Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and

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Published Ahead of Print on August 5, 2013 as 10.1200/JCO.2012.47.8313
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.47.8313
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Tamoxifen and Risk of Contralateral Breast Cancer for
BRCA1 and BRCA2 Mutation Carriers
Kelly-Anne Phillips, Roger L. Milne, Matti A. Rookus, Mary B. Daly, Antonis C. Antoniou, Susan Peock,
Debra Frost, Douglas F. Easton, Steve Ellis, Michael L. Friedlander, Saundra S. Buys, Nadine Andrieu,
Catherine Noguès, Dominique Stoppa-Lyonnet, Valérie Bonadona, Pascal Pujol, Sue Anne McLachlan,
Esther M. John, Maartje J. Hooning, Caroline Seynaeve, Rob A.E.M. Tollenaar, David E. Goldgar,
Mary Beth Terry, Trinidad Caldes, Prue C. Weideman, Irene L. Andrulis, Christian F. Singer, Kate Birch,
Jacques Simard, Melissa C. Southey, Håkan L. Olsson, Anna Jakubowska, Edith Olah, Anne-Marie Gerdes,
Lenka Foretova, and John L. Hopper
Author affiliations appear at the end of
this article.
Published online ahead of print at
www.jco.org on August 5, 2013.
Written on behalf of the International
BRCA1, and BRCA2 Carrier Cohort
Study, the Kathleen Cuningham Foundation Consortium for Research into
Familial Breast Cancer, and the Breast
Cancer Family Registry.
K.-A.P. and R.L.M. contributed equally
to this work.
Presented in part at the 47th Annual
Meeting of the American Society of
Clinical Oncology, June 3-7, 2011,
Chicago, IL.
The content of this article does not
necessarily reflect the views or policies
of the National Cancer Institute or any
of the collaborating centers in the
Breast Cancer Family Registry (BCFR),
nor does mention of trade names,
commercial products, or organizations
imply endorsement by the US Government or the BCFR.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Kelly-Anne
Phillips, MD, Division of Cancer Medicine, Peter MacCallum Cancer Centre,
Locked Bag 1, A’Beckett St, Victoria,
8006, Australia; e-mail: [email protected]
petermac.org.
© 2013 by American Society of Clinical
Oncology
0732-183X/13/3199-1/$20.00
DOI: 10.1200/JCO.2012.47.8313
A
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Purpose
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with
reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
Methods
Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the
International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women
were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other
invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with
tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis,
country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss
to follow-up.
Results
Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took
tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation.
The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for
BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the
cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05)
based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years
of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for
56% of cases).
Conclusion
This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for
BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased
statistical power for future prospective analyses.
J Clin Oncol 31. © 2013 by American Society of Clinical Oncology
INTRODUCTION
Women who carry a mutation in BRCA1 or BRCA2
have a high lifetime risk of breast cancer (BC).1
Bilateral mastectomy and premenopausal bilateral salpingo-oophorectomy (BSO) are associated
with a reduced BC risk of greater than 90%2,3 and
approximately 50%, respectively,4 but are not acceptable interventions for many women.5,6 Randomized, placebo-controlled primary prevention
trials of women who are at increased risk of BC
have shown that selective estrogen receptor modulators (SERMs), such as tamoxifen, reduce BC
risk by 40%.7-11The preventive effect of tamoxifen
is sustained for at least 5 years after cessation of
therapy,11 and the absolute risk of serious adverse
effects is low, particularly for premenopausal
women.9,12 For women in the general population,
randomized controlled trials have also shown that
adjuvant tamoxifen treatment after a first BC diagnosis halves the risk of contralateral breast cancer (CBC).13 However, it is uncertain whether
tamoxifen has any efficacy for women carrying
mutations in BRCA1 or BRCA2, and it is not
commonly prescribed to carriers14,15 for the purpose of BC prevention.
© 2013 by American Society of Clinical Oncology
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Copyright © 2013 American Society
of Clinical Oncology. All rights reserved.
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Copyright 2013 by American Society of Clinical Oncology
1
Phillips et al
Inadequate data regarding efficacy is a major barrier to prescribing SERMS to BRCA1 and BRCA2 mutation carriers to prevent BC.16
Randomized primary prevention trials of mutation carriers are unlikely to be feasible and would take many years to generate reliable
conclusions. Prospective observational studies of the efficacy of
SERMS for primary prevention of BC would depend on uptake of
tamoxifen by mutation carriers and would also take many years. Yet
the issue is an important one right now for the tens of thousands of
women who currently know that they carry a BRCA1 or BRCA2
mutation. Information about the efficacy or otherwise of tamoxifen
for the prevention of CBC could assist BRCA1 and BRCA2 mutation
carriers make decisions about whether to take tamoxifen for primary
BC prevention. It might also have implications for the adjuvant treatment of BRCA1 and BRCA2 mutation carriers who do not wish to
have bilateral mastectomy after an initial diagnosis of a hormone
receptor–negative BC.
The aim of this study was to determine whether adjuvant tamoxifen treatment for first BC is associated with a reduction in the risk of
CBC for BRCA1 and/or BRCA2 mutation carriers and whether the
strength of any association differs according to the estrogen receptor
(ER) status of the first BC.
METHODS
Participants
Participants were female BRCA1 or BRCA2 mutation carriers from Europe, Australia, New Zealand, the United States, and Canada, enrolled between September 1, 1993, and December 2, 2009, in three cohort studies; the
International BRCA1 and BRCA2 Carrier Cohort Study (IBCCS),17 the Kathleen Cuningham Foundation Consortium for Research into Familial Breast
Cancer (kConFab),18 and the Breast Cancer Family Registry (BCFR).19 All
cohorts include participants recruited through BC family clinics, and the
BCFR also includes some population-based recruitment. All participants provided written informed consent, and all studies were approved by the relevant
institutional review boards.
A woman was eligible for the current study if she had a pathogenic
mutation in BRCA1 or BRCA2 and a BC diagnosed since 1970 (when tamoxifen started to be prescribed for early-stage BC) that was not bilateral at the
time of diagnosis (defined as within 6 months of first BC diagnosis). Women
with a history of other invasive cancers or tamoxifen use before their first BC
were excluded.
Data Collection
Information on family cancer history, demographics, potential risk factors for BC (eg, exogenous hormone use, alcohol intake, and reproductive
history), uptake of surgical and medical prevention strategies, and cancer
treatment including use of tamoxifen and chemotherapy was self-reported at
cohort entry and at follow-up. Cancer outcomes were self-reported and/or
collected by linkage with a cancer registry. Each study in each cohort collected
this information systematically using similar questionnaires. Frequency of
follow-up varied between studies. Pathology data were abstracted from several
sources, including diagnostic pathology reports, medical records, and cancer
registry records, or through central pathology review.
Statistical Analysis
Participants were considered to have used tamoxifen if they took it for
any period of time after their first BC diagnosis. Hazard ratios (HRs) for CBC
associated with tamoxifen use (no, yes) after first BC, excluding use after CBC,
were estimated separately for BRCA1 and BRCA2 mutation carriers using Cox
regression, modeling time from first BC diagnosis to the development of CBC.
Analysis time was censored at the date of contralateral mastectomy, death, or
last follow-up.
