Download A Case-Match Study Comparing Unilateral With Synchronous

VOLUME 29 䡠 NUMBER 36 䡠 DECEMBER 20 2011
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
A Case-Match Study Comparing Unilateral With
Synchronous Bilateral Breast Cancer Outcomes
Alan M. Nichol, Rinat Yerushalmi, Scott Tyldesley, Mary Lesperance, Chris D. Bajdik, Caroline Speers,
Karen A. Gelmon, and Ivo A. Olivotto
Alan M. Nichol, Rinat Yerushalmi, Scott
Tyldesley, Chris D. Bajdik, Caroline
Speers, and Karen A. Gelmon, British
Columbia Cancer Agency-Vancouver
Centre; Alan M. Nichol, Scott Tyldesley,
Chris D. Bajdik, Karen A. Gelmon, and
Ivo A. Olivotto, University of British
Columbia, Vancouver; Mary Lesperance,
University of Victoria; and Ivo A. Olivotto,
British Columbia Cancer AgencyVancouver Island Centre, Victoria, British
Columbia, Canada.
Submitted February 21, 2011; accepted
September 27, 2011; published online
ahead of print at www.jco.org on
November 21, 2011.
Supported by the British Columbia
Cancer Agency Breast Cancer
Outcomes Unit.
Presented at the 33rd San Antonio
Breast Cancer Symposium, December
8-12, 2010, San Antonio, TX.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Alan M. Nichol,
MD, FRCPC, Department of Radiation
Oncology, BC Cancer AgencyVancouver Centre, 600 West 10th Ave,
Vancouver, BC, Canada V5Z 4E6;
e-mail: [email protected].
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2936-4763/$20.00
DOI: 10.1200/JCO.2011.35.0165
A
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R
A
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Purpose
There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have
similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of
this study was to determine whether survival outcomes for patients with SBBC can be estimated
from the characteristics of their individual cancers.
Patients and Methods
Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed
in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed ⱕ
2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer–
specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined
and matched with three breast cancers from the unilateral cohort to select 621 high-risk
matches. The priority sequence of matching the prognostic and predictive variables was
positive lymph node number, primary tumor size, age, grade, lymphovascular invasion,
estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and
type of systemic therapy used.
Results
With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the
unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to
77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year
BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches.
Conclusion
BCSS was not significantly different between the SBBC cases and their high-risk matches.
J Clin Oncol 29:4763-4768. © 2011 by American Society of Clinical Oncology
INTRODUCTION
Synchronous breast cancers have been variously
defined as two breast cancers diagnosed within 1
month,1 2 months,2 3 months,3 6 months,4 or 1
year.5 They represent 0.2% to 3.2% of all newly
diagnosed breast cancers, depending on the era of
the study, which definition of the term synchronous was used, and whether invasive metastatic
or noninvasive ductal and lobular carcinomas
were included.6,7
Although synchronous breast cancers can occur in the same breast, most investigators have studied synchronous bilateral breast cancer (SBBC)
because distinguishing synchronous primary cancers from intrabreast metastases can be difficult and
because the presence of two or more ipsilateral primaries confounds the axillary staging. Older studies,
typically with small sample sizes, compared out-
comes of SBBC with unilateral breast cancer and
reported either worse8 or similar1,9 outcomes. Several studies published from 2000 to 20103,7,10-14 have
reported significantly worse outcomes for SBBC
compared with that for unilateral breast cancer
(Table 1). However, publication bias might be responsible for the similarity of recent study reports,
contributing to a perception that patients with SBBC
fare less well than patients with unilateral invasive
breast cancer.
This study was initiated to evaluate whether
the decision to offer systemic treatment to patients with synchronous breast cancers should be
directed by outcome estimates based on only the
higher-risk cancer or based on both the higherrisk and lower-risk cancers.18 If the lower-risk
cancer had no effect on outcome, treatment selection that assumed a worse prognosis for synchronous cancers might result in overtreatment.
Conversely, if the lower-risk cancer diminished
© 2011 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at INST FOR CANCER RESEARCH on September 26,
Copyright © 2011 American
Society
of Clinical Oncology. All rights reserved.
