Journal of Cancer Therapy, 2013, 4, 1306-1312 Published Online October 2013 (
Improvement of Survival in Patient with Primary
Metastatic Breast Cancer over a 10-Year Periode:
Prospective Analyses Based on Individual Patient Date
from a Multicenter Data Bank
Jana Barinoff1*, Florian Heitz2, Sherko Kuemmel2, Christine Dittmer2, Rita Hils3,
Fatemeh Lorenz-Salehi3, Alexander Traut2, Andreas du Bois2
1Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany; 2Kliniken Essen Mitte, Essen, Germany; 3Dr. Horst-Schmidt
Klinik, Wiesbaden, Germany.
Email: *,,,,
Received July 23rd, 2013; revised August 22nd, 2013; accepted September 1st, 2013
Copyright © 2013 Jana Barinoff et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Approximately 6% of patients with breast cancer have distant metastases at the time of the initial diagnosis. The aim of
this analysis was to examine the overall survival rate over time and to investigate the effect of new therapy options.
Methods: This retrospective analysis was performed based on the data bank of the Clinic for Gynaecological Oncology/
Dr. Horst Schmidt Klinik, Wiesbaden and the Clinic for Gynaecological Oncology and Senology/Kliniken Essen Mitte,
Essen. The patients with primary metastatic breast cancer (pmBC) who were diagnosed and treated at the accredited
breast cancer centres of these clinics were enrolled between 1998 and 2007. The date of diagnosis was used to define 2
specifically chosen 5-year periods: 1998-2002 and 2003-2007. The follow-up time was on average 76 months. The
Breslow Test was used to evaluate changes in the median survival time and to detect factors associated with the increase
in survival rates. Results: Two hundred sixteen patients with complete baselines were analysed. Ninety patients were
diagnosed between 1998 and 2002, and 126 patients received their diagnosis of pmBC between 2003 and 2007. The
tumour-biological factors were the same in both groups, whereas the therapeutic concepts were different—the later
group (2003-2007) received more aromatase inhibitors, taxane-based chemotherapy and trastuzumab. This finding re-
sulted in an increased median survival time from 31 months in the years 1998-2002 to 44 months in the group with the
first diagnosis between 2003 and 2007. Conclusions: Primary metastatic breast cancer occurred at constant rates over
last 10 years. The tumour findings did not change in the time between the two examined groups; however, the treatment
options in the 2003-2007 group included newly approved therapies. The time period of the first diagnosis was detected
as a risk factor for overall survival. Those patients diagnosed in the more recent time frame had a significantly im-
proved survival rate. The establishment of new therapy options may explain this finding.
Keywords: Breast Cancer; Primary Metastatic Breast Cancer; Therapy of Metastatic Breast Cancer; Survival of
Metastatic Breast Cancer
1. Introduction
Breast cancer is the most common malignant tumour of
women worldwide. In Germany, breast cancer accounts
for 27.8% (70,000 cases) of new cancer diagnoses annu-
aly, and it is responsible for 18% of all female cancer
death [1,2].
One in five patients develops metastatic disease over
time [3-5]. Once the metastatic disease is diagnosed,
breast cancer becomes incurable and therapy options
become palliative. The post diagnosis 5-year survival
rate is approximately 30% [6-8].
Patients with metastatic breast cancer can be separated
into two groups: those with primary metastatic disease
and those with secondary metastatic disease. The differ-
ence is based on the time of the initial diagnosis. Primary
metastatic breast cancer is diagnosed synchronously with
primary tumours and distant metastases. The patients
with secondary metastatic disease develop their metasta-
*Corresponding author.
Copyright © 2013 SciRes. JCT
Improvement of Survival in Patient with Primary Metastatic Breast Cancer over a 10-Year Periode: Prospective
Analyses Based on Individual Patient Date from a Multicenter Data Bank 1307
ses months or years after the first breast carcinoma diag-
nosis [9,10].