2
© 2013 by American Society of Clinical Oncology
Two main analyses were performed. The first combined retrospective
(ie, time before cohort entry) and prospective (ie, time after cohort entry)
follow-up. For this analysis, all women were eligible, and follow-up started at
date of diagnosis of the first BC. To investigate whether the inclusion of
prevalent CBC cases may have introduced bias, a second analysis was performed that applied left truncation of analysis time at the date of cohort entry
and therefore considered outcome data from prospective follow-up only.
Age and year of diagnosis (both continuous), country of residence (categorical), and BSO (dichotomous, time-varying) were considered as covariates in
all multivariable analyses and were included in analyses of retrospective
follow-up data. Adjustment for year of diagnosis and BSO made no substantial
difference to HR estimates from the analyses of prospective data only; given the
smaller number of contralateral events, only age at diagnosis and country of
residence were included in the final prospective models. Robust estimates of
variance were derived to account for the nonindependence of women from the
same family. ER status of the first BC was considered as a covariate and as a
stratifying variable in separate multivariable analyses of the combined retrospective and prospective data. Sensitivity analyses were undertaken using the
combined and prospective-only data.
These included stratifying by menopausal status at diagnosis of the first
BC, adjusting for chemotherapy use (no, yes) and histologic subtype (lobular,
nonlobular), adjusting for use of oral contraceptives (no, yes) or hormone
replacement therapy after the first BC diagnosis (no, yes), excluding those who
took other endocrine therapy (eg, aromatase inhibitors or gonadotropinreleasing hormone agonists) after the first BC, and censoring at the date of the
first subsequent ipsilateral breast event or at diagnosis of the first nonbreast
primary cancer.
All statistical analyses were conducted using STATA 10 (STATA, College
Station, TX). Gene-specific post hoc power calculations were carried out using
StatCalc in Epi Info20 based on the number of participants the observed
prevalence of tamoxifen use, and the observed 11% of nonusers who developed contralateral disease during follow-up.
RESULTS
A total of 3,267 BRCA1 and BRCA2 mutation carriers with a personal
history of BC were identified from the three cohorts. Of these, 803
were excluded because of first BC diagnosis before 1970 (n ⫽ 107),
CBC occurring within 6 months after the first BC diagnosis (n ⫽ 115),
no follow-up after the first BC diagnosis (n ⫽ 130), other invasive
cancer before first BC diagnosis (n ⫽ 86), use of tamoxifen before their
first BC diagnosis (n ⫽ 34), and missing information on tamoxifen use
or information only available from a relative (proxy; n ⫽ 331). Thus
the final sample of 2,464 women comprised 1,583 BRCA1 and 881
BRCA2 mutation carriers, 95.7% of whom were ascertained through
BC family clinics and an estimated 96% of whom were of white
European origin. Prospective follow-up data (since date of cohort
entry) were available for 1,083 women (44%), comprising 657 BRCA1
and 426 BRCA2 mutation carriers who had been diagnosed with their
first BC a median of 3.9 years before study entry.
Participant characteristics are shown in Table 1. The median time
since diagnosis of first BC was 6.6 years, and the median time since
cohort entry was 3.2 years. ER status of the first BC was known for 44%
of women. Where ER status was known, the first BC was ER negative
for 76% of BRCA1 mutation carriers and ER positive for 77% of
BRCA2 mutation carriers. In total, 24% of BRCA1 and 52% of BRCA2
mutation carriers used tamoxifen after their first BC. Overall, 67% of
those with an ER-positive first BC used tamoxifen (60% and 71% for
BRCA1 and BRCA2 mutation carriers, respectively) compared with
17% of those with an ER-negative first BC (15% and 25%, respectively). A total of 581 BRCA1 mutation carriers (37%) and 289 BRCA2
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Copyright © 2013 American Society
of Clinical Oncology. All rights reserved.
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Tamoxifen and Risk of Contralateral BC in BRCA1/2 Carriers
Table 1. Participant Characteristics
BRCA1
Mutation
Carriers
(n ⫽ 1,583)
Characteristic
No.
%
Data available
Retrospective only
926
58
Prospective
657
42
Follow-up in years
Since first BC diagnosis
Median
6.5
Interquartile range
3.0-11.8
Since cohort enrollment
Median
3.4
Interquartile range
2.0-6.1
Cohort
IBCCS
1,063
67
kConFab
321
20
BCFR
199
13
Country of residence
Australia
286
18
Austria
65
4
Canada
47
3
France
267
17
Italy
21
1
New Zealand
21
1
Poland
50
3
Spain
41
3
The Netherlands
202
13
United States of America
181
11
United Kingdom
297
19
105
7
Otherⴱ
Year of first BC diagnosis
1970-1979
97
6
1980-1989
341
22
1990-1999
815
51
ⱖ 2000
330
21
Age at first BC diagnosis, years
⬍40
801
51
40-49
527
33
50-59
200
13
ⱖ 60
55
3
Menopausal status at first BC
diagnosis
Pre/perimenopausal
1,349
85
Postmenopausal
234
15
Estrogen receptor status of first BC
Negative
504
32
Positive
157
10
Unknown
922
58
Took tamoxifen for first BC
No
1,200
76
Yes
383
24
Yes, ER-negative first BC
76
15
Yes, ER-positive first BC
94
60
Chemotherapy administered for
first BC
No
233
15
Yes
717
45
Unknown
633
40
(continued in next column)
Table 1. Participant Characteristics (continued)
BRCA1
Mutation
Carriers
(n ⫽ 1,583)
BRCA2
Mutation
Carriers
(n ⫽ 881)
No.
455
426
%
52
48
6.6
3.0-11.2
3.1
1.6-6.0
509
242
130
58
27
15
226
18
44
143
10
8
0
48
31
117
204
32
26
2
5
16
1
1
5
4
13
23
4
35
157
442
247
4
18
50
28
311
355
159
56
35
40
18
6
691
190
78
22
100
331
450
11
38
51
427
454
25
234
48
52
25
71
148
366
367
17
42
42
Characteristic
Bilateral oophorectomy
No
Yes
BRCA2
Mutation
Carriers
(n ⫽ 881)
No.
%
No.
%
1,002
581
63
37
592
289
67
33
Abbreviations: BC, breast cancer; BCFR, Breast Cancer Family Registry; ER,
estrogen receptor; IBCCS, International BRCA1, and BRCA2 Carrier Cohort
Study; kConFab, Kathleen Cuningham Foundation Consortium for Research
into Familial Breast Cancer.
ⴱ
European countries, with the exception of eight BRCA1 mutation carriers
and one BRCA2 mutation carrier from other countries.
mutation carriers (33%) underwent BSO, either before (n ⫽ 64 and
44, respectively) or after (n ⫽ 517 and 245, respectively) their first BC.
Several tumor and patient characteristics are associated with risk
of CBC,21,22 although there are only limited data on these associations
for BRCA1 and BRCA2 mutation carriers.23-25 Table 2 compares tamoxifen users and nonusers with regard to such characteristics. Tamoxifen users tended to be older at first BC diagnosis (P ⬍ .001),
which was more likely to have been ER positive (P ⬍ .001) and of
lobular histology (P ⫽ .01). Tamoxifen users were also more likely
to have received chemotherapy (P ⫽ .001) and to have had BSO
(P ⬍ .001).
Table 2. Characteristics Potentially Associated With Contralateral BC Risk:
Tamoxifen Users Versus Nonusers
Characteristic
Mutation type
BRCA1
BRCA2
Age at first BC, years
Median
Interquartile range
Estrogen receptor status of
first BC
Negative
Positive
Unknown
Histology of first BC
Lobular
Nonlobular
Unknown
Chemotherapy administered for
first BC
No
Yes
Unknown
Bilateral oophorectomy
No
Yes
Tamoxifen
Users
Tamoxifen
Nonusers
No.
