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

doi:10.4236/jct.2013.48154

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Journal of Cancer Therapy, 2013, 4, 1306-1312

http://dx.doi.org/10.4236/jct.2013.48154 Published Online October 2013 (http://www.scirp.org/journal/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

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: *barinoff.jana@googlemail.com, [email protected], [email protected], [email protected],

rita.hils@hsk-wiesbaden, fatemeh.loremz-saleh[email protected], [email protected], [email protected]

Received July 23rd, 2013; revised August 22nd, 2013; accepted September 1st, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

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.

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

causes.

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

2003-2007).

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-

tor.

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-

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

1308

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%)

Her2

unknown 14 (6.5%)

1 - 2 101 (46.8%)

3 70 (32.4%)

Grading

unknown 45 (20.8%)

Duktal 137 (63.4%)

Lobulär 35 (16.2%)

Others 18 (8.3%)

Histology

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),

months

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-

ferent?

Andre F. et al. demonstrated that their collective was

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

1309

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

1310

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%)

0.880X2

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%)

0.124X2

1 - 2 47 (52.2%) 54 (42.9%)

3 23 (25.6%) 47 (37.3%) Grading

unknown 20 (22.2%) 25 (19.8%)

0.186X2

Duktal 55 (61.1%) 82 (65.1%)

Lobulär 17 (18.9%) 18 (14.3%)

Others 5 (5.6%) 13 (10.3%)

Histology

unknown 13 (14.4%) 13 (10.3%)

0.393X2

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)

0.28∫

!! = 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

[12,13,17].

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

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

[21].

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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