 years at first breast cancer
diagnosis (31%) compared with those diagnosed after age
50 years (23.5%; Fig 2). Neither radiotherapy nor chemotherapy use modified the risk significantly, but there was a
moderate and borderline-significant decrease in the risk of
contralateral breast cancer associated with tamoxifen use
(HR, 0.59; 95% CI, 0.35 to 1.01; P ⫽ .05). After adjustment
for age, mutation, and other treatments, the reduction associated with tamoxifen was no longer significant (HR,
0.62; P ⫽ .12).
One hundred seven of the 336 women with an intact
contralateral breast had a bilateral oophorectomy at some
time; 14 women had an oophorectomy before breast cancer
(13%); 15 women had an oophorectomy within 1 year of
the diagnosis of breast cancer (14%); and 78 women had an
oophorectomy from 1 year to 25 years after their initial
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BRCA Mutations and Contralateral Breast Cancer
Table 3. Characteristics of Treatments Received Among 482 Women
With Unilateral Breast Cancer
Treatment
Surgical
Lumpectomy
Unilateral mastectomy
Bilateral mastectomy
Chemotherapy
Yes
No
Missing
Tamoxifen
Yes
No
Missing
Oophorectomy
Never
Ever
Missing
Timing of oophorectomy
Prior to diagnosis
After diagnosis
Missing
Radiotherapy
Yes
No
Missing
No.
%
191
254
37
39.6
52.7
7.7
296
176
10
61.4
36.5
2.1
144
310
28
29.9
64.3
5.8
259
209
14
53.7
43.4
2.9
33
174
2
15.8
83.3
1.0
221
253
8
45.9
52.5
1.7
breast cancer diagnosis. To adjust for the effects of the
timing of oophorectomy, oophorectomy was treated as a
time-dependent covariate in the survival analysis. Oopho-
Fig 1. Actuarial risks of contralateral breast cancer in carriers of BRCA1 and
BRCA2 mutations. Dx, diagnosis.
rectomy was associated with a 59% reduction in the risk of
contralateral breast cancer (HR, 0.41; 95% CI, 0.18 to 0.90).
The magnitude of the risk reduction observed with oophorectomy was greater for women younger than 50 years at
diagnosis (HR, 0.24; 95%CI, 0.07 to 0.77; P ⫽ .02) than for
women 50 years or older (HR, 0.91; 95% CI, 0.26 to 3.21).
There was only a modest difference in the risk of contralateral breast cancer for women who had their oophorectomy
before or at the time of diagnosis (HR, 0.32; P ⫽ .12) and
those who had their oophorectomy after initial breast cancer surgery (HR, 0.50; P ⫽ .15). All factors were considered
Table 4. Risks of Contralateral Breast Cancer Associated With Selected Factors
Univariate
Factor
HR
BRCA
BRCA1
BRCA2
Age, years
⬍ 50
⬎ 50
Oophorectomy
No
Yes
Chemotherapy
No
Yes
Radiotherapy
No
Yes
Tamoxifen
No
Yes
Multivariate
95% CI
P
0.47 to 1.15
.17
1.0
0.73
95% CI
P
0.39 to 1.09
.10
0.45 to 1.51
.52
0.18 to 0.90
.03
0.68 to 1.70
.74
0.56 to 1.34
.51
0.34 to 1.14
.12
1.0
0.65
0.36 to 1.10
.11
1.0
0.63
1.0
0.82
0.21 to 0.91
.03
1.0
0.44
1.0
0.41
0.68 to 1.55
.90
1.0
1.03
1.0
1.08
0.51 to 1.16
.21
1.0
0.77
1.0
0.86
0.35 to 1.01
1.0
0.59
HR
.05
1.0
0.62
NOTE. Multivariate estimates are adjusted for age, mutation (BRCA1 or BRCA2), and other treatments. Analyses restricted to 336 women with intact
contralateral breast.
Abbreviation: HR, hazard ratio.
2331
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Metcalfe et al
Fig 2. Actuarial risks of contralateral breast cancer in BRCA carriers
diagnosed prior to or after age 50 years. Dx, diagnosis.
jointly in a multivariate analysis, but oophorectomy was
found to be the only intervention protective against contralateral breast cancer at a statistical level of significance
(HR, 0.41; P ⫽ .03).
