Full text of DOI:10.1007/BF03215857

World J. Surg. 25, 1117–1124, 2001
DOI: 10.1007/s00268-001-0091-7
WOR LD
Journal of
SURGERY
©
2001 by the Soci e´ t e´
Internationale de Chirurgie
Prognostic Significance of Synchronous and Metachronous Bilateral Breast
Cancer
1
2
2
James Kollias, M.B., B.S., Ian O. Ellis, M.B., B.S., Christopher W. Elston, M.B., Ch.B.,
Roger W. Blamey, M.B., B.S., M.D.1
1
Professorial Unit of Surgery, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
Department of Histopathology, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
2
Abstract. Women previously treated for primary operable breast cancer Patients and Methods
are at increased risk of developing cancer in the contralateral breast, but
the clinical significance of this development is unclear. The purpose of
this study was to assess the impact of synchronous bilateral breast cancer
Patients
or the development of a metachronous contralateral breast primary on
The study comprised a consecutive series of 3210 women age Յ 70
years (range 24–70 years; median 54 years) who underwent treat-
the prognosis. In a series of 3210 women age < 70 years treated between
975 and 1995 for primary operable breast cancer, 106 were identified to
1
have bilateral breast cancer. Of these women, 26 were noted to have ment for primary operable invasive breast cancer with a histologic
synchronous bilateral breast primaries (0.8%), and 80 developed a con-
tralateral breast cancer after treatment for an initial primary breast
the Nottingham City Hospital between 1975 and 1995. Twenty-six
cancer. Using life-tables analysis, there was a significant difference in
tumor diameter of Յ 5 cm or ductal carcinoma in situ (DCIS) at
women (0.8%) were identified to have synchronous CBC (defined
survival between women with unilateral breast cancer, those with syn-
chronous bilateral breast cancers, and those with metachronous con- as a histologically confirmed contralateral breast cancer diagnosed
tralateral breast with survivals at 16 years of 53.8%, 42.4%, and 60.1%, clinically or mammographically and treated simultaneously with
respectively (p < 0.0001), from the date of the diagnosis of the first
the ipsilateral breast primary). The median age at diagnosis for
primary tumor. There was no difference in survival seen between the three
those with synchronous bilateral breast cancer was 60 years (range
groups when survival was calculated from the date of diagnosis of the
3
7–70 years).
second primary in cases of metachronous contralateral breast cancer
p ؍ 0.31). When contralateral breast cancer was incorporated as a
(
time-dependent covariate in a Cox multivariate model together with the
three factors used to determine the Nottingham Prognostic Index (inva-
sive tumor size, grade, and lymph node stage), contralateral breast cancer
continued to be a significant prognostic determinant (p ؍ 0.02). The
Surgical Treatment of the Breast Primary
Complete tumor excision was achieved by mastectomy or subcu-
survival of women with synchronous bilateral breast cancer or metachro- taneous mastectomy in 2155 patients (67.1%) and by breast-
nous breast cancers diagnosed within 2 years of the original primary was conserving surgery in 1055 (32.9%). The radiotherapy schedule
worse than those with unilateral disease. However, the time duration to
consisted of 45 Gy in fractionated doses and a 15 Gy boost to the
tumor bed using a 4- or 6-mV linear accelerator over 6 weeks.
metachronous contralateral breast cancer did not have prognostic signif-
icance in a multivariate model compared with the prognostic features of
Sixty-three patients treated for DCIS by breast-conserving surgery
did not receive radiotherapy. In total, 985 patients underwent
radiotherapy to the intact breast after breast-conserving surgery
or to the chest wall after mastectomy. The lymph node sampling
technique consisted of triple node biopsy for all patients under-
going mastectomy before 1989 and has been previously described
the original primary.
The breast is a paired organ, so hormonal, environmental, and
genetic influences are likely to affect both breasts over time. There-
fore bilateral breast cancer is not uncommon. It has been estimated
that 5% to 10% of women treated for breast cancer subsequently
develop a cancer in the contralateral breast [1–5]. Although a large
number of predictive and prognostic factors have been identified for
invasive breast cancer, the clinical significance of the development of
a contralateral breast cancer (CBC) is unclear. The aim of this study
was to determine the prognostic significance of bilateral breast can-
cer diagnosed as a synchronous or metachronous event.