No.
%
%
Pⴱ
⬍ .001
383
454
46
54
1,200
427
74
26
⬍ .001
43
37-49
40
34-47
101
328
408
24
76
502
160
965
76
24
⬍ .001
19
532
286
3
97
16
1,039
572
2
98
.01
105
399
333
21
79
276
684
667
29
71
.001
486
351
58
42
1,108
519
68
32
⬍ .001
Abbreviation: BC, breast cancer.
ⴱ
Determined using Fisher’s exact test on known values for all characteristics
except age, for which the rank-sum test was applied.
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© 2013 by American Society of Clinical Oncology
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3
Phillips et al
Table 3. Association Between Tamoxifen Use After First BC and CBC
CBC
Variable
BRCA1 mutation carriers
Combined data
Took tamoxifen for first
No
Yes
Prospective data only
Took tamoxifen for first
No
Yes
BRCA2 mutation carriers
Combined data
Took tamoxifen for first
No
Yes
Prospective data only
Took tamoxifen for first
No
Yes
No.
Person-Years
No.
%/Person-Year
HR
95% CI
P
1,200
383
9,893
3,086
338
35
3.4
1.1
1.00
0.38ⴱ
0.27 to 0.55
⬍ .001
481
176
1,989
716
54
12
2.7
1.7
1.00
0.58†
0.29 to 1.13
.1
427
454
3,762
3,364
115
32
3.1
1.0
1.00
0.33ⴱ
0.22 to 0.50
⬍ .001
191
235
791
896
21
13
2.7
1.5
1.00
0.48†
0.22 to 1.05
.07
BC
BC
BC
BC
Abbreviations: BC, breast cancer; CBC, contralateral breast cancer; HR, hazard ratio.
ⴱ
Adjusted for age at diagnosis (continuous), year of diagnosis (continuous), bilateral prophylactic oophorectomy (time varying), and country of residence (categorical,
as per Table 1).
†Adjusted for age at diagnosis (continuous) and country (categorical: Australia, Canada, France, United States, United Kingdom, other).
CBCs occurred in 520 women (24% of BRCA1 and 17% of
BRCA2 mutation carriers), and 100 of these occurred after cohort
entry. Results from Cox regression analysis assessing an association
between tamoxifen use after first BC and risk of CBC are shown in
Table 3 and Figure 1. For BRCA1 mutation carriers, from analysis of
the combined retrospective and prospective data, the estimated HR
was 0.38 (95% CI, 0.27 to 0.55; P ⬍ .001). From analysis using only the
prospective data, the estimated HR was 0.58 (95% CI, 0.29 to 1.13;
P ⫽ .1). For BRCA2 mutation carriers, the corresponding HRs were
BRCA2
BRCA1
HR (95% CI)
All data
0.38 (0.27 to 0.55)
All data (ER-)
0.33 (0.13 to 0.79)
All data (ER+)
0.59 (0.23 to 1.52)
Prospective
data only
0.58 (0.29 to 1.13)
All data
0.33 (0.22 to 0.50)
All data (ER-)
0.44 (0.14 to 1.35)
All data (ER+)
0.30 (0.15 to 0.62)
Prospective
data only
0.48 (0.22 to 1.05)
0
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Hazard Ratio
Fig 1. Hazard ratio (HR) estimates (represented by circles) and corresponding
95% CIs (represented by horizontal lines) for risk of contralateral breast cancer
associated with tamoxifen use by women with BRCA1 mutations (BRCA1) and
BRCA2 mutations (BRCA2). Separate estimates are provided based on combined
retrospective and prospective data, overall, and by estrogen receptor (ER) status
and on prospective data only.
4
© 2013 by American Society of Clinical Oncology
0.33 (95% CI, 0.22 to 0.50; P ⬍ .001) and 0.48 (95% CI, 0.22 to 1.05;
P ⫽ .07), respectively. There were no significant differences in the
HR estimates between BRCA1 and BRCA2 mutation carriers using
the combined data (Pheterogeneity ⫽ .7) or the prospective data only
(Pheterogeneity ⫽ .9), nor were the results different between BRCA1
and BRCA2 mutation carriers based on the retrospective data only
(Pheterogeneity ⫽ .7). Analyses of combined data adjusting for, or
stratifying on, ER status of the first BC revealed that the observed
associations were not accounted for by this tumor characteristic;
there was no evidence that the HRs for tamoxifen use differed by
ER status (Pheterogeneity ⫽ .3 and .3 for BRCA1 and BRCA2 mutation
carriers, respectively), although the number of ER-positive BCs in
BRCA1 mutation carriers and ER-negative BCs in BRCA2 mutation carriers was small (Table 4). The results from all sensitivity
analyses were similar (Table 5).
For BRCA1 mutation carriers who were premenopausal at first
BC diagnosis, the association of reduced BC risk with tamoxifen was
weaker for those who underwent BSO compared with those who did
not (using combined retrospective and prospective data, HR ⫽ 0.70
[95% CI, 0.32 to 1.53] v 0.26 [95% CI, 0.16 to 0.43]; Pheterogeneity ⫽
.004). This difference was less evident when the analysis was restricted
to the prospective data (HR ⫽ 0.61 [95% CI, 0.23 to 1.65] v 0.40 [95%
CI, 0.12 to 1.32]; Pheterogeneity ⫽ .3). For BRCA2 mutation carriers from
the combined data, the corresponding HR estimates were 0.70 (95%
CI, 0.27 to 1.82) versus 0.21 (95% CI, 0.12 to 0.36; Pheterogeneity ⫽ .08),
and from prospective data only, they were 0.76 (95% CI, 0.10 to 5.64)
versus 0.33 (95% CI, 0.06 to 1.91; Pheterogeneity ⫽ .5).
DISCUSSION
In this study, use of tamoxifen after first BC was associated with
reduced risk of CBC for BRCA1 and BRCA2 mutation carriers based
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of Clinical Oncology. All rights reserved.
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Tamoxifen and Risk of Contralateral BC in BRCA1/2 Carriers
Table 4. Analysis by ER Status of First Breast Cancer (combined retrospective and prospective data)
CBC
Person-Years
Variable
BRCA1 mutation carriers
ER negative
ER positive
Adjusted for ER status
BRCA2 mutation carriers
ER negative
ER positive
Adjusted for ER status
No Tam
Tam
No Tam
Tam
No Tam
Tam
No.
%/Person-Year
No.
%/Person-Year
HR
95% CI
P
428
63
491
76
94
170
2,628
482
3,110
521
547
1,068
95
12
107
3.6
2.5
3.4
6
7
13
1.2
1.3
1.2
0.33†
0.59ⴱ
0.44‡
0.13 to 0.79
0.23 to 1.52
0.25 to 0.85
.01
.3
.01
75
97
172
25
234
259
531
558
1,090
264
1,428
1,692
14
22
36
2.6
3.9
3.3
3
14
17
1.1
1.0
1.0
0.44ⴱ
0.30†
0.33‡
0.14 to 1.35
0.15 to 0.62
0.17 to 0.64
.2
.001
.001
Abbreviations: CBC, contralateral breast cancer; ER, estrogen receptor; HR, hazard ratio; No Tam, did not take tamoxifen for first breast cancer; Tam, took tamoxifen
for first breast cancer.
