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BMC Cancer

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Prognosis of breast cancer molecular subtypes in routine clinical care: A large prospective cohort study

  • André Hennigs1,
  • Fabian Riedel1,
  • Adam Gondos2,
  • Peter Sinn3,
  • Peter Schirmacher3,
  • Frederik Marmé1, 4,
  • Dirk Jäger4,
  • Hans-Ulrich Kauczor5,
  • Anne Stieber5,
  • Katja Lindel5,
  • Jürgen Debus5,
  • Michael Golatta1,
  • Florian Schütz1,
  • Christof Sohn1,
  • Jörg Heil1Email author and
  • Andreas Schneeweiss6
Contributed equally
BMC Cancer201616:734

https://doi.org/10.1186/s12885-016-2766-3

Received: 26 November 2015

Accepted: 6 September 2016

Published: 15 September 2016

Abstract

Background

In Germany, most breast cancer patients are treated in specialized breast cancer units (BCU), which are certified, and routinely monitored. Herein, we evaluate up-to-date oncological outcome of breast cancer (BC) molecular subtypes in routine clinical care of a specialized BCU.

Methods

The study was a prospectively single-center cohort study of 4102 female cases with primary, unilateral, non-metastatic breast cancer treated between 01 January 2003 and 31 December 2012. The five routinely used molecular subtypes (Luminal A-like, Luminal B/HER2 negative-like, Luminal B/HER2 positive-like, HER2-type, Triple negative) were analyzed. The median follow-up time of the whole cohort was 55 months. We calculated estimates for local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and relative overall survival (ROS).

Results

Luminal A-like tumors were the most frequent (44.7 %) and showed the best outcome with LCR of 99.1 % (95 % CI 98.5; 99.7), OS of 95.1 % (95 % CI 93.7; 96.5), and ROS of 100.0 % (95 % CI 98.5; 101.5). Triple negative tumors (12.3 %) presented the poorest outcome with LCR of 89.6 % (95 % CI 85.8; 93.4), OS of 78.5 % (95 % CI 73.8; 83.3), and ROS of 80.1 % (95 % CI 73.8; 83.2).

Conclusions

Patients with a favorable subtype can expect an OS above 95 % and an LCR of almost 100 % over 5 years. On the other hand the outcome of patients with HER2 and Triple negative subtypes remains poor, thus necessitating more intensified research and care.

Keywords

Breast cancerMolecular subtypesOutcomeBreast care unit

Background

Breast cancer (BC) mortality has declined over the past decade in most developed countries, due to new developments in screening, diagnostics, surgery, radiotherapy, and (neo) adjuvant systemic therapy, in conjunction with structural improvements (multidisciplinarity, implementation of specialized breast cancer units) and target agreements (evidence-based guidelines, certification processes) [1, 2]. Over the past decade, increasing molecular and genetic knowledge [36] has provided a new understanding of breast cancer as a heterogeneous, systemic disease that can be classified into different subtypes with different clinical and pathological features, different therapeutic response patterns, and different outcomes [7, 8]. The main molecular classification of breast cancer have been distinguished by gene expression profiling into intrinsic subtypes by Peru et at [5]. These modern microarray-based gene expression profiles (GEP) are the best way to visualize the heterogeneity of breast cancer, but lacking gene expression profiling in clinical routine due to cost and practicability made a surrogate classification necessary [9]. The molecular subtypes of breast cancer correspond reasonably well to a clinical characterization on the basis of hormone-and HER2 status, as well as proliferation markers or histological grade [10]. So the classification based on immunohistochemistry (IHC) markers was recommended by the St. Gallen Expert Consensus in 2011 [11] and confirmed again in 2013 [12]. It has become the accepted standard in routine clinical patient care. Classification into five molecular subtypes (Luminal A-like, Luminal B/HER2 negative-like, Luminal B/HER2 positive-like, HER2-type, Triple negative) helps to sort patients into groups with divergent prognoses and different response patterns to specific Every-day-routine outcome assessment of specialized breast cancer unit (BCU) must validate guideline-based care of BC patients in order to optimize the therapy of every individual case. This paper reports the outcome data of a prospective cohort of 4102 patients with primary, unilateral, non-metastatic BC treated at a specialized BCU according to routinely used molecular subtype definitions based on immunohistochemistry markers.

Methods

Patients

Since 01 January 2003 the medical history and the demographic, diagnostic, therapeutic, and follow-up data of all breast cancer patients referred to the BCU at Heidelberg University have been prospectively entered into our database. This register is routinely used for certification purposes and is monitored.