The present analysis involves only those patients with
primary metastatic breast cancer. Approximately 6% of
all breast cancer patients test positive for metastatic dis-
ease at the time of their first diagnosis [11-13]. The inci-
dence rate of this disease has persisted over the last 20
years [14]. The aim of the current retrospective study
was to analyse the development of the median survival
time over a fixed period and determine the underlying
2. Methods
The sample group for the present study was recruited
from 6315 patients with breast cancer who were regis-
tered at the prospective tumour data bank of the two cen-
tres. Data for all patients were continuously collected,
and the data bank was updated annually. To be included
in the current study, patients had to meet the following
criteria: a complete initial treatment at the Dr. Horst
Schmidt-Klinik (HSK), Wiesbaden or at the Kliniken
Essen Mitte (KEM), Essen; invasive breast cancer (pa-
tients with an exclusive DCIS after a primary diagnosis
were excluded) with known hormone receptor as well as
Her2 status; a primary diagnosis between January 1,
1998 and December 31, 2007; and a diagnosis of metas-
tatic disease within 4 weeks after the initial diagnosis and
before the start of any systemic treatment. The date of
diagnosis was used to define 2 specifically chosen 5-year
time periods: 1998-2002 (first period, N = 90, first di-
agnosis during the period 1998-2002) and 2003-2007
(second period, N = 126, first diagnosis in the period
The baseline was defined by age and menopausal
status at the time of the first diagnosis, tumour-biological
characteristics (T-stage, histological subtype, grading,
hormone receptor status, Her2 status), and location of the
first metastatic manifestation. Systemic treatments in-
cluded chemotherapy, endocrine therapy, targeted ther-
apy and bisphosphonate therapy. Chemotherapy was
specified as anthracycline based (EC, AC, liposomal an-
thracycline) or taxane based (paclitaxel or docetaxel).
Targeted therapy was defined as therapy with the mono-
clonal antibody trastuzumab. Endocrine therapy was de-
fined as therapy with tamoxifen or an aromatase inhibi-
Patients were monitored for at least 24 months after
the primary diagnosis. All information regarding bio-
logical tumour properties and treatment modalities were
retrieved from the database. Follow-up data were gath-
ered using internal data updates and from practising gy-
naecologists organised in the “Network Quality Assur-
ance Wiesbaden” and “Network Quality Assurance Es-
sen” in cooperation with the HSK and KEM.
Data are expressed as percentages, means ± standard
deviation or 95% confidence interval (CI) or medians, as
appropriate. Normally distributed continuous variables
were analysed using Student’s unpaired t-test and cate-
gorical variables using Χ2 or Fisher’s exact test. The
Kaplan-Meier method was employed for survival analy-
sis. Differences between groups were evaluated by the
Breslow test. All tests were two sided, and differences
were deemed significant at p 0.05. All statistical analy-
ses were performed using the SPSS (version 20.0, SPSS
Inc., 2011 Chicago, IL).
3. Results
Two hundred sixteen patients were diagnosed with pri-
mary metastatic breast cancer between 1998 and 2007.
The age was on average 61 years. The manifestation of
the first metastases was registered in the bone, liver, lung,
non-axillar lymph node, pleura, skin, or brain. The rates
at which these organs were affected varied: 56.9%,
26.9%, 20.4%, 9.7%, 8.3%, 6.5%, and 3.7%, respectively.
Approximately, 8.8% of patients were found to have dis-
tant metastases in other locations not listed above. In
general, visceral metastases were documented in just
over half of all patients (58.3%). Sixty-seven patients
(31%) had more than one organ affected at the time of
the initial diagnosis. Additionally, 19% of the patients
were diagnosed at the stage T1. One in three patients
(34.3%) was diagnosed at the stage T2. Approximately
half of all patients were registered with T3/4-tumours
[11.6% (T3) and 30.6% (T4), respectively). Invasive
ductal breast carcinoma was found in 63.4% of all pa-
tients. Grades I and II were diagnosed in 46.8% of pa-
tients, grade III was found in 32.4%, and unknown grad-
ing was registered in 20.8% of patients. Two in three
patients (78.2%) tested positive for hormone receptor
status and 75.9% of patients had a negative Her2-status
(Table 1).
The next step was to analyse the baselines in the sub-
group: the patients from the first period were compared
with patients from the second period. The patients in
both subgroups showed no difference in age, menopausal
status, tumour-biological characteristics or metastases
distribution (Table 2).