ⴱ
Adjusted for age at diagnosis (continuous).
†Adjusted for age at diagnosis (continuous) and country of residence (categorical: Australia, France, the Netherlands, United Kingdom, United States, other).
‡Adjusted for age at diagnosis (continuous), year of diagnosis (continuous), bilateral prophylactic oophorectomy (time varying), and country of residence
(categorical, as in †).
on combined retrospective and prospective data. No differences in the
reduction of risk associated with tamoxifen use were found by the ER
status of the first BC. Our findings are consistent with those of other
smaller observational studies that used retrospective data26-29 and
strengthen those findings.
Only one other prospective study has examined the association
between tamoxifen use and BC risk for BRCA1 and BRCA2 mutation
carriers. In the primary prevention setting, a substudy of a doubleblind, placebo-controlled trial estimated the HRs for BC with tamoxifen use to be 1.67 (95% CI, 0.32 to 10.7) and 0.38 (95% CI, 0.06 to
1.56) for BRCA1 and BRCA2 mutation carriers, respectively15; the
wide CIs suggest that these analyses were essentially uninformative. In
the current study, when the analyses were restricted to prospective
data only, there was only weak evidence that tamoxifen use is associated with reduced risk of CBC, with statistically nonsignificant HR
estimates that were less than 1. The post hoc power for the analysis of
prospective data only was limited; for each of BRCA1 and BRCA2
mutation carriers, there was 80% power at P ⬍ .05 to detect HRs of
0.35 or less. Therefore, our statistically nonsignificant findings from
analysis of the prospective data only should not necessarily be interpreted as a lack of confirmation of the highly significant results from
the analysis of the pooled retrospective and prospective data, especially
given the consistency in the HR estimates from the two analyses.
Previous studies have suggested that tamoxifen use only reduces
the risk of ER-positive BC.7-11 The majority (75% to 80%) of BCs
arising in BRCA2 mutation carriers are ER positive,30 whereas most
BCs arising in BRCA1 mutation carriers are ER negative at the time of
diagnosis.31 Nevertheless, estrogen might be important in the pathogenesis of BCs in BRCA1 mutation carriers, particularly given the
observation that premenopausal bilateral oophorectomy is associated
with reduced BC risk for BRCA1 mutation carriers3 and that preclinical data suggest that BRCA1-associated BCs may have an estrogenresponsive occult phase.32-34 A link between estrogen and BC
development in BRCA1 mutation carriers is suggested by the finding
that two single-nucleotide polymorphisms located close to ESR1
(which encodes ER ␣) are associated with BC risk in BRCA1 mutation
carriers.35 Furthermore, ER ␤ is commonly expressed in BCs of
BRCA1 mutation carriers36,37 and could be a target for tamoxifen.38
www.jco.org
Thus there are important plausible mechanisms by which tamoxifen
might prevent BC for both BRCA1 and BRCA2 mutation carriers.39
BRCA1 and BRCA2 mutation carriers have increased risks of
both breast and high-grade serous gynecologic cancers.1 Given that
screening for the latter is ineffective,40-45 many carriers elect to undergo premenopausal BSO, which dramatically reduces their risk of
serous gynecologic cancer and is associated with about a halving of BC
risk.4 Therefore, in the primary prevention setting, an important clinical question is whether tamoxifen use might further reduce BC risk
for mutation carriers who have had premenopausal BSO. Although
we could not distinguish between pre- and postmenopausal BSO, our
findings suggest that the inverse association between tamoxifen use
and risk of CBC is stronger if ovaries are still in situ.
The strengths of the current study include the systematic data
collection and the inclusion of women with an ER-negative first BC
who received tamoxifen. The latter occurred because in many countries in the 1970s and early 1980s, adjuvant tamoxifen was prescribed
to postmenopausal women with BC irrespective of hormone receptor
status. Another strength of this study is the relatively large sample size,
although, despite this, prospective data were limited.
A major limitation of the study is the nonrandomized design,
which could have resulted in biased estimates owing to nonrandom
use of tamoxifen. Compared with nonusers, tamoxifen users were
significantly older and more likely to have had an ER-positive first BC,
to have received chemotherapy, and to have had BSO, all features
generally associated with reduced risk of CBC. However, adjustment
for age at diagnosis and ER status of the first BC in multivariate
analysis, as well as stratifying on ER status, made no substantive difference to the results. Sensitivity analyses showed little influence of
adjustment for chemotherapy or histologic subtype. Thus it is unlikely
that our finding of an association between tamoxifen use and reduced
CBC is explained solely by nonrandom use of tamoxifen.
A randomized study to address this secondary prevention question is unlikely to be feasible given that (1) a substantial proportion of
young mutation carriers undergo contralateral mastectomy after their
first BC diagnosis,46,47 and (2) it could only be conducted in women
with ER-negative BC because adjuvant endocrine therapy (with tamoxifen and/or an aromatase inhibitor) is the standard of care for
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155.98.164.38
5
Phillips et al
Table 5. Association Between Tamoxifen Use and Risk of CBC: Sensitivity Analyses
Variable
BRCA1 mutation carriers
Combined dataⴱ
Main analysis
Premenopausal women
Postmenopausal women
Chemotherapy use known
Adjusted for chemotherapy
Histology of first BC known
Adjusted for histology
Adjusted for use of OC or HRT
Excluding women who used OC or HRT
Excluding women who used other endocrine therapy
Censoring at ipsilateral events after first BC
Censoring at diagnosis of non-breast primary cancers
Prospective data only†
Main analysis
Premenopausal women
Postmenopausal women
Chemotherapy use known
Adjusted for chemotherapy
Histology of first BC known
Adjusted for histology
Adjusted for use of OC or HRT
Excluding women who used OC or HRT
Excluding women who used other endocrine therapy
Censoring at ipsilateral events after first BC
Censoring at diagnosis of non-breast primary cancers
BRCA2 mutation carriers
Combined dataⴱ
Main analysis
Premenopausal women
Postmenopausal women
Chemotherapy use known
Adjusted for chemotherapy
Histology of first BC known
Adjusted for histology
Adjusted for use of OC or HRT
Excluding women who used OC or HRT
Excluding women who used other endocrine therapy
Censoring at ipsilateral events after first BC
Censoring at diagnosis of non-breast primary cancers
Prospective data only†
Main analysis
Premenopausal women
Postmenopausal women
Chemotherapy use known
Adjusted for chemotherapy
Histology of first BC known
Adjusted for histology
Adjusted for use of OC or HRT
Excluding women who used OC or HRT
Excluding women who used other endocrine therapy
Censoring at ipsilateral events after first BC
Censoring at diagnosis of non-breast primary cancers
No.