2013
from 131.249.80.201
4763
Nichol et al
Table 1. End Points and Outcomes of Studies Comparing SBBC to Unilateral Breast Cancer, Published From 2000 to 2010
Study (reference)
Patients With
SBBC/Total Patients
SBBC (%)
Diagnosis
Interval (Months)
End Point
Unilateral
Breast Cancer (%)
Bilateral
Breast Cancer (%)
P
Heron et al7
Kollias et al15
Carmichael et al11
Polednak et al13
Jobsen et al10
Levi et al9
Takahashi et al16
Verkooijen et al12
Hartman et al3
Vuoto et al14
Beckmann et al17
This study
47/1,465
26/3,210
43/1,945
300/15,542
26/1,760
81/6,084
13/1,214
155/7,912
1,893/123,757
80/3,864
52/2,425
207/21,209
3.2
0.8
2.2
1.9
1.5
1.3
1.1
2.0
2.9
2.1
2.1
1.0
12
—
3
3
3
3
6
6
3
12
3
2
8-year OS
10-year OS
10-year OS
5-year OS
10-year BCSS
10-year OS
10-year BCSS
10-year BCSS
10-year BCSS
10-year OS
5-year BCSS
10-year BCSS
86
54
57
76
84
59
72
66
67
73
94
81
79
42
20
64
41
51
64
51
55
44
88
71
.04
.13
.047
Sⴱ
.005†
.11
N/S
S†
⬍ .001‡
⬍ .001
N/S
⬍ .001
Abbreviations: BCSS, breast cancer–specific survival; N/S, not significant; OS, overall survival; S, significant; SBBC, synchronous bilateral breast cancer.
ⴱ
S including ductal carcinoma in situ; N/S including only invasive cancers.
†S including stage IV; N/S after adjustment for baseline characteristics.
‡S after adjustment for baseline characteristics.
outcome, treatment selection that considered only the higher-risk
cancer might result in undertreatment.
Three studies have compared survival outcomes of SBBC cases to
survival outcomes of unilateral controls that were matched to the
higher-risk of the synchronous cancers. Newman et al19 used age alone
to match 27 SBBC cases with 27 unilateral breast cancer cases. They
reported similar overall survival in the two cohorts. Schmid et al20
used six variables—age, time of diagnosis, tumor size, axillary node
status, histologic grade, and estrogen receptor status—to perform
one-to-three matching of 34 SBBC cases with unilateral breast cancer
controls. They reported no difference in disease-specific survival between the SBBC cases and their unilateral controls. Irvine et al18 used
eight variables—age, menopausal status, date of diagnosis, primary
tumor size, histologic type, grade, estrogen receptor status, and nodal
status— to perform one-to-two matching of 68 SBBC cases with 132
unilateral breast cancer controls. No significant difference was observed between survival outcomes for the two cohorts. The authors of
these studies concluded that the lower-risk synchronous cancers did
not exert a significant effect on the outcome of patients with SBBC.
However, these studies had small sample sizes, and their validity is
difficult to judge because neither the matching methodology nor the
pool of unilateral potential matches was described.
The hypothesis of this study was that the survival probability of a
patient with SBBC would be lower than the survival probability of a
similar patient with only the higher-risk of the two synchronous cancers. This study investigated this hypothesis for a large cohort of SBBC
cases by applying a rigorous case matching algorithm to a large pool of
unilateral potential matches.
characteristics, treatment details, and outcomes for 21,209 women referred to
the British Columbia Cancer Agency (BCCA) with a first diagnosis of in situ or
invasive breast cancer (Fig 1). Eligible patients had bilateral breast cancers
diagnosed within 60 days, with clinical or pathologic stage (T1-T4c, N0-3).
Excluded were in situ, inflammatory, and metastatic presentations. In total,
207 SBBC cases met the study entry criteria. Using the same exclusion criteria,
a contemporaneous cohort of 15,497 potential matches with unilateral breast
cancers (T1-T4c, N0-3) was also identified. The characteristics of this unilateral cohort and the SBBC cases are described in Table 2.
For each of the SBBC cases, patient characteristics, treatment used, and
tumor characteristics of each cancer were entered into Adjuvant! Online version 8.0 to estimate the 10-year BCSS outcome of each cancer as if it were
unilateral.21-23 To maximize the accuracy of the outcome estimates, lymphovascular invasion status was entered into the Adjuvant! Online Prognostic
Factor Impact Calculator by using 1.5 as the relative risk and 36% as the
percentage of patients in the high-risk group, on the basis of the findings of an
Adjuvant! Online validation study conducted by the Breast Cancer Outcomes
Unit.23 The higher-risk cancer of each SBBC case was identified by using these
unilateral 10-year BCSS estimates (Fig 1).