Because women who took tamoxifen or had an oophorectomy experienced lower risks of contralateral breast cancer, the cumulative risk was re-estimated in women who did
not receive either of these adjuvant hormonal treatments.
This estimate accurately represents the underlying risk for
contralateral breast cancer owing to the presence of the
susceptibility gene in the absence of intervention. For
BRCA1 carriers, the 5-year actuarial risk was 27.1%, and the
10-year risk was 43.4%. For BRCA2 carriers, the 5-year
actuarial risk was 23.5%, and the 10-year risk was 34.6%. In
comparison, the 10-year risks for women who used tamoxifen or who had an oophorectomy were 18.8% for BRCA1
carriers and 13.1% for BRCA2 carriers. The HR associated
with either of these hormonal treatments, compared with
neither treatment, was 0.41 (95% CI, 0.24 to 0.70; P ⫽ .001;
Fig 3). For women diagnosed before age 50 years, the HR
associated with the combination of tamoxifen and oophorectomy was 0.09 (95% CI, 0.01 to 0.68; P ⫽ .02). The risk
reduction associated with tamoxifen treatment was similar
for BRCA1 and BRCA2 carriers (Tables 5 and 6). Oophorectomy seemed to be more effective for BRCA1 carriers
than for BRCA2 carriers, but the CIs were wide. Because the
tumor estrogen receptor (ER) status was missing for many
women, it was not possible to estimate the effects of hormonal therapies separately for the subgroup of ER-negative
breast cancer patients. We did not see a reduction in contralateral breast cancer risk associated with chemotherapy
(Tables 4, 5, and 6). Among women younger than 50 years,
who may have undergone early menopause due to chemotherapy, the HR for contralateral breast cancer was 0.92
(95% CI, 0.58 to 1.45).
2332
Fig 3. Actuarial risks of contralateral breast cancer in BRCA carriers with
either tamoxifen or oophorectomy, compared with carriers receiving neither
treatment. Dx, diagnosis.
Information was available on ipsilateral cancers for 188
of 191 women who had breast-conserving surgery. It was
not possible to distinguish between local recurrences and
new primary ipsilateral cancers, and therefore, the number
of observed events represents the sum of these two categories. The 10-year risk of ipsilateral cancer was 11.5% for
BRCA1 carriers and BRCA2 carriers combined (9.8% for
BRCA1 carriers and 14.6% for BRCA2 carriers). The 10year risk of ipsilateral cancer was 9.1% for 171 women who
received radiotherapy, and was 33.8% for 17 women who
did not receive radiotherapy (HR, 0.23; P ⫽ .01; Fig 4).
Tamoxifen use and chemotherapy were also associated with
a reduction in the risk of ipsilateral breast cancer in the
univariate analysis (Table 7).
DISCUSSION
We report a high risk of contralateral breast cancer among
491 women with breast cancer and for whom a BRCA1 or
BRCA2 mutation was documented in the family. We estimate the 5-year actuarial risk of contralateral breast cancer
to be 17%, and the 10-year risk to be 30%. Previous studies
have been much smaller in size. Pierce et al4 estimated the
5-year contralateral rate of breast cancer to be 20% in a
historical cohort of 71 BRCA carriers. Chappuis et al5 estimated the 5-year risk of contralateral breast cancer to be
10% in a study of 32 carriers. Haffty et al7 estimated the
12-year risk of contralateral breast cancer to be 42% in a
study of 22 women with BRCA mutations. We found the
10-year risk of contralateral breast cancer to be modestly
greater for women diagnosed before age 50 years than
after age 50 years. Verhoog et al6 estimated the 10-year
risk of contralateral breast cancers among 124 BRCA1
carriers diagnosed before age 50 years to be 40%, versus
12% for 40 patients diagnosed after age 50 years. Robson
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BRCA Mutations and Contralateral Breast Cancer
Table 5. Risks of Contralateral Breast Cancer Associated With Selected Factors (BRCA1 carriers)
Univariate
Factor
HR
Age, years
⬍ 50
⬎ 50
Oophorectomy
No
Yes
Chemotherapy
No
Yes
Radiotherapy
No
Yes
Tamoxifen
No
Yes
95% CI
0.33 to 1.35
Multivariate
P
HR
.25
1.0
0.66
95% CI
P
0.44 to 1.94
.83
0.13 to 0.84
.020
0.61 to 1.76
.89
0.59 to 1.62
.98
0.26 to 1.33
.59
1.0
0.92
0.16 to 0.86
.021
1.0
0.37
1.0
0.33
0.60 to 1.62
.96
1.0
0.99
1.0
1.04
0.56 to 1.50
.74
1.0
0.92
1.0
0.98
0.26 to 1.27
.17
1.0
0.57
1.0
0.59
NOTE. Multivariate estimates are adjusted for age, mutation, and other treatments. Analyses restricted to 224 women with an intact contralateral breast.