[6]. From 1989, patients underwent sampling of four or more
lower axillary nodes together with internal mammary node sam-
pling for tumors located in the medial quadrant only.
Histopathology and the Nottingham Prognostic Index
The method of tumor fixation, measurement of histologic invasive
tumor size, and descriptions of histologic invasive tumor grade (I,
II, III) and tumor type have been previously reported [7, 8]. The
clinical and histologic characteristics of the original primary breast
cancer for cases of unilateral, synchronous (where the tumor
Correspondence to: J. Kollias, M.B., B.S., Breast-Endocrine Surgical
Oncology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South
Australia 5000, e-mail: jkollias@mail.rah.sa.gov.au

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World J. Surg. Vol. 25, No. 9, September 2001
Table 1. Univariate analysis of clinical and histologic variables assessed for synchronous bilateral breast cancer, metachronous contralateral breast
cancer, and unilateral breast cancer.
Synchronous
bilateral
Metachronous
bilateral
Clinical and histologic variables
Unilateral
␹2
5.2
P
Age (years)
b
b
b
Ͻ 50
1084 (35)
2020 (65)
6 (23)
20 (67)
36 (45)
44 (55)
0.07
0.85
0.5
5
0–70
Radiotherapy
Yes
No
984 (32)
2120 (68)
8 (31)
18 (69)
23 (29)
57 (71)
0.3
1.4
Chemotherapy
Yes
No
206 (7)
2897 (93)
1 (4)
25 (96)
3 (4)
77 (996)
Hormone therapy
Yes
No
DCIS only
Yes
No
394 (13)
2710 (87)
9 (35)
17 (65)
4 (5)
76 (95)
15.5
1.3
Ͻ0.0001
0.54
235 (8)
2869 (92)
1 (4)
25 (96)
4 (5)
76 (95)
Invasive tumor size
Ͻ 2 cm
1312 (46)
1537 (54)
7 (28)
32 (42)
44 (58)
3.7
0.16
2
–5 cm
18 (72)
a
Invasive tumor type
Ductal
2131 (74)
386 (13)
352 (13)
19 (76)
4 (16)
2 (8)
50 (66)
19 (25)
7 (9)
8.9
0.06
Lobular
Special type
a
Lymph node status
Negative
1814 (64)
1023 (36)
12 (50)
12 (50)
55 (74)
19 (26)
5.5
8.5
0.06
0.01
Positive
Invasive tumor grade
I/II
III
1564 (55)
1296 (45)
12 (46)
14 (54)
54 (71)
22 (29)
DCIS: ductal carcinoma in situ.
a
Special type includes tubular, cribriform, and papillary subtypes.
Numbers in parentheses are percents.
b
characteristics relate to the side with worse prognostic features), Follow-up
and metachronous bilateral breast cancer are summarized in Ta-
ble 1. The numerical differences in patient numbers are explained The remaining 3185 women were followed up in a Primary Breast
by differing numbers of patients having unknown values for some Cancer Clinic at regular intervals indefinitely. Those developing a
of the variables assessed.
locoregional recurrence continued to be followed in the Primary
The previous Nottingham-Tenovus studies on all patients who Breast Clinic, and those developing distant metastases were man-
underwent locoregional treatment alone for primary operable aged in an Advanced Breast Cancer Clinic until death. Women
invasive breast cancer have shown that tumor size, histologic who were no longer able to attend the clinic or who moved to
grade, and lymph node stage are independent prognostic indica- another vicinity were followed by regular inquiry to the relevant
tors for breast cancer-specific survival in retrospective [9] and general practitioner or clinic. Locoregional recurrence was con-
prospective [10, 11] patient groups. These three histologic factors firmed by histologic or cytologic examination. Systemic recur-
are used to determine the Nottingham Prognostic Index (NPI), rences were assessed by appropriate imaging and, where appro-
which identifies four prognostic groups (excellent, good, moder- priate, confirmed by histology/cytology. Death due to breast
ate, poor) in terms of breast cancer-specific survival and identifies cancer or otherwise was ascertained by the results of autopsy
patients who would benefit most from the use of adjuvant systemic findings or death certificates or by the confirmation of death of
therapy [12].
patients admitted for symptomatic metastatic disease. Patients
without metachronous CBC were censored at the time of last
follow-up or death. Survival data were complete for all women
within 12 months of the completion date of this study.