The analysis of first-line therapies in the subgroups
showed that approximately half of the patients in both
groups received chemotherapy as the first therapy option
(1998-2002: 55.6%; 2003-2007: 50%) (Table 3, Figure
1). Analysis of the therapies revealed that the anthracy-
cline-based chemotherapy in the first period was admin-
istered more often than in the second period (40% vs.
27%, respectively; p = 0.044). By contrast, the taxane-
based chemotherapy was documented in the period 2003-
Copyright © 2013 SciRes. JCT
Improvement of Survival in Patient with Primary Metastatic Breast Cancer over a 10-Year Periode: Prospective
Analyses Based on Individual Patient Date from a Multicenter Data Bank
Table 1. Patient and tumor characteristics.
N 216 (100%)
Age, years (median) 61 ± 0.9
1 41 (19%)
2 74 (34.3%)
3 25 (11.6%)
4 66 (30.6%)
T stage
unknown 10 (4.6%)
Positive 162 (75%)
N stage Negative 54 (25%)
Positive 169 (78.2%)
ER/PR Negative 47 (21.8%)
Positive 164 (75.9%)
Negative 38 (17.6%)
unknown 14 (6.5%)
1 - 2 101 (46.8%)
3 70 (32.4%)
unknown 45 (20.8%)
Duktal 137 (63.4%)
Lobulär 35 (16.2%)
Others 18 (8.3%)
unknown 26 (12%)
yes 126 (58.3%)
Viscerale metastases no 90 (41.7%)
yes 67 (31%)
Multiple localisation no 149 (69%)
Pleura 18 (8.3%)
Liver 58 (26.9%)
Lung 44 (20.4%)
Lymph node 21 (9.7%)
Skin 14 (6.5%)
Brain 8 (3.7%)
Bone 123 (56.9%)
First matastases
Others 19 (8.8%)
1998-2002 90 (41.7%)
Periods 2003-2007 126 (58.3%)
Time of follow-up time, median, months 76
Events (death) 160 (74.1%)
75% 15
50% (Median 95% CI) 38 (30 - 46)
Survival (quantiles),
25% 71
T: clinical or pathological tumor size, N: clincial or pathological nodes
status, ER: estrogen receptor, PR: progesterone receptor.
2007 at 69.8% vs. 16.7% in the period 1998-2002 (p =
0.023). During both periods, the same site of patients
received endocrine therapy as the first option (1998-2002:
61.1%; 2003-2007: 63.5%; p = 0.722); however, the type
of endocrine therapy was altered: during the first period,
tamoxifen was the medicine used (p = 0.000); during the
second period, aromatase inhibitors were the therapy of
choice to a significant range (25.6% vs. 50.8%; p =
0.000). Targeted therapy with trastuzumab was adminis-
tered more often in the later years 2003-2007 (4.4% vs.
16.1%; p = 0.007).
The analysis of local therapy options revealed that ap-
proximately 67.8% of the patients during the period
1998-2002 had breast surgery (breast-conserving therapy
as well as mastectomy), and 40% of patients received
this treatment between 2003 and 2007 (p = 0.000). The
number of bone metastases patients who received radia-
tion therapy was the same during both periods (34.4% vs.
36.5%, respectively).
Finally, the time of diagnosis was determined in the
analysis as a risk factor for the median survival. The me-
dian survival for all patients with a first diagnosis of
pmBC was 38 months; the OS during the period 1998-
2002 was 31 months, and the OS during the period 2003-
2001 was 44 months (p = 0.028) (Figure 2).
4. Discussion
Metastatic breast cancer is a heterogeneous disease with
a list of various scenarios of progress ranging from ef-
fects on individual organs with a benign prognosis to
extensive systemic metastases resulting in a shortened
overall survival rate. The time of metastases also differs.
Possibilities range from synchronous diagnosis—for
example, primary metastatic breast cancer—to the de-
velopment of metastases many years after the first diag-
nosis of breast carcinoma [15].