Abbreviation: HR, hazard ratio.
et al3 estimated the 5-year risk of contralateral breast
cancer to be 31% in a group of 30 BRCA carriers diagnosed before age 42 years.
The current study has strengths in addition to its large
sample size. All women with breast cancer in the BRCA
mutation–positive families were identified, and those who
had been diagnosed with breast cancer from 1975 to 2000 at
65 years or younger were eligible to enter the study population. Eighty women with breast cancer who had not had
genetic testing were included; however, women who had
tested negative were excluded. We included untested and
deceased women in the study in order to avoid the survivor-
ship bias that would arise if only tested women were included. The majority of genetic tests were done several years
after the diagnosis of breast cancer. Restricting the study
population to living women who were available for testing
would inevitably have introduced a survivorship bias. However, given the presence of a documented mutation in all of
the study families, the inclusion of untested women should
not introduce significant misclassification bias. Of the 430
women with breast cancer in known BRCA-positive families who received genetic testing, 411 (96%) were found to
be mutation carriers, and 19 (4%) were found to be noncarriers. Forty-three of the 80 untested women were de-
Table 6. Risks of Contralateral Breast Cancer Associated With Selected Factors (BRCA2 carriers)
Univariate
Factor
HR
Age, years
⬍ 50
⬎ 50
Oophorectomy
No
Yes
Chemotherapy
No
Yes
Radiotherapy
No
Yes
Tamoxifen
No
Yes
Multivariate
95% CI
P
0.27 to 1.66
.38
1.0
0.67
95% CI
P
0.22 to 1.93
.45
0.16 to 3.48
.72
0.45 to 3.08
.75
0.23 to 1.44
.24
0.25 to 1.70
.37
1.0
0.66
0.13 to 2.45
.47
1.0
0.58
1.0
0.75
0.51 to 2.34
.81
1.0
1.10
1.0
1.17
0.22 to 1.04
.06
1.0
0.47
1.0
0.58
0.33 to 1.65
1.0
0.73
HR
.45
1.0
0.65
NOTE. Multivariate estimates are adjusted for age, mutation, and other treatments. Analyses restricted to 112 women with an intact contralateral breast.
Abbreviation: HR, hazard ratio.
2333
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Metcalfe et al
Fig 4. Actuarial risks of ipsilateral breast cancer in BRCA carriers
with breast-conserving surgery, with and without radiotherapy (Radio.).
Dx, diagnosis.
ceased (54%). The average age of diagnoses of both the
tested and untested women was 42.2 years. However, compared with the tested women, the untested women were
more likely to have stage II tumors (64% v 51%).
Bilateral breast cancer was not among the eligibility
criteria for genetic testing in the participating centers. However, if families with members with bilateral breast cancer
were more likely to seek and to obtain genetic testing than
families with single primary cancers only, then our study
sample would be enriched for women with bilateral cancers.
This would have the effect of spuriously raising the estimate
of the contralateral cancer risk. This is a potential bias
among all studies reported to date, but this problem will be
lessened for purely prospective studies.