Adjuvant Systemic Therapy
There were 871 deaths during the follow-up period. The me-
Patients were not routinely given adjuvant systemic therapy be- dian follow-up was 108 months (range 1–252 months). During this
fore October 1988. Our current protocol is to offer adjuvant time 80 patients were identified with a metachronous CBC, which
systemic therapy to all patients in the medium- and poor-progno- was defined as histologically confirmed CBC that had not been
sis groups. In this series, adjuvant systemic therapy was given to detected and treated at the time of the initial breast primary. The
6
18 patients: hormone therapy (tamoxifen in most cases) to 407 criteria used for diagnosing a CBC were in accordance with those
patients and chemotherapy to 211 patients. described by Chaudary et al.: demonstration of in situ change and

Kollias et al.: Prognosis with Contralateral Breast Primary
1119
histologic features different from those of the first primary, no
evidence of locoregional or distant metastases from the original
primary at the time of diagnosis, or a combination of these
findings [3]. For patients with metachronous CBC the median
follow-up after diagnosis of the contralateral primary was 49
months (range 1–187 months).
Factors Assessed and Statistics
Analyses are presented for all patients entered in the Nottingham
primary breast series between 1976 and 1995. The time to meta-
chronous CBC occurrence was calculated from the date of surgi-
cal treatment of the first primary tumor. Annual and cumulative
incidence rates for CBC were calculated using a variation of the
standard life tables [13]. Actuarial survival was also determined
using the life-tables method, and differences in survival curves
were evaluated by univariate analysis using the Wilcoxon rank test
[
14]. To determine whether the development of a subsequent
CBC had a significant effect on breast cancer-specific survival,
CBC was entered into a Cox multivariate analysis as a time-
dependent covariate [15]. As such, the model allowed a case to be
included in the unilateral group until the second breast cancer was
diagnosed and then subsequently evaluated in the bilateral group.
The model chosen included the three variables used to determine
the Nottingham Prognostic Index: histologic tumor size, grade,
and lymph node stage. Cases of DCIS and synchronous CBC were
excluded from the analysis. To assess the impact of the time
duration between the diagnosis of the first and second breast
cancers on survival, time delay (1–24 months, 25– 60 months, Ͼ 60
months) was incorporated as a time-dependent covariate in a Cox
model together with the three NPI variables. For both multivar-
iate analyses the model of best-fit involved 2913 cases where data
for all variables was complete. The impact of each prognostic
factor is reported as a relative risk (RR). For categoric variables,
the lowest indicator was assigned an RR of 1.0. Ninety-five per-
cent confidence intervals (CI) were calculated for each RR, and p
values Ͻ 0.05 were deemed significant. Parameters other than
survival were compared using the chi-square or Fisher’s exact test.
All statistical analyses were performed using an SPSS for Win-
dows package.
Fig. 1. Annual prevalence of synchronous bilateral breast cancer accord-
ing to year of diagnosis.
Fig. 2. Annual hazard rates for metachronous contralateral breast can-
cer.
Results
Contralateral Breast Cancer Incidence
Twenty-six women (0.8%) were identified with synchronous bilat-
eral breast cancer. The annual prevalence of synchronous bilateral more, a larger proportion of women with metachronous tumors
breast cancer rose sharply after 1987 (Fig. 1). After diagnosis of had original breast cancers with uninvolved lymph nodes or lob-
the initial breast cancer, the cumulative rate for metachronous ular tumor histology. A significant difference was demonstrated
CBC was 5.6% at 10 years and 9.9% at 15 years of follow-up. The for histologic tumor grade, where high-grade tumors accounted
mean Ϯ SD annual incidence for metachronous CBC was 6.45 Ϯ for 29% of the lesions in patients who subsequently developed a
1
.61 per 1000 woman-years (median 6 per 1000 woman-years; metachronous CBC, compared with 45% and 54% of those with
2
range 2–8 per 1000 woman-years). Annual hazard rates continued unilateral and synchronous bilateral tumors, respectively (␹ ϭ
to be relatively constant up to 15 years (Fig. 2).