Patients from the registry were included in the present analysis if they had invasive or carcinoma-in-situ cancer of the breast and were newly diagnosed or treated between 01 January 2003 and 31 December 2012.

Patients were excluded from this analysis for any of the following reasons: male sex (n = 38), distant metastasis at the intake visit (M1, n = 296) or bilateral tumors (n = 619).

Patients with incomplete immunohistological information (149, i.e. 4.1 % of 3603) were included in the overall analysis, but they could not be considered in the subgroup outcome analysis.

Histology and stage

Tumors were defined according to the World Health Organization [13], graded along Elston and Ellis [14], and grouped into stages according to the TNM classification [15]. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 were assessed with an IHC assay of formalin-fixed, paraffin-embedded tumor tissue according to international standards.

Subgroups

According to the St. Gallen International Expert Consensus recommendations 2011 [11], five molecular subtypes of invasive breast cancer have been differentiated by their expression of the IHC markers ER, PR, HER2, and Ki-67:

Intrinsic suptype

 

ER and/or PR

HER2

Ki-67

Luminal A-like

(LumA)

+

<14 %

Luminal B/HER2 negative-like

(LumB/HER2 neg.)

+

≥14 %

Luminal B/HER2 positive-like

(LumB/HER2 pos.)

+

+

any

HER2-type

(HER2)

both−

+

any

Triple negative

(TN)

both−

any

The classification of 2011 was used because it corresponded best to the way we had categorized patients during the time period covered in this report [11].

Positivity for ER and PR was defined as an Immunoreactive Score [16] of at least 1 out of 12 or a Total Score [17] of at least 1 out of 8. All cases of non-invasive carcinoma-in-situ (CIS, regardless of specific subtype) have been defined as an additional subgroup for a separate analysis.

For invasive BC, the cell proliferation marker Ki-67 was available in the majority of our cohort (3004/3603, 83.4 %), while grading, either 1 or 3, was used in 599 of the 3603 cases (16.6 %) for subgroup classification (Table 1). For the differentiation of Luminal-like tumors, cases with a negative HER2 receptor status in combination with a positive ER or PR receptor and a grading of 1 led to the attribution of the Luminal A-like subgroup. In contrast a grading of G3 was assigned to the subgroup of Luminal B/HER2 negative-like tumors.
Table 1

Patient, tumor, and surgical therapy characteristics of all female cases with primary, non-metastatic, unilateral breast cancer diagnosed at the Heidelberg Breast Care Unit between 01 January 2003 and 31 December 2012

Total cases (n = 4102)

Number of cases

Percent (%)

Patient characteristics

Age at diagnosis in years (n = 4102)

 median

57 years

  < 51

1355

33.0

 51–65

1638

39.9

  > 65

1109

27.0

 total

4102

100.0

Menopausal status (n = 4102)

 pre

1377

33.6

 peri

130

3.2

 post

2498

60.9

 missing

97

2.4

 total

4102

100.0

Affected breast (n = 4102)

 left

2066

50.4

 right

2036

49.6

 total

4102

100.0

Tumor characteristics

Main tumor histology (n = 4102)

 In-situ Carcinoma

499

12.2

 Invasive Carcinoma

3603

87.8

 Invasive ductal carcinoma (no specific type)

3082

85.5

 Invasive lobular carcinoma

481

13.3

 other (e.g. invasive medullar/mixed)

40

1.1

 total

4102

100.0

T stage for invasive cases with adjuvant therapy (n = 2997)

pT1

1863

62.2

 pT1a

161

 

 pT1b

486

 pT1c

1202

 pTmic

7

 unknown

7

pT2

909

30.3

pT3

138

4.6

pT4

58

1.9

pTx/missing

29

1.0

total

2997

100.0

T stage for invasive cases with neoadjuvant therapy (n = 606)

ypT0

168

27.7

ypTis

16

2.6

ypT1

224

37.0

 ypT1a

47

 

 ypT1b

52

 ypT1c

115

 ypTmic

8

 unknown

2

ypT2

127

21.0

ypT3

47

7.8

ypT4

16

2.6

ypTx/missing

8

1.3

total

606

100.0

N stage for invasive cases (n = 3603)

 pN0

2473

68.6

 pN1

655

18.2

 pN2

243

6.7

 pN3

158

4.4

 pNx/missing

74

2.1

 total

3603

100.0

Grading (invasive cases, n = 3603)