CBC
Person-Years
HR
95% CI
1,583
1,312
234
950
950
1,047
1,047
1,583
1,419
1,574
1,572
1,580
373
329
35
194
194
244
244
373
345
372
351
364
12,979
11,045
1,699
7,306
7,306
8,076
8,076
12,979
11,536
12,940
12,499
12,495
0.38
0.35
0.51
0.41
0.41
0.33
0.33
0.38
0.35
0.38
0.38
0.35
0.27 to 0.55
0.24 to 0.53
0.20 to 1.29
0.26 to 0.67
0.25 to 0.67
0.20 to 0.53
0.20 to 0.54
0.27 to 0.55
0.24 to 0.51
0.27 to 0.55
0.26 to 0.56
0.24 to 0.51
657
550
93
385
385
297
297
657
579
649
629
609
66
59
5
39
39
37
37
66
60
65
60
62
2,705
2,295
357
1,827
1,827
1,207
1,207
2,705
2,379
2,688
2,588
2,462
0.58
0.55
—
0.61
0.60
0.43
0.45
0.57
0.56
0.58
0.58
0.49
0.29 to 1.13
0.27 to 1.13
0.26 to 1.48
0.25 to 1.47
0.17 to 1.08
0.18 to 1.14
0.29 to 1.12
0.28 to 1.11
0.29 to 1.15
0.28 to 1.18
0.23 to 1.01
881
667
190
514
514
559
559
881
803
863
869
880
147
117
26
78
78
95
95
147
136
146
138
143
7,125
5,559
1,382
4,117
4,117
4,212
4,212
7,124
6377
7,051
6,823
6,943
0.33
0.28
0.41
0.39
0.41
0.43
0.43
0.32
0.35
0.33
0.37
0.32
0.22 to 0.50
0.17 to 0.46
0.18 to 0.92
0.22 to 0.70
0.23 to 0.75
0.26 to 0.72
0.26 to 0.72
0.22 to 0.49
0.23 to 0.53
0.22 to 0.49
0.24 to 0.56
0.21 to 0.48
426
321
91
256
256
195
195
426
386
412
410
412
34
23
8
26
26
23
23
34
32
33
31
32
1,687
1,301
348
1,182
1,182
692
692
1,687
1,512
1,650
1,607
1,586
0.48
0.58
0.35
0.43
0.55
0.79
0.78
0.45
0.46
0.47
0.48
0.46
0.22 to 1.05
0.21 to 1.61
0.08 to 1.48
0.16 to 1.15
0.21 to 1.45
0.31 to 2.05
0.31 to 1.99
0.21 to 0.99
0.21 to 1.04
0.21 to 1.05
0.21 to 1.08
0.20 to 1.05
Abbreviations: BC, breast cancer; CBC, contralateral breast cancer; HR, hazard ratio; HRT, hormone replacement therapy; OC, oral contraceptive.
ⴱ
Analysis adjusted for age at diagnosis (continuous), year of diagnosis (continuous), bilateral prophylactic oophorectomy (time varying), and country of
residence (categorical).
†Analysis adjusted for age at diagnosis (continuous) and country (categorical).
6
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Tamoxifen and Risk of Contralateral BC in BRCA1/2 Carriers
ER-positive first BC. Certainly it would take many years to initiate and
complete such a trial so that results would not be available for more
than a decade.
The large proportion of participants in the current study with
missing ER data for the first BC reduced the power of the corresponding stratified analysis. Nevertheless, because ER status is associated
with both tamoxifen use and risk of CBC,22 it is convincing that the
stratified analyses gave consistent results.
The analyses of all data combined included prevalent cases of BC
and therefore could be subject to survival bias. For this reason, we
repeated the analyses using prospective data only. The results were
consistent, but the inverse associations were somewhat attenuated.
Tamoxifen has not been widely prescribed for primary prevention of BC for BRCA1 and BRCA2 mutation carriers, in part because
there has been inadequate evidence of efficacy.16 The data presented
here add to the current evidence base. Some clinicians might consider
the statistically significant inverse association between tamoxifen use
and development of CBC, seen in the combined analysis, as adequate
reason to prescribe tamoxifen for BC prevention in BRCA1 and
BRCA2 mutation carriers, despite the fact that the association was not
confirmed by the less strongly powered prospective analysis. Others
might not consider the evidence to be sufficient. Because mutations in
BRCA1 and BRCA2 are associated with early-onset BC, premenopausal women are the most relevant group in this setting. Tamoxifen
can cause hot flushes and night sweats, but for premenopausal
women, the main serious adverse effect is deep venous thrombosis; the
risk is similar to that from use of the combined oral contraceptive
pill.48,49 Endometrial cancer risk is increased for women who take
tamoxifen for treatment of BC or for BC prevention. Some small
retrospective observational studies have suggested increased endometrial cancer risk specifically for BRCA1 and BRCA2 mutation carriers
who take tamoxifen,50,51 although caution must be exercised in interpreting these findings.52 Therefore, for BRCA1 and BRCA2 mutation
carriers with breast tissue, particularly those who have not undergone
premenopausal BSO, the option of tamoxifen for BC prevention
should perhaps be discussed along with the evidence of benefits and
REFERENCES
1. 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
72:1117-1130, 2003
2. Lostumbo L, Carbine NE, Wallace J: Prophylactic mastectomy for the prevention of breast
cancer. Cochrane Database Syst Rev CD002748,
2010
3. 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 304:967-975, 2010
4. Rebbeck TR, Kauff ND, Domchek SM: Metaanalysis of risk reduction estimates associated with
risk-reducing salpingo-oophorectomy in BRCA1 or
BRCA2 mutation carriers. J Natl Cancer Inst 101:8087, 2009
5. Phillips KA, Jenkins MA, Lindeman GJ, et al:
Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriwww.jco.org
potential adverse effects, allowing women themselves to decide
whether they wish to use the medication.
This study provides observational evidence that, for BRCA1 and
BRCA2 mutation carriers, tamoxifen use for first BC might reduce the
risk of CBC. Further follow-up of these cohorts will provide increased
statistical power for prospective analyses and thus a more definitive
answer to this important question in the future.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Kelly-Anne Phillips, Roger L. Milne, Douglas F.
Easton, Michael L. Friedlander, Nadine Andrieu, John L. Hopper
Financial support: Kelly-Anne Phillips, Melissa C. Southey, John
L. Hopper
Administrative support: Prue C. Weideman, Kate Birch
Provision of study materials or patients: Kelly-Anne Phillips, Matti A.
Rookus, Mary B. Daly, Antonis C. Antoniou, Michael L. Friedlander,
Saundra S. Buys, Sue Anne McLachlan, Esther M. John, Maartje J.
Hooning, Rob A.E.M. Tollenaar, Trinidad Caldes, Irene L. Andrulis,
Melissa C. Southey, Håkan L. Olsson, Edith Olah, John L. Hopper
Collection and assembly of data: Kelly-Anne Phillips, Matti A. Rookus,
Mary B. Daly, Antonis C. Antoniou, Susan Peock, Debra Frost, Douglas
F. Easton, Steve Ellis, Michael L. Friedlander, Saundra S. Buys, Catherine
Noguès, Dominique Stoppa-Lyonnet, Valérie Bonadona, Sue Anne
McLachlan, Esther M. John, Maartje J. Hooning, Caroline Seynaeve, Rob
A.E.M. Tollenaar, David E. Goldgar, Mary Beth Terry, Trinidad Caldes,
Prue C. Weideman, Irene L. Andrulis, Christian F. Singer, Kate Birch,
Jacques Simard, Melissa C. Southey, Håkan L. Olsson, Anna Jakubowska,
Edith Olah, Anne-Marie Gerdes, Lenka Foretova, John L. Hopper
Data analysis and interpretation: Kelly-Anne Phillips, Roger L. Milne,
Matti A. Rookus, Antonis C. Antoniou, Douglas F. Easton, Michael L.