There was a clear and dramatic benefit of contralateral
mastectomy in terms of cancer incidence. Future studies
will be required to determine whether this confers a benefit
in terms of mortality. We also found the risk of contralateral
cancer to be reduced when there was a history of either
oophorectomy or use of tamoxifen, in keeping with the
results of our earlier case-control study.8 The combination
of the two was particularly effective among young women
(HR, 0.09; 95% CI, 0.01 to 0.68). This degree of protection
is perhaps surprising, given that the majority of these tumors (approximately 60%) will be ER-negative (Table 2).
Unfortunately, we did not obtain data on the ER status of
the contralateral tumors and data on ER status was missing
for many of the tumors diagnosed before 1985. The observed protective effect of tamoxifen was slightly greater for
the BRCA1 carriers (HR, 0.57) than for the BRCA2 carriers
(HR, 0.73; Tables 5 and 6), but this difference was not
statistically significant.
Our findings have important implications for the primary prevention of hereditary breast cancer. It is now generally well accepted that oophorectomy protects against
breast cancer in BRCA carriers,9,10 but the role of tamoxifen
remains controversial. King et al11 found no primary protective role for tamoxifen against BRCA1-associated breast
cancer, but the study included only eight carriers with
breast cancer. In our study the observed magnitude of the
protective effect was larger for oophorectomy (59%) than
Table 7. Risks of Ipsilateral Breast Cancer Associated With Selected Factors
Univariate
Factor
HR
BRCA
BRCA1
BRCA2
Age, years
⬍ 50
⬎ 50
Oophorectomy
No
Yes
Chemotherapy
No
Yes
Radiotherapy
No
Yes
Tamoxifen
No
Yes
Multivariate
95% CI
P
0.37 to 2.83
.97
1.0
1.02
95% CI
P
0.24 to 2.52
.67
0.74 to 13.2
.67
0.07 to 1.59
.17
0.10 to 1.07
.06
0.10 to 1.25
.11
0.02 to 1.51
.11
1.0
0.77
0.65 to 6.54
.22
1.0
2.07
1.0
3.13
0.11 to 1.80
.26
1.0
0.45
1.0
0.33
0.07 to 0.73
.013
1.0
0.23
1.0
0.32
0.09 to 0.97
.045
1.0
0.29
1.0
0.35
0.02 to 1.26
1.0
0.17
HR
.084
0.11
0.17
NOTE. Multivariate estimates are adjusted for age, mutation (BRCA1 or BRCA2), and other treatments.
Abbreviation: HR, hazard ratio.
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BRCA Mutations and Contralateral Breast Cancer
for tamoxifen (38%). Potential benefits of oophorectomy in
the management of primary breast cancer include reduction in risk of contralateral breast cancer, reduction in risk
of primary breast cancer recurrence, and in prevention of
primary ovarian cancer. Ovarian ablation has been shown
to be an effective treatment for premenopausal breast cancer. In a large meta-analysis of women treated for breast
cancer younger than 50 years, 15-year survival after breast
cancer improved from 46% to 52% with ovarian ablation.12
We also observed a (nonsignificant) reduction in the risk of
ipsilateral breast cancer with oophorectomy (OR, 0.33), but
it has not yet been established whether oophorectomy impacts on total mortality in this situation. These studies are
now underway.
It has been suggested that BRCA1-associated tumors
show enhanced chemosensitivity. This may be related to
their rapid growth rate and the impaired ability of BRCAdeficient cells to repair double stranded DNA breaks.13 In
the present study, we saw a protective effect of chemotherapy on the risk of ipsilateral cancer (Table 7) but not on the
risk of contralateral cancer (Table 4). In contrast, a strong
protective effect of chemotherapy on contralateral breast
cancer risk was seen in our case-control study.8 The reason
for the observed discrepancy between the two studies is
unknown, but some of the variation may be due to chance.