Matching
The study used a case-match design with one-to-three matching. The
207 higher-risk synchronous cancers of the SBBC cases were matched with
three unilateral cancers from the pool of 15,497 potential matches in the
unilateral cohort to select 621 high-risk matches. The matching procedure
used for this study was used in two previous studies.24,25 Cases were matched
All breast cancer patients referred
to BC Cancer Agency, 1989-2000
(N = 21,209)
PATIENTS AND METHODS
SBBCs were defined as two pathologic diagnoses, one in each breast, within 2
months. The 2-month interval was selected because it is used by the Surveillance, Epidemiology, and End Results Program.2 Approval was obtained from
institutional research ethics boards before commencing the study.
Patients
Patients for the study were identified from the Breast Cancer Outcomes
Unit database which, for the years 1989 to 2000, contained the pretreatment
4764
© 2011 by American Society of Clinical Oncology
Unilateral breast cancers
(T1-4c, N0-3, M0)
(15,497 potential matches)
Matches to
higher-risk cancers
(n = 621)
Synchronous bilateral cancers
(T1-4c, N0-3, M0)
(n = 207)
Fig 1. Synchronous
British Columbia.
bilateral
breast
cancer
study
schema.
BC,
JOURNAL OF CLINICAL ONCOLOGY
Synchronous Bilateral Breast Cancer
Table 2. Patient, Treatment, and Tumor Characteristics of the Potential Matches in the Unilateral Cohort, the Higher-Risk Cancers of the SBBC Cases, and Their
High-Risk Matches
Characteristic
No. of positive nodes
0
1
2
3
4-9
10⫹
Unknown/no axillary surgery
Median
Tumor size, cm
0.1-1.0
1.1-1.5
1.6-2.0
2.1-3.0
3.1-5.0
⬎ 5.0
Unknown
Median
Age, years
⬍ 50
50-59
60-69
70-79
ⱖ 80
Mean
Grade
1
2
3
Unknown
LVI status
Absent
Present
Unknown
ER status
Positive
Negative
Unknown
Local therapy
None
BCS only
BCS ⫹ RT
Mastectomy ⫾ RT
Margins
Negative
Positive
Unknown
BCCA Center
1
2
3
4
Mean year of diagnosis
Systemic therapy
None
HT only
CT only
HT and CT
P for Unilateral
Cohort v SBBC
Higher-Risk
Cancers
Unilateral Cohort
(n ⫽ 15,497)
SBBC Higher-Risk
Cancers
(n ⫽ 207)
High-Risk Matches
(n ⫽ 621)
No.
%
No.
%
No.
%
8,938
2,028
1,054
596
1,237
403
1,241
58
13
7
4
8
2
8
81
29
22
10
23
8
34
39
14
11
5
11
4
16
243
87
66
30
69
27
99
39
14
11
5
11
4
16
⬍ .001*
P for SBBC
Higher-Risk
Cancers v
Matches
1.0*
2
2
2
⬍ .001*
1.0*
3,346
3,416
2,720
3,416
1,665
909
25
22
22
18
22
11
6
⬍1
15
28
28
71
45
20
0
1.8
7
14
14
34
22
10
0
45
84
84
213
135
60
0
2.5
7
14
14
34
22
10
0
2.5
⬍ .001*
.99*
4,358
3,558
3,598
3,067
916
28
23
23
20
6
33
35
49
52
38
59
16
17
24
25
18
98
97
148
171
107
68
16
16
24
28
17
67
.86*
.81*
2,396
6,815
5,308
978
16
44
34
6
30
93
67
17
14
45
32
8
79
296
203
43
13
48
33
7
9,960
4,523
1,014
64
29
7
118
68
21
57
33
10
367
208
46
59
33
7
10,354
3,270
1,873
67
21
12
145
35
27
70
17
13
456
99
66
73
16
11
279
756
8,233
6,229
2
5
53
40
5
11
60
131
2
5
29
63
20
40
211
350
3
6
34
56
13,265
1,273
959
86
8
6
171
25
11
83
12
5
535
45
41
86
7
7
8,749
3,392
2,289
1,067
56
22
15
7
105
60
33
9
51
29
16
4
327
148
104
42
53
24
17
7
.12*
.46*
.16*
.57*
⬍ .001*
.37*
.05*
.17*
.05*
.35*
.56†
⬍ .001*
1995
5,299
5,136
2,767
2,295
1995
34
33
18
15
40
108
24
35
1995
19
52
12
17
129
314
86
92
.58†
.74*
21
51
14
15
Abbreviations: BCCA, British Columbia Cancer Agency; BCS, breast-conserving surgery; CT, chemotherapy; ER, estrogen receptor; HT, hormone therapy; LVI,
lymphovascular invasion; RT, radiotherapy; SBBC, synchronous bilateral breast cancer.