The overall survival rate for primary metastatic breast
cancer has constantly improved at a rate of 1% - 2%
yearly as shown in published analyses. The reason for
this development seems to be the establishment of new
therapy options [12,14-16]. Thus, based on the current
published data, patients survived longer in the last decade
than in the earlier period [17]. Apparently, there is a fac-
tor influencing the progress of disease, and this factor is
strong enough to affect the overall survival rates. This
trend is also observed in our analysis of data concerning
primary metastatic breast cancer. To explain this change,
we must consider the following questions: Were the tu-
mour-biological characteristics identical during the two
separate time periods? Additionally, were the therapy
options during these two time periods significantly dif-
Andre F. et al. demonstrated that their collective was
Copyright © 2013 SciRes. JCT
Improvement of Survival in Patient with Primary Metastatic Breast Cancer over a 10-Year Periode: Prospective
Analyses Based on Individual Patient Date from a Multicenter Data Bank
Copyright © 2013 SciRes. JCT
Figure 1. First-line therapies according to time periods: 1998-2002 vs. 2003-2007 (%).
Figure 2. Survival in patients with pmBC according to time periods: 1998-2002 vs. 2003-2007; CI-95% confidence intervals,
estimated by Breslow-test.
equal regarding tumour characteristics during the ex-
plored periods (1987-1993 vs. 1994-2000), and their
findings have been corroborated by many other publica-
tions [12,16]. Our data from 2009 also showed no dif-
ference in patient baselines and tumour characteristics
between the periods 1998-2002 and 2003-2006 [18]. This
finding has once again been confirmed in the present
study: the distribution of tumour-biological characteris-
tics in patients with primary metastatic breast cancer did
not significantly differ between the periods 1998-2002
and 2003-2007. Lung metastases were diagnosed more
often in the later period, a finding that is attributed to
staging examinations performed using computer tomo-
graphy. Unusually high rates of brain metastases during
the period 1998-2002 cannot be explained despite data
clearance. Because the effect of brain metastases on
overall survival has not been determined, we should not
over interpret this finding. According to the published
data, patients with primary metastatic breast cancer have
been presented as a homogeneous cohort during the last
25 years.
Analysis of therapy over time in our study showed that
the anthracycline-based therapy and tamoxifen were ap-
plied more often during the early period (1998-2002),
Improvement of Survival in Patient with Primary Metastatic Breast Cancer over a 10-Year Periode: Prospective
Analyses Based on Individual Patient Date from a Multicenter Data Bank
Table 2. Patents and tumor characteristics according to time periods: 1998-2002 vs. 2003-2007.
1998-2002 (%) 2003-2007 (%) p-Value
N 90 (100%) 126 (100%)
Age, years (median) 62 ± 1.4 60 ± 1.2 0.23!!
1 17 (18.9%) 24 (1.0%)
2 32 (35.6%) 42 (33.3%)
3 8 (8.9%) 17 (13.5%)
4 29 (32.2%) 37 (29.4%)
T stage
unknown 4 (4.4%) 6 (4.8%)
Positive 67 (74.4%) 95 (75.4%)
N stage Negative 23 (25.6%) 31 (24.6%) 0.873X2
Positive 70 (77.8%) 99 (78.6%)
ER/PR Negative 20 (22.2%) 27 (21.4%) 1.000X2
Positive 63 (70%) 101 (80.2%)
Negative 18 (20%) 20 (15.8%) Her2
unknown 9 (10%) 5 (4%)
1 - 2 47 (52.2%) 54 (42.9%)
3 23 (25.6%) 47 (37.3%) Grading
unknown 20 (22.2%) 25 (19.8%)
Duktal 55 (61.1%) 82 (65.1%)
Lobulär 17 (18.9%) 18 (14.3%)
Others 5 (5.6%) 13 (10.3%)
unknown 13 (14.4%) 13 (10.3%)
yes 49 (54.4%) 77 (61.1%)
Viscerale FM no 41 (45.6%) 49 (38.9%) 0.327X2
yes 33 (36.7%) 34 (27%)
Multiple Lokal. no 57 (63.3%) 92 (73%) 0.129X2
Time of follow-up time, median, months 116 63
Events (death) 82 (91%) 78 (62%)
75% 11 20 (+10 m)
50% (Median 95% CI) 31 (16 - 45) 44 (35 - 54) (+13 m) Survival (quantiles), months
25% 68 75 (+7 m)
!! = T:Test, X2 = Chi-Quadrat-Test, = Breslow-Test; T-clinical or pathological tumor size, N-clincial or pathological nodes status, ER-estrogen receptor, PR-
progesterone receptor.