It has also been speculated that radiotherapy (or mammography) may be hazardous to BRCA carriers because of
the potential for increased mutability due to impaired DNA
repair. Despite this theoretical concern, radiotherapy treatment was associated with a significant decrease in the risk of
ipsilateral cancer following breast-conserving surgery in
BRCA mutation carriers. Among patients treated for breast
cancer with breast-conserving surgery and radiotherapy,
the 10-year risk of contralateral breast cancer (27.4%)
greatly exceeded that of ipsilateral cancer (11.5%). This was
largely due to the protective effect of radiotherapy on ipsiREFERENCES
1. Ford D, Easton DF, Stratton M, et al:
Genetic heterogeneity and penetrance analysis
of the BRCA1 and BRCA2 genes in breast cancer
families. Am J Hum Genet 62:676-689, 1998
2. Verhoog LC, Brekelmans CTM, Synaeve
C, et al: Survival and tumor characteristics of
breast cancer patients with germline mutations
of BRCA1. Lancet 351:316-321, 1998
3. Robson M, Gilewki T, Haas B, et al: BRCAassociated breast cancer in young women. J Clin
Oncol 16:1642-1649, 1998
4. Pierce LJ, Strawderman M, Narod SA, et
al: Effect of radiotherapy after breast-conserving
treatment in women with breast cancer and
germline BRCA1/2 mutations. J Clin Oncol 18:
3360-3369, 2000
lateral breast cancer (HR, 0.29) but not on contralateral
breast cancer (HR, 1.02). Chappuis et al5 also reported a
higher 5-year rate of contralateral breast cancer (10%) than
of ipsilateral cancers (6%) in a study of 32 BRCA carriers. In
contrast Haffty et al7 reported similar high rates of ipsilateral (49%) and contralateral (42%) cancers in BRCA carriers at 12 years, but their study was small (22 carriers).
In the present study, the rate of contralateral breast
cancer in subjects with breast tissue at risk was similar to the
rate of ipsilateral cancer observed in the small group of
women who did not receive radiotherapy as part of their
initial breast cancer treatment (Fig 4). This suggests that
radiotherapy following breast-conserving surgery is valuable for prevention of local recurrence in BRCA carriers. We
saw no evidence of a hazardous effect of radiotherapy for
contralateral or ipsilateral breast cancers throughout the
course of this study, but it will be important to follow-up all
patients in this cohort for a longer period before the longterm effects of radiotherapy can be properly assessed.
Patients with hereditary susceptibility to breast cancer
are generally treated according to protocols established for
nonhereditary forms of cancer (ie, most premenopausal
women with ER-negative, high-grade tumors of ⬍ 2 cm in
diameter are offered breast-conserving surgery and adjuvant chemotherapy, but not ovarian ablation or tamoxifen). In this scenario, the risk of contralateral breast cancer
is approximately 4% per year, or 40% at 10 years. The risk of
contralateral cancer is almost zero for women who undergo
bilateral mastectomy, and is decreased for women who
undergo oophorectomy or are treated with tamoxifen.
■ ■ ■
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
5. Chappuis PO, Kapusta L, Begin LR, et al:
Germline BRCA1/2 mutations and p27kip protein
levels independently predict outcome after
breast cancer. J Clin Oncol 18:4045-4052, 2000
6. Verhoog LC, Brekelmans CTM, Seynaeve
C, et al: Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated
breast cancer. Br J Cancer 83:384-386, 2000
7. Haffty BG, Harrold E, Khan AJ, et al:
Outcome of conservatively managed early-onset
breast cancer by BRCA1/2 status. Lancet 359:
1471-1477, 2002
8. Narod SA, Brunet JS, Ghadirian P, et al:
Tamoxifen and the risk of contralateral breast
cancer in BRCA1 and BRCA2 mutation carriers:
A case-control study. Lancet 356:1876-1881,
2000
9. Rebbeck TR, Levin AM, Eisen A, et al:
Reduction in breast cancer risk after bilateral
prophylactic oophorectomy in BRCA1 mutation
carriers. JNCI 91:1475-1479, 1999
10. Rebbeck TR, Lynch HT, Neuhausen SL, et
al: Prophylactic oophorectomy in carriers of
BRCA1 and BRCA2 mutations. N Engl J Med
346:1616-1622, 2002
11. 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) Breast Cancer Prevention Trial.
JAMA 286:2251-2256, 2001
12. Early Breast Cancer Trialists’ Collaborative
Group: Ovarian ablation in early breast cancer:
Overview of the randomized trials. Lancet 348:
1189-1196, 1996
13. Hoeijmakers JH: Genomic maintenance
mechanisms for preventing cancer. Nature 441:
366-374, 2001
2335
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