Friedlander, Pascal Pujol, Sue Anne McLachlan, Maartje J. Hooning,
John L. Hopper
Manuscript writing: All authors
Final approval of manuscript: All authors
ers: A prospective cohort study. Clin Genet 70:
198-206, 2006
6. Metcalfe KA, Birenbaum-Carmeli D, Lubinski
J, et al: International variation in rates of uptake of
preventive options in BRCA1 and BRCA2 mutation
carriers. Int J Cancer 122:2017-2022, 2008
7. Powles TJ, Ashley S, Tidy A, et al: Twentyyear follow-up of the Royal Marsden randomized,
double-blinded tamoxifen breast cancer prevention
trial. J Natl Cancer Inst 99:283-290, 2007
8. Fisher B, Costantino JP, Wickerham DL, et al:
Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast
and Bowel Project P-1 study. J Natl Cancer Inst
97:1652-1662, 2005
9. Veronesi U, Maisonneuve P, Rotmensz N, et
al: Tamoxifen for the prevention of breast cancer:
Late results of the Italian Randomized Tamoxifen
Prevention Trial among women with hysterectomy.
J Natl Cancer Inst 99:727-737, 2007
10. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296-300, 2003
11. Cuzick J, Forbes JF, Sestak I, et al: Long-term
results of tamoxifen prophylaxis for breast cancer:
96-month follow-up of the randomized IBIS-I trial.
J Natl Cancer Inst 99:272-282, 2007
12. Nelson HD, Fu R, Griffin JC, et al: Systematic
review: Comparative effectiveness of medications
to reduce risk for primary breast cancer. Ann Intern
Med 151:703-715, W-226-235, 2009
13. Rutqvist LE, Cedermark B, Glas U, et al:
Contralateral primary tumors in breast cancer
patients in a randomized trial of adjuvant tamoxifen therapy. J Natl Cancer Inst 83:1299-1306,
1991
14. Visvanathan K, Chlebowski RT, Hurley P, et al:
American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic
interventions including tamoxifen, raloxifene, and
aromatase inhibition for breast cancer risk reduction.
J Clin Oncol 27:3235-3258, 2009
15. 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
286:2251-2256, 2001
16. Keogh LA, Hopper JL, Rosenthal D, et al: Australian clinicians and chemoprevention for women at
© 2013 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY UTAH on September 4, 2014 from
Copyright © 2013 American Society
of Clinical Oncology. All rights reserved.
155.98.164.38
7
Phillips et al
high familial risk for breast cancer. Hered Cancer Clin
Pract 7:9, 2009
17. Goldgar D, Bonnardel C, Renard H, et al: The
International BRCA1/2 Carrier Cohort Study: Purpose, rationale, and study design. http://breast-cancerresearch.com/content/2/6/E010
18. Mann GJ, Thorne H, Balleine RL, et al: Analysis of cancer risk and BRCA1 and BRCA2 mutation
prevalence in the kConFab familial breast cancer
resource. Breast Cancer Res 8:R12, 2006
19. John EM, Hopper JL, Beck JC, et al: The
Breast Cancer Family Registry: An infrastructure
for cooperative multinational, interdisciplinary and
translational studies of the genetic epidemiology
of breast cancer. Breast Cancer Res 6:R375-R389,
2004
20. Dean AG, Sullivan KM, Soe MM: OpenEpi:
Open Source Epidemiologic Statistics for Public
Health, Version 3.01, updated April 6, 2013.
www.OpenEpi.com
21. Chen Y, Thompson W, Semenciw R, et al:
Epidemiology of contralateral breast cancer. Cancer
Epidemiol Biomarkers Prev 8:855-861, 1999
22. Kurian AW, McClure LA, John EM, et al:
Second primary breast cancer occurrence according
to hormone receptor status. J Natl Cancer Inst
101:1058-1065, 2009
23. Malone KE, Begg CB, Haile RW, et al:
Population-based study of the risk of second primary
contralateral breast cancer associated with carrying
a mutation in BRCA1 or BRCA2. J Clin Oncol 28:
2404-2410, 2010
24. Metcalfe K, Gershman S, Lynch HT, et al:
Predictors of contralateral breast cancer in BRCA1
and BRCA2 mutation carriers. Br J Cancer 104:13841392, 2011
25. Graeser MK, Engel C, Rhiem K, et al: Contralateral breast cancer risk in BRCA1 and BRCA2
mutation carriers. J Clin Oncol 27:5887-5892, 2009
26. Gronwald J, Tung N, Foulkes WD, et al:
Tamoxifen and contralateral breast cancer in BRCA1
and BRCA2 carriers: An update. Int J Cancer 118:
2281-2284, 2006
27. Reding KW, Bernstein JL, Langholz BM, et al:
Adjuvant systemic therapy for breast cancer in
BRCA1/BRCA2 mutation carriers in a populationbased study of risk of contralateral breast cancer.
Breast Cancer Res Treat 123:491-498, 2010
28. Pierce LJ, Levin AM, Rebbeck TR, et al:
Ten-year multi-institutional results of breastconserving surgery and radiotherapy in BRCA1/2associated stage I/II breast cancer. J Clin Oncol
24:2437-2443, 2006
29. Metcalfe K, Lynch HT, Ghadirian P, et al:
Contralateral breast cancer in BRCA1 and BRCA2
mutation carriers. J Clin Oncol 22:2328-2335, 2004
30. Mavaddat N, Barrowdale D, Andrulis IL, et al:
Pathology of breast and ovarian cancers among
BRCA1 and BRCA2 mutation carriers: Results from
the Consortium of Investigators of Modifiers of
BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers
Prev 21:134-147, 2012
31. Phillips KA: Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol 18:107S-12S,
2000
32. Asselin-Labat ML, Vaillant F, Sheridan JM, et
al: Control of mammary stem cell function by steroid
hormone signalling. Nature 465:798-802, 2010
33. Li W, Xiao C, Vonderhaar BK, et al: A role of
estrogen/ERalpha signaling in BRCA1-associated
tissue-specific tumor formation. Oncogene 26:72047212, 2007
34. Jones LP, Tilli MT, Assefnia S, et al: Activation
of estrogen signaling pathways collaborates with
loss of Brca1 to promote development of ERalphanegative and ERalpha-positive mammary preneoplasia and cancer. Oncogene 27:794-802, 2008
35. Antoniou AC, Kartsonaki C, Sinilnikova OM, et
al: Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2
mutation carriers. Hum Mol Genet 20:3304-3321,
2011
36. Daidone MG, Veneroni S, Cappelletti V, et al:
Estrogen receptor-beta expression in hereditary
breast cancer. J Clin Oncol 20:3752-3753, 2002;
author reply 3753
37. Litwiniuk MM, Roznowski K, Filas V, et al:
Expression of estrogen receptor beta in the breast
carcinoma of BRCA1 mutation carriers. BMC Cancer
8:100, 2008
38. Murphy LC, Watson PH: Is oestrogen
receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer? Endocr Relat
Cancer 13:327-334, 2006
39. Noruzinia M, Coupier I, Pujol P: Is BRCA1/
BRCA2-related breast carcinogenesis estrogen dependent? Cancer 104:1567-1574, 2005
40. Meeuwissen PA, Seynaeve C, Brekelmans
CT, et al: Outcome of surveillance and prophylactic
salpingo-oophorectomy in asymptomatic women at
high risk for ovarian cancer. Gynecol Oncol 97:476482, 2005
41. Oei AL, Massuger LF, Bulten J, et al: Surveillance of women at high risk for hereditary ovarian
cancer is inefficient. Br J Cancer 94:814-819, 2006
42. Woodward ER, Sleightholme HV, Considine
AM, et al: Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both highrisk and population risk women is ineffective. BJOG
114:1500-1509, 2007
43. Stirling D, Evans DG, Pichert G, et al: Screening for familial ovarian cancer: Failure of current
protocols to detect ovarian cancer at an early stage
according to the International Federation of Gynecology and Obstetrics system. J Clin Oncol 23:55885596, 2005
44. van der Velde NM, Mourits MJ, Arts HJ, et al:
Time to stop ovarian cancer screening in BRCA1/2
mutation carriers? Int J Cancer 124:919-923, 2009
45. Cancer Australia: Surveillance of women at
high or potentially high risk of ovarian cancer, 12/
2009.
http://canceraustralia.gov.au/about-us/positionstatements/surveillance-women-high-or-potentiallyhigh-risk
46. Metcalfe KA, Lubinski J, Ghadirian P, et al:
Predictors of contralateral prophylactic mastectomy
in women with a BRCA1 or BRCA2 mutation: The
Hereditary Breast Cancer Clinical Study Group.