8.5, p ϭ 0.01). On the other hand, synchronous bilateral tumors
were more often Ͼ 2 cm in diameter, had lymph node involve-
ment, and were of high histologic grade. No differences were seen
between the three groups in terms of initial DCIS diagnosis, use
Clinical and Histologic Variables
Women who developed a metachronous CBC at less than 50 years of radiotherapy, or use of adjuvant chemotherapy; but signifi-
of age at the time of diagnosis comprised a larger group than cantly more women with synchronous bilateral cancers undertook
2
those with synchronous or unilateral tumors (Table 1). Further- adjuvant hormone treatment (␹ ϭ 15.5, p Ͻ 0.0001).

1
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World J. Surg. Vol. 25, No. 9, September 2001
Fig. 3. Actuarial survival for women
with synchronous contralateral
breast cancer (CBC), metachronous
CBC, and unilateral breast cancer
calculated from the date of diagnosis
of the first primary breast cancer.
Univariate Analysis for Contralateral Breast Cancer Survival
CBC diagnosis, which did not appear to have a significant impact
on mortality when the analysis contained the three variables used
to calculate the NPI for the original breast cancer (Table 3). In
both multivariate models, histologic grade and lymph node stage
of the initial breast primary were shown to be the strongest
predictors of survival according to their higher values for the
regression coefficient (␤), an indicator of the weight of signifi-
cance.
There was a significant difference in breast cancer-specific survival
for the three groups analyzed from the date of diagnosis of the
2
first breast cancer (␹ ϭ 17.73, p ϭ 0.0001) (Fig. 3). Women who
developed a metachronous CBC had a survival advantage over
those with synchronous bilateral breast cancer and the unilateral
breast cancer cohort. Although survival at 5 and 10 years for the
unilateral cohort was better than that of women with synchronous
2
tumors, the difference failed to reach statistical significance (␹ ϭ
2
.47, p ϭ 0.13). When survival was reevaluated from the time to
Discussion
diagnosis of the second tumor in the metachronous group, no
differences in survival were demonstrated between the three The proportion of CBCs that are synchronous depends on the
2
groups (␹ ϭ 2.33, p ϭ 0.31) (Fig. 4). There was a significant definition of CBC and the investigative nature and duration of
difference in survival between groups when the time interval follow-up. The results of our study demonstrated the prevalence
between the first and second breast cancers was considered for the of synchronous bilateral breast cancer to be 0.8%. This is in
metachronous bilateral group from the date of first cancer diag- keeping with the results of previous studies, which have reported
2
nosis (␹ ϭ 22.4, p ϭ 0.0002) (Fig. 5). The pairwise comparisons a mean prevalence of approximately 1.0% [3, 4, 16, 17]. Further-
suggested that survival was similar for women with synchronous more, there was a steep rise in the annual prevalence of synchro-
bilateral breast cancer and those whose metachronous cancer nous breast cancers in 1987 followed by a modest increase during
2
developed within 2 years of the first cancer (␹ ϭ 1.9, p ϭ 0.2). A subsequent years. This occurred shortly after introduction of the
significant improvement in survival was demonstrated for meta- use of bilateral mammography for symptomatic breast disease and
chronous CBC cases where the second cancer was diagnosed at population-based screening. Others have also reported this in-
least 2 years after the original primary compared with the unilat- crease in synchronous breast cancer following the introduction of
2
eral cohort (␹ ϭ 6.8, p ϭ 0.009) or the synchronous CBC group mammography [4, 18].
2
(
␹ ϭ 6.8, p ϭ 0.009). The best survival was demonstrated for
It is well recognized that a history of breast cancer increases the
metachronous CBC cases where the second cancer was diagnosed risk of subsequent breast cancer in the contralateral breast. Our
at least 5 years after the original primary (5- and 10-year survivals results have demonstrated a mean annual incidence of 6.5 per
of 100% and 96%, respectively).
thousand women per year for the development of metachronous
CBC. The annual hazard rates were relatively constant up to 15
years, giving a cumulative incidence for survivors of 5.6% at 10
years and 9.9% at 15 years. These results are similar to those
Multivariate Analysis
Subsequent development of a metachronous CBC had a statisti- previously reported of 0.5% to 1% per year [1, 3, 4, 19].
cally significant adverse effect on prognosis when used as a time-
It has been argued that women who develop a metachronous
dependent covariate in the Cox model containing the three vari- CBC are those whose original cancer predicted a reasonably good
ables used to calculate the NPI for the original breast cancer prognosis and who lived long enough to experience bilateral
(
Table 2). However, no trends were demonstrated with the time to disease [20, 21]. Other studies have shown that those with meta-

Kollias et al.: Prognosis with Contralateral Breast Primary
1121
Fig. 4. Actuarial survival for women
with synchronous CBC,
metachronous CBC, and unilateral
breast cancer calculated from the
date of diagnosis of the second
primary breast cancer.