*Pearson ␹2 test of homogeneity.
†Mann-Whitney test.
www.jco.org
© 2011 by American Society of Clinical Oncology
4765
Analysis
The patient, tumor, and treatment variables were compared with ␹2 and
Mann-Whitney tests. Kaplan-Meier survival curves were compared by using
the log-rank test in SPSS Version 14.0.2 (SPSS, Chicago, IL) and R 2.8.1 (R
Development Core Team: The R project for statistical computing). All comparisons used two-sided testing and were considered statistically significant
with an alpha less than .05. Data on the cause of death for the Breast Cancer
Outcomes Unit were obtained from the British Columbia Department of Vital
Statistics. The 10-year BCSS was compared for the SBBC cases and the unilateral cohort. To address the study hypothesis, the 10-year BCSS was compared
for the SBBC cases and their high-risk matches.
RESULTS
Overall, invasive SBBC cases accounted for 1.0% (207 of 21,209) of
new breast cancers diagnosed during 1989 to 2000 in British Columbia
and referred to the BCCA. The characteristics of the higher-risk cancers of the 207 SBBC cases and the cancers of the 15,497 potential
matches in the unilateral cohort are provided in Table 2. The SBBC
cases were significantly older and their higher-risk cancers had higher
T stage and N stage than the unilateral cohort. A higher proportion of
the SBBC cases had no pathologic axillary staging (16% SBBC v 8%
unilateral; P ⬍ .001). Mastectomy was used more often for the higherrisk cancers of the SBBC cases (63%) than for the cancers of the
unilateral cohort (40%; P ⬍ .001). Surgical management for the SBBC
cases was 2% with biopsy alone, less than 1% with only unilateral
breast-conserving surgery (BCS), 7% with BCS and mastectomy, 34%
with bilateral BCS, and 57% with bilateral mastectomy.
With a median follow-up of 8.8 years for all patients and 10.2
years for living patients, the 10-year BCSS results were 71% (95% CI,
63% to 77%) for the SBBC cases and 81% (95% CI, 81% to 82%) for
the unilateral cohort (P ⬍ .001; Fig 2).
The SBBC cases and their high-risk matches exhibited no significant difference for the 11 matching variables (Table 2). The SBBC
cases had statistically similar 10-year BCSS compared with their highrisk matches. The 10-year BCSS was 71% (95% CI, 63% to 77%) for
the SBBC cases and 74% (95% CI, 69% to 77%) for the high-risk
matches (P ⫽ .5; Fig 3).
DISCUSSION
This study demonstrated significantly worse 10-year BCSS for the
SBBC cases, as compared with the unilateral cohort (Fig 2), a finding
consistent with several other studies (Table 1). However, there was no
significant difference in 10-year BCSS when the SBBC cases were
compared with their high-risk matches (Fig 3).
4766
© 2011 by American Society of Clinical Oncology
100
80
60
40
20
Unilateral
SBBC
P < .001
0
5
10
15
Time (years)
Fig 2. Unadjusted breast cancer–specific survival for synchronous bilateral
breast cancer (SBBC) cases (n ⫽ 207) and unilateral breast cancers (n ⫽ 15,497)
diagnosed in British Columbia from 1989 to 2000. Median follow-up of living
patients was 10.2 years.
The poor outcomes observed in previous SBBC cohort studies
have generated considerable speculation.26 Explanations include
metastatic disease to the contralateral breast,27 late presentation,28
aggressive tumor biology,5 impaired host factors,29 and the independent increased risk due to the second cancer.30,31 The metastatic explanation has been rendered unlikely by several genetic
studies of SBBC cases showing that these cancers rarely metastasize
to the other breast.32-35
Verkooijen et al12 reported that BCSS was significantly worse for
155 SBBC cases compared with unilateral cancers. However, after
Breast Cancer–Specific Survival (%)
sequentially on the basis of positive lymph node number (0, 1, 2, 3, 4-9, 10⫹,
unknown), primary tumor size (0.1 to 1.0, 1.1 to 1.5, 1.6 to 2.0, 2.1 to 3.0, 3.1 to
5.0, ⬎ 5.0 cm, unknown), age (⫾ 2 years), grade, lymphovascular invasion
status, estrogen receptor status, local therapy used, margin status, BCCA
treatment center, year of diagnosis (⫾ 1 year), and type of systemic therapy
used (Table 2). Matching proceeded with a computer program that first
attempted to match on all (N ⫽ 11) variables for each cancer of each SBBC
case. If N variables matched for a potential match in the unilateral cohort, it
was selected and removed from the pool. If there was no match in the unilateral
cohort for all N variables, the last variable in the list was dropped and a match
for the remaining N ⫺ 1 variables was sought. The program proceeded iteratively in this fashion to maximize the number of variables matched for each
higher-risk cancer of the SBBC cases.