whereas the targeted therapy with trastuzumab played no
role during this time period. Later (2003-2007), the tax-
ane-based therapy was the first choice of chemotherapy
options, and aromatase inhibitors and trastuzumab ther-
apy were administered more frequently. A similar de-
velopment has been subsequently described worldwide
Breast surgery as a part of therapy was provided dur-
ing the period 1998-2002 nearly twice as often as during
the period 2003-2007.This finding can be explained by
the recent dominant theory that no survival advantage
results from surgery of primary tumours in patients with
synchronous metastases, with perhaps the exception of
patients with bone metastases [18]. In a recent publica-
tion, Ruiterkamp J. et al. (2011) discussed the indication
of breast tumour resection in patients with primary me-
tastases [19]. In 2012, Petrelli published a meta-analysis
regarding surgery for primary tumours in stage IV breast
Copyright © 2013 SciRes. JCT
Improvement of Survival in Patient with Primary Metastatic Breast Cancer over a 10-Year Periode: Prospective
Analyses Based on Individual Patient Date from a Multicenter Data Bank 1311
Table 3. Initial tehrapies as first-line option in according to time periods: 1998-2002 vs. 2003-2007.
1998-2002 (%) 2003-2007 (%) p-Value
N 90 (100%) 126 (100%)
Yes 61 (67.8%) 50 (39.7%)
surgery No 29 (32.2%) 76 (60.3%) 0.000X2
Yes 50 (55.6%) 63 (50%)
chemotherapy No 44 (44.4%) 63 (50%) 0.420X2
Yes 36 (40%) 34 (27%)
antracycline No 54 (60%) 92 (73%) 0.044X2
Yes 15 (16.7%) 88 (69.8%)
taxane No 75 (83.3%) 38 (30.2%) 0.023X2
Yes 4 (4.4%) 20 (16.1%)
trastuzumab No 86 (95.6%) 104 (83.9%) 0.007X2
Yes 55 (61.1%) 80 (63.5%)
endocrine therapy No 35 (38.9%) 46 (36.5%) 0.722X2
Yes 23 (25.6%) 64 (50.8%)
aromatase inhibitor No 67 (74.4%) 62 (49.2%) 0.000X2
Yes 31 (34.4%) 46 (36.5%)
radiation No 59 (65.6%) 80 (63.5%) 0.755X2
X2 = Chi-Quadrat-Test.
cancer and could show that this option seems to offer a
survival benefit in those patients [20]. Surgery of the
primary tumour could represent a novel way of thinking
and plays a role in a multimodality treatment program
The limitation of our analysis is small number of pa-
tients. Nevertheless the group of patients in the present
study is an excellent indicator of the change in therapy
strategies over time. This change depends on the ap-
proval of new medications, published data and current
therapy guidelines. Because of this development, patients
from different time periods demonstrated different out-
comes. In our study, the group diagnosed in the later pe-
riod was treated with more modern therapy options and
demonstrated an improvement in overall survival. The
worldwide published data corroborate this finding: the
advent of new and more effective agents, combined with
surgery for primary tumour and distant metastasis, has
supported radiotherapy and it has led breast cancer pa-
tients with stage IV disease to live longer in the last dec-
ade [22].
5. Conclusion
The data analysis provides us with the information we
required to develop future therapy strategies for our pa-
tients with primary metastatic breast cancer. Recently, a
first randomised, controlled clinical trial for that collec-
tive is completed. The aim was to observe whether pri-
mary surgery improves survival in metastatic breast can-
cer. There were two study arms: primary surgery and
systemic chemotherapy groups. In the primary surgery
group patients had adjuvant therapies after they had the
breast surgery. In the systemic chemotherapy group pa-
tients would be followed after their initial therapy and
would have surgery only if they had locoregional prob-
lems. 281 patients were enrolled; the results have not yet
been published [23]. Such prospective trials should be
designed and supported to define evidence-based therapy
guidelines for this particular group. There is no better
patient collective to investigate questions about the im-
pact of new medicine, because of a lack of systemic
therapy in these women.
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