Fig. 5. Actuarial survival for women
with synchronous CBC (asterisks),
unilateral breast cancer (circles), and
metachronous (metach) CBC,
(
diagnosed 1–24 months, triangles;
2
5–60 months, squares; and Ͼ 60
months, diamonds, after the initial
primary) calculated from the date of
diagnosis of the first primary breast
cancer.
chronous CBC have a better survival than a unilateral cohort
Patients with a metachronous CBC were younger at the age of
when survival time is calculated from the date of first diagnosis onset of the original primary and had a higher percentage of
20, 22]. The results of our study have demonstrated that women lobular cancers. In accordance with previous studies, the lobular
[
who develop a CBC after treatment of an initial primary had more subtype was demonstrated to be an independent prognostic risk
small, low-grade, lymph node-negative tumors than women with factor for CBC development [1, 2, 4, 24, 25]. Family history [2, 3,
unilateral or synchronous bilateral breast cancer. As such, their 26] and early age of onset [1, 19, 27] have been reported to
prognosis from the date of treatment of the first primary was increase the risk of CBC development. Other studies have found
expected to be better, which was demonstrated in the survival no such associations with early age of onset [4, 25, 26] or family
analysis. However, when survival was calculated from the date of history [4, 27]. We have reported that family history, early age of
diagnosis of the metachronous CBC, the survival was similar to onset, and lobular histology are independent predictors of meta-
those with unilateral disease. This is in keeping with the results of chronous contralateral breast cancer development [28]. These
previous studies [22, 23].
characteristics suggest a possible genetic predisposition. Women

1
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World J. Surg. Vol. 25, No. 9, September 2001
Table 2. Multivariate survival analysis for Nottingham Prognostic Index Table 3. Multivariate survival analysis for Nottingham Prognostic Index
factors and contralateral breast cancer as a time-dependent covariate.
factors and time to contralateral breast cancer from date of first
primary as a time-dependent covariate.
Variable
␤
p
95% CI
RR
Variable
␤
p
95% CI
RR
Tumor size
0.25
Ͻ 0.0001
1.21–1.35
1.28
Tumor grade
Tumor size
0.25
Ͻ 0.0001
1.21–1.35
1.28
I
—
1.11
1.79
—
Ͻ 0.0001
Ͻ 0.0001
—
1.0
3.04
5.99
Tumor grade
II
2.19–4.19
4.39–8.18
I
—
1.13
1.81
—
Ͻ 0.0001
Ͻ 0.0001
—
1.0
3.10
6.12
III
II
2.25–4.29
4.39–8.18
Lymph node stage
III
A
—
—
—
1.0
Lymph node stage
B
1.13
1.68
0.51
Ͻ 0.0001
Ͻ 0.0001
0.02
2.20–4.20
4.39–8.18
1.08–2.56
3.12
5.35
1.67
A
—
1.14
1.68
—
Ͻ 0.0001
Ͻ 0.0001
—
1.0
3.14
5.35
C
B
2.66–3.72
4.44–6.44
Contralateral breast cancer
C
(time-dependent covariate)
Contralateral breast cancer
(
time-dependent covariate)
RR: relative risk (for categorical variables the lowest indicator was
designated RR 1.0); CI: confidence interval.