J Clin Oncol 26:1093-1097, 2008
47. Kiely BE, Jenkins MA, McKinley JM, et al:
Contralateral risk-reducing mastectomy in BRCA1
and BRCA2 mutation carriers and other high-risk
women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
(kConFab). Breast Cancer Res Treat 120:715-723,
2010
48. Nelson HD, Huffman LH, Fu R, et al: Genetic
risk assessment and BRCA mutation testing for
breast and ovarian cancer susceptibility: Systematic evidence review for the US Preventive Services Task Force. Ann Intern Med 143:362-379,
2005
49. Harvey SL, Francis JE, McBride AJ, et al:
Medication to prevent breast cancer: Too much to
swallow? Med J Aust 195:646-649, 2011
50. Beiner ME, Finch A, Rosen B, et al: The risk of
endometrial cancer in women with BRCA1 and
BRCA2 mutations: A prospective study. Gynecol
Oncol 104:7-10, 2007
51. Duffy DL, Antill YC, Stewart CJ, et al: Report
of endometrial cancer in Australian BRCA1 and
BRCA2 mutation-positive families. Twin Res Hum
Genet 14:111-118, 2011
52. Lu KH, Kauff ND: Does a BRCA mutation plus
tamoxifen equal hysterectomy? Gynecol Oncol 104:
3-4, 2007
Affiliations
Kelly-Anne Phillips, Sue Anne McLachlan, Prue C. Weideman, and Kate Birch, Peter MacCallum Cancer Centre; Kelly-Anne Phillips, Roger
L. Milne, Sue Anne McLachlan, Melissa C. Southey, and John L. Hopper, University of Melbourne; Sue Anne McLachlan, St Vincent’s Hospital,
Melbourne, Victoria; Michael L. Friedlander, Prince of Wales Hospital, Randwick, New South Wales, Australia; Roger L. Milne, Spanish National
Cancer Research Centre; Trinidad Caldes, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain; Matti A.
Rookus, Netherlands Cancer Institute, Amsterdam; Maartje Hooning and Caroline Seynaeve, Erasmus University Medical Center–Daniel den
Hoed Cancer Center, Rotterdam; Rob A.E.M. Tollenaar, Leiden University Medical Centre, Leiden, the Netherlands; Mary B. Daly, Fox Chase
Cancer Center, Philadelphia, PA; Antonis C. Antoniou, Susan Peock, Debra Frost, Douglas F. Easton, Steve Ellis, University of Cambridge,
Cambridge, United Kingdom; Saundra S. Buys and David Goldgar, Huntsman Cancer Institute at the University of Utah, UT; Nadine Andrieu
and Dominique Stoppa-Lyonnet, Institut Curie; Nadine Andrieu, L’Institut National de la Santé et de la Recherche Médicale, U900; Dominique
Stoppa-Lyonnet, L’Institut National de la Santé et de la Recherche Médicale, U830; Dominique Stoppa-Lyonnet, Université Paris-Descartes,
Paris; Nadine Andrieu, Mines ParisTech, Fontainebleau; Catherine Noguès, Institut Curie, Hôpital René Huguenin, St Cloud; Valérie Bonadona,
Université Lyon 1; Valérie Bonadona, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5558; Valérie Bonadona, Centre
Léon Bérard, Lyon; Pascal Pujol, Centre Hospitalier Universitaire Arnaud de Villeneuve; Pascal Pujol, L’Institut National de la Santé et de la
Recherche Médicale 896, Centre de Recherche en Cancérologie de Marseille Val d’Aurelle, Montpellier, France; Esther M. John, Cancer
8
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY UTAH on September 4, 2014 from
Copyright © 2013 American Society
of Clinical Oncology. All rights reserved.
155.98.164.38
Tamoxifen and Risk of Contralateral BC in BRCA1/2 Carriers
Prevention Institute of California, Fremont; Esther M. John, Stanford University School of Medicine, Stanford, CA; Mary Beth Terry, Columbia
University, New York, NY; Irene L. Andrulis, University of Toronto, Toronto, Ontario; Jacques Simard, Centre Hospitalier Universitaire de
Québec and Laval University, Quebec City, Quebec, Canada; Christian F. Singer, Medical University of Vienna, Vienna, Austria; Håkan Olsson,
Lund University, Lund, Sweden; Anna Jakubowska, Pomeranian Medical University, Szczecin, Poland; Edith Olah, National Institute of
Oncology, Budapest, Hungary; Anne-Marie Gerdes, Rigshospitalet and Copenhagen University, Copenhagen, Denmark; and Lenka Foretova,
Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Support
Supported by the (Australian) National Breast Cancer Foundation and Cancer Australia Grant No. 628333. International BRCA1 and
BRCA2 Carrier Cohort Study (IBCCS) –Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers, UK (EMBRACE) is supported by
Cancer Research UK Grants No. C1287/A10118 and C1287/A11990. IBCCS–Gene Etude Prospective Sein Ovaire, France (GENEPSO) is
supported by the Fondation de France and the Ligue Nationale Contre le Cancer. IBCCS–Hereditary Breast and Ovarian Cancer Research Group
Netherlands (HEBON) is supported by Dutch Cancer Society Grants No. NKI1998 1854, NKI2004-3088, NKI2007-3756 and the Netherlands
Organization for Scientific Research Grant No. NWO/91109024. IBCCS–Interdisciplinary Health Research Internal Team Breast Cancer
Susceptibility Study (INHERIT) was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs research program (Grant
No. CRT 43822) and Canadian Institute Health Research (CIHR) Team in Familial Risks of Breast Cancer program (Grant No. CRN 87521), the
Canadian Breast Cancer Research Alliance (Grant No. 019511), and the Ministry of Economic Development, Innovation and Export Trade
(Grant No. PSR-SIIRI 701). IBCCS–National Institute of Oncology (NIO) Hungary was funded by European Against Cancer (subcontract
between International Agency for Research on Cancer Lyon and NIO Budapest). This study at NIO, Budapest, Hungary, was supported in part
by Norwegian European Economic Area (EEA) Financial Mechanism (Grant No. HU0115/NA/2008-3/ÖP-9). IBCCS-Brno, Masaryk Memorial
Cancer Institute (MMCI), Czech Republic was supported by IBCCS and by the European Regional Development Fund and the State Budget of
the Czech Republic (Regional Center for Applied Molecular Oncology [RECAMO], Grant No. CZ.1.05/2.1.00/03.0101). IBCCS–Molecular
Oncology Laboratory, Madrid (MOL) was supported by Grant No. RD06/0020/0021 from Red Tematica Investigacion Cooperative en Cancer
(RTICC; ISCIII), Spanish Ministry of Economy and Competitivity. The Kathleen Cuningham Foundation Consortium for Research into
Familial Breast Cancer (kConFab) and the kConFab Follow-Up Study are supported by grants from the National Breast Cancer Foundation, the
National Health and Medical Research Council, and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria,
Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The Breast Cancer Family Registry (BCFR) was supported by
the National Cancer Institute, National Institutes of Health under Grant No. UMI CA164920 and through cooperative agreements with members
of the BCFR and principal investigators, including Cancer Care Ontario (Grant No. U01 CA69467), Cancer Prevention Institute of California
(Grant No. U01 CA69417), Columbia University (Grant No. U01 CA69398), Fox Chase Cancer Center (Grant No. U01 CA69631), Huntsman
Cancer Institute (Grant No. U01 CA69446), the University of Melbourne (Grant No. U01 CA69638), and Georgetown University Medical
Center Informatics Support Center (Grant No. HHSN261200900010C).