 Grade 1

600

16.7

 Grade 2

1924

53.4

 Grade 3

962

26.7

 missing

117

3.2

 total

3603

100.0

Estrogen receptor (invasive cases, n = 3603)

 positive

2877

79.9

 negative

585

16.2

 missing

141

3.9

 total

3603

100.0

Progesterone receptor (invasive cases, n = 3603)

 positive

2599

72.1

 negative

859

23.8

 missing

145

4.0

 total

3603

100.0

HER2 receptor (invasive cases, n = 3603)

 positive

346

9.6

 negative

3118

86.5

 missing

139

3.9

 total

3603

100.0

Ki-67 status (invasive cases, n = 3603)

 < 14 %

1463

40.6

 ≥ 14 %

1541

42.8

 missing

599

16.6

 total

3603

100.0

Surgical therapy characteristics

Surgical therapy (n = 4102)

 Breast Conserving Surgery

2999

73.1

 Mastectomy

1103

26.9

 total

4102

100.0

Axillary staging (n = 4102)

 SLND only

1671

40.7

 SLND + ALND

501

12.2

 ALND only

1600

39.0

 none

330

8.1

 total

4102

100.0

SLND sentinel lymphadenectomy, ALND axillary lymphadenectomy

Treatment

The Heidelberg University BCU was fully certified on 10 October 2003, by the German certification board of the German Cancer Society and the German Society for Senology on the basis of the management of cases in 2002 and 2003. Thus all the cases included in this study were managed under certified conditions, which were confirmed by an annual re-certification process [18, 19].

Endpoints and outcome assessment

The outcome from the time of diagnosis was assessed for the whole cohort, the five BC subtypes, and the CIS cases for several outcome parameters. The endpoints were local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and relative overall survival (ROS). Relative survival was defined as the ratio of the observed survival to the survival expected in the general West German population of the same age and sex during the same period of time [20].

Outcome was assessed as follows. First, hospital records were reviewed to obtain information with regard to survival, local and regional relapse, and distant metastasis. If outcome information was not available in the hospital record, the patient’s family doctor or gynecologist was contacted by mail or phone. If the required information could not be obtained by this approach either, an inquiry about the patient’s survival status was made at the responsible residents’ registration office. If the patient was still alive, she was contacted by mail and asked whether she had developed local or distant relapse with a detailed questionnaire. Follow-up was performed for cases diagnosed until 31 December 2012. Within this study period (starting 01 January 2003) n = 2322 patients had a complete follow-up information (i.e. could be followed until either death or study end. Of the remaining 1780 patients, 140 were lost to follow-up during the years 2003–2011, i.e. in total 140/4102 (3.4 %). The median time of follow-up was 45 months among those who were lost to follow-up, slightly shorter than among the whole cohort (55 months).

Statistical analysis

The data were analyzed using SAS software version 9.3 (SAS Institute Inc.; Cary, NC, USA) and SPSS software version 22 (IBM; Armonk, NY, USA). The proportions of patients experiencing events at 5 years, the corresponding 95 % confidence intervals (95 % CI), and all survival plots are based on Kaplan-Meier estimates using PROC LIFETEST with the actuarial approach. Relative survival rates at 5 years were also calculated. The expected survival of the general population was calculated according to the Ederer II method [21], based on life tables for Germany for the years 2002 to 2010.

Results

Patient characteristics

The final cohort comprised 4102 patients, of which, 3603 (87.8 %) had invasive carcinoma and 499 (12.2 %) had CIS. Most invasive carcinoma cases were hormone receptor positive (ER: 79.9 %, PR: 72.1 %), HER2 negative (86.5 %), and had a grading of 2 (53.4 %). Most of the patients had a maximum tumor size of 2 cm (pT1: 62.2 %) without axillary lymph node involvement (pN0 68.6 %). Median age of the whole cohort was 57 years and most patients were postmenopausal (60.9 %). Breast conservation surgery was performed in 73.1 % of the study cohort and a mastectomy in 26.9 %. Concerning surgical management of the axilla sentinel lymph node biopsy alone (SLND) was performed in 40.7 % and axillary lymph node dissection in 39.0 % of the patients. Detailed patient characteristics of the cohort are shown in Table 1.

The UICC stage distribution (Additional file 1: Table S4) as well as the frequency of age, menopausal status and laterality (Additional file 2: Table S5) for the different subtypes can be found in the supplementary material.

Outcome analysis

For all patients with invasive disease, LCR was 96.1 % (95 % CI 95.3; 96.9); DFS was 83.7 % (95 % CI 82.2; 85.2); DDFS was 85.7 % (95 % CI 84.3; 87.1); OS was 90.5 % (95 % CI 89.3; 91.7) and ROS was 97.7 % (95 % CI 93.4; 96.0) at 5 years. As regards cancer subtypes, 44.7 % were luminal A-like, 31.8 % Luminal B/HER