1
2
–24 Months
0.49
1.57
1.84
0.15
0.24
0.14
0.84–3.17
0.74–3.32
0.81–4.19
1.62
1.57
1.85
5–60 Months
Ͼ 60 Months
with a strong family history who develop breast cancer at an early second cancers is relatively short [21, 29, 36]. The results of our
age are at considerable risk of contralateral breast cancer as a first current study have also demonstrated a survival disadvantage
event of recurrence, particularly if the first primary is of lobular when a short time interval was seen between the first and second
histology or predicts a favorable prognosis. Consideration could cancers using a univariate model. Time intervals used to define
be given for bilateral mastectomy in this subgroup of women.
synchronous and metachronous vary between 1 and 12 months,
Synchronous CBC appears to have a worse prognosis than a depending on the cancer registry or individual investigator. From
unilateral CBC or metachronous CBC [20, 21, 29]. Theoretically, a biologic perspective, our results have demonstrated that the
women with synchronous CBCs have a higher tumor burden than survival of women with metachronous CBCs diagnosed within 2
women with unilateral disease, which may jeopardize their sur- years of the original primary is similar to that of women with
vival prospects [30]. Others have failed to demonstrate any sur- synchronous bilateral disease. However, when the time interval
vival difference between women with unilateral breast cancer and was incorporated in a Cox model as a time-dependent covariate
those with synchronous CBC [22, 31, 32]. The results of our study using the NPI variables from the first tumor, no significant differ-
have shown that the prognostic features of the major cancer in ences were seen. Hence the important predictors of survival con-
women with synchronous CBC were worse than in those with tinue to be histologic tumor size, grade, and lymph node stage of
unilateral disease or metachronous CBC. This is in keeping with the initial primary and the subsequent CBC irrespective of the
the results of other studies, suggesting that the prognostic features time delay between the two cancers.
of synchronous cancers are worse that those of a unilateral cancer
[
20, 29]. The survival for women with synchronous CBC in our
Conclusions
study was worse but failed to reach statistical significance, possibly
due to the relatively small sample size and short duration of The results of our study suggest that the development of a con-
follow-up. Furthermore, a significantly higher proportion of tralateral breast cancer is a significant risk factor in women pre-
women with synchronous CBC had adjuvant hormone therapy, viously treated for a breast primary. It is likely that these two
which would have improved their prognosis.
tumors occur as two biologically separate events and contribute
Healey et al. [33] attempted to determine the prognostic sig- independently to the patient’s survival prospects.
nificance of the development of a metachronous CBC by using its
occurrence as a time-dependent covariate in a Cox multivariate
model. Their results demonstrated significant worsening of the
R ´e sum ´e
metastasis-free interval for the CBC group but no difference in Toute femme trait ´e e pour cancer du sein a un risque accru de
survival. It was argued that the short follow-up after a CBC d ´e velopper un cancer du sein oppos ´e . N ´e anmoins, la signification
diagnosis limited the statistical power to detect a survival differ- clinique du d ´e veloppement d’un cancer du sein controlat e´ rale
ence. The long follow-up after CBC diagnosis in our current study n’est pas claire. Le but de cette e´ tude a ´e t ´e d’ ´e valuer le
was able to address this problem.
retentissement d’un cancer du sein bilat ´e ral synchrone ou le
The Nottingham Prognostic Index (NPI) has previously been d ´e veloppement m ´e tachrone d’un cancer controlat ´e ral sur le
shown to be a strong predictor of breast cancer-specific survival in pronostic. Dans cette s ´e rie de 3210 femmes ˆa g ´e es aux alentours
studies other than those from Nottingham [34, 35]. The three de 70 ans, toutes trait ´e es pour cancer du sein op ´e rable entre 1975
variables used to calculate the NPI were used in a multivariate et 1994, on a identifi ´e 106 femmes ayant un cancer du sein
model using CBC as a time-dependent covariate. Our results have bilat ´e ral. On a not ´e 26 cas de cancer bilat ´e ral synchrones (0.8%)
demonstrated a statistically significant impact of CBC develop- alors que 80 femmes ont vu se d e´ velopper un cancer du sein
ment on ultimate survival. Previous studies have looked at the controlat ´e ral (m ´e tachrones). Gr ˆa ce `a l’analyse des courbes de
impact of the time interval between first and second primary survie, on a not´ une diff ´e rence significative en ce qui concerne la
breast tumors in metachronous cases. The results of these studies survie entre les femmes ayant un cancer du sein unilat ´e ral, celles
suggest a worse prognosis if the time interval between the first and qui avaient un cancer du sein bilat e´ ral synchrones et celles qui

Kollias et al.: Prognosis with Contralateral Breast Primary
1123
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