■ ■ ■
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9
Phillips et al
Acknowledgment
We thank all the participants in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this
work to be carried out. In particular, the International BRCA1 and BRCA2 Carrier Cohort Study (IBCCS) acknowledges Marie-José Blom for her
solid work as the central data manager of this collaborative study; IBCCS–Interdisciplinary Health Research Internal Team Breast Cancer
Susceptibility Study (INHERIT) acknowledges Martine Dumont for managing epidemiologic and pathologic data collected by Cancer Genomics
Laboratory research nurses, Quebec City, Canada; IBCCS-Brno, Masaryk Memorial Cancer Institute (MMCI), Czech Republic, acknowledges
Dita Hanouskova, Jitka Berkovcova, and other staff members for their consulting work with families, data collection, and data entry; IBCCS
Poland acknowledges all members and collaborators of the International Hereditary Cancer Centre, Szczecin, Poland; IBCCS–National Institute
of Oncology (NIO), Hungary, acknowledges Miklos Kasler for his support of the study and Marie Balogh Kovacs for her help in submission of
IBCCS questionnaires; T.C. acknowledges Pedro Perez Seguar, MD, for his clinical work; the Kathleen Cuningham Foundation Consortium for
Research into Familial Breast Cancer (kConFab) acknowledges Lucy Stanhope, Heather Thorne, Eveline Niedermayr, the kConFab research
nurses and staff, the heads and staff of the Family Cancer Clinics, and the families for their contributions to the resource.
Appendix
K.-A.P. is a National Breast Cancer Foundation Practitioner Fellow; A.C.A. is a Cancer Research–United Kingdom Senior Cancer
Research Fellow (C12292/A11174); D.F.E. is a Cancer Research–United Kingdom Principal Research Fellow; I.L.A. is the Anne and Max
Tanenbaum Chair in Molecular Medicine at Mount Sinai Hospital; J.S. is Chairholder of the Canada Research Chair in Oncogenetics;
J.L.H. is an Australia Fellow; M.C.S. is a Senior Research Fellow of the National Health and Medical Research Council of Australia; M.C.S.
and J.L.H. are Group Leaders of the Victorian Breast Cancer Research Consortium.
Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers, UK (EMBRACE) Collaborating Centers are as follows: Coordinating
Centre, Cambridge: Susan Peock, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte. North of Scotland Regional Genetics Service,
Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West
Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics
Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Marc Tischkowitz, Joan Paterson,
Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital,
Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics
Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne
Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday,
Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East
Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional
Genetics Service, Harrow: Angela Brady, Huw Dorkins, Athalie Melville, Kashmir Randhawa. Leicestershire Clinical Genetics Service,
Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical
Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona
Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin.
Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle:
Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday,
Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind A. Eeles, Susan
Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins,
Elena Castro, Emma Killick, Sue Martin, Gillian Rea, Anjana Kulkarni. North Trent Clinical Genetics Service, Sheffield: Jackie Cook,
Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice,
Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard, Anna Lehmann. Wessex Clinical Genetics Service, Princess Anne
Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. D. Gareth Evans and Fiona
Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer
Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The
Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by
Cancer Research United Kingdom (Grant C5047/A8385).
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers:
Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K.
Schmidt, J.L. de Lange; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve,
C.H.M. van Deurzen; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van
Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL:
M.G.E.M. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center,
Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok;
University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock. The Netherlands Foundation
for the detection of hereditary tumors, Leiden, NL: H.F. Vasen.
10
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JOURNAL OF CLINICAL ONCOLOGY
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Copyright © 2013 American Society
of Clinical Oncology. All rights reserved.
155.98.164.38
Tamoxifen and Risk of Contralateral BC in BRCA1/2 Carriers
Gene Etude Prospective Sein Ovaire, France (GENEPSO) Collaborating Centers are as follows: Coordinating Center, Hôpital René
Huguenin/Institut Curie,Saint Cloud: Catherine Noguès, Emmanuelle Fourme, Rosette Lidereau; Etienne Rouleau, Sandrine Caputo,
Shirley Wakselman, Collaborating Centers: Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Bruno Buecher,
Institut Gustave Roussy, Villejuif :Olivier Caron; Hôpital René Huguenin/Institut Curie, Saint Cloud: Catherine Noguès, Liliane
Demange; Centre Paul Strauss, Strasbourg: Jean-Pierre Fricker; Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona; Centre
François Baclesse, Caen: Pascaline Berthet; Hôpital d’Enfants CHU Dijon – Centre Georges François Leclerc, Dijon: Laurence Faivre;
Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Centre Antoine Lacassagne, Nice: Marc Frénay; Institut Claudius
Regaud, Toulouse: Laurence Gladieff; Réseau Oncogénétique Poitou Charente, Niort: Paul Gesta; Institut Paoli-Calmettes, Marseille:
Hagay Sobol, François Eisinger, Laetitia Huiart; Institut Bergonié, Bordeaux: Michel Longy, Centre Eugène Marquis, Rennes: Catherine
Dugast; GH Pitié Salpétrière, Paris: Chrystelle Colas, Florent Soubrier; CHU Arnaud de Villeneuve, Montpellier: Isabelle Coupier, Pascal
Pujol; Centres Paul Papin, and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Oscar Lambret, Lille: Philippe Vennin,
Claude Adenis; Institut Jean Godinot, Reims: Tan Dat Nguyen; Centre René Gauducheau, Nantes: Capucine Delnatte; Centre Henri
Becquerel, Rouen: Annick Rossi, Julie Tinat, Isabelle Tennevet; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Christine Maugard;
Hôpital Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon; Polyclinique Courlancy, Reims: Liliane Demange; Clinique Sainte
Catherine, Avignon: Hélène Dreyfus; Hôpital Saint-Louis, Paris: Odile Cohen-Haguenauer; CHRU Dupuytren, Limoges: Brigitte Gilbert;
Couple-Enfant-CHU de Grenoble: Dominique Leroux; Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; Inserm U900, Ecole
des Mines de Paris, ParisTech, Service de Biostatistiques, Institut Curie, Paris: Nadine Andrieu; Inserm U535, Villejuif: Catherine Bonaïti;
Inserm U379, Marseille: Claire Julian-Reynier; Inserm.
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