Breast Cancer–Specific Survival (%)
Nichol et al
100
80
60
40
20
High-risk matches
SBBC
P = .5
0
5
10
15
Time (years)
Fig 3. Breast cancer-specific survival of the synchronous bilateral breast cancer
(SBBC) cases (n ⫽ 207) compared with the unilateral matches to their higher-risk
cancers (high-risk matches ⫽ 621).
JOURNAL OF CLINICAL ONCOLOGY
Synchronous Bilateral Breast Cancer
adjustment for age, social class, and public sector medical care, they
concluded that the difference in outcome between their cohorts was
due to persistent significant differences between the baseline variables.
Hartman et al3 determined that BCSS was also significantly worse for
355 SBBC cases compared with unilateral cancers. In contrast to
Verkooijen’s findings, in Hartman’s subset of 46 cases with complete
treatment information, the 5-year adverse BCSS difference persisted
after adjustment for age, year of diagnosis, TNM stage, adjuvant treatment, and estrogen receptor status (hazard ratio, 1.7; 95% CI, 1.2 to
2.2). This current study demonstrated significant differences in baseline variables between the SBBC cases and the unilateral cohort. The
SBBC cases were 9 years older, on average, and had more advanced
stage (Table 2), which contributed to the initial observation that patients with SBBC had worse outcomes compared with patients with
unilateral breast cancer.
In this case-match study, one-to-three matching was performed
by using 11 variables in the order of priority given in Table 2. Highquality matching was obtained by using a previously validated methodology and a large pool of 15,497 unilateral potential matches. The
success of matching was demonstrated by the statistically similar distributions of patient, tumor, and treatment characteristics between
the SBBC cases and their high-risk matches.
A limitation of this study was that the matching used only clinical
and pathologic variables available in the Breast Cancer Outcomes Unit
database. Human epidermal growth factor receptor 2 (HER2) status is
known to be an important clinical prognostic variable.36 However, it
was not available for newly diagnosed breast cancers during the years
from 1989 to 2000. Studies that use gene expression profiling have
demonstrated that BCSS outcome is greatly influenced by the intrinsic
subtype of a patient’s breast cancer and that bioinformatic data, in
addition to clinical variables, improves outcome estimates.37-39 This
study did not use gene expression profiling data because they were
unavailable. Investigation of SBBC outcomes by using gene expression
profiling may be a productive avenue for future research.
Despite being the largest case-match analysis that has addressed
this question, this study was limited by the relatively small number of
cases. The absolute difference in 10-year BCSS for the SBBC cases and
their high-risk matches was 3%. With 207 cases, the study had a large
enough sample size to detect a difference as large as 8% but insufficient
power to exclude the possibility of a real difference as small as 3%.
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One explanation for SBBC cases having survival outcome similar
to their high-risk matches would be that the synchronous cancers
shared the same germline host factors.40 Genetic studies of SBBC cases
have demonstrated that the two cancers almost always have different
clonal origins.32-35 However, if the two cancers shared sufficient biologic similarity that their tendency to metastasize and their response to
treatment were highly correlated, the lower-risk synchronous cancer
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This study concluded that the SBBC cases had worse BCSS than
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equivalent for the SBBC cases and their high-risk matches. Thus, for a
patient with SBBC, an appropriate systemic therapy selection can be
made by considering the prognosis of their higher-risk cancer.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Alan M. Nichol, Mary Lesperance, Chris D.
Bajdik, Karen A. Gelmon, Ivo A. Olivotto
Collection and assembly of data: Alan M. Nichol, Rinat Yerushalmi,
Mary Lesperance, Caroline Speers
Data analysis and interpretation: Alan M. Nichol, Rinat Yerushalmi,
Scott Tyldesley, Mary Lesperance, Chris D. Bajdik, Karen A. Gelmon, Ivo
A. Olivotto
Manuscript writing: All authors
Final approval of manuscript: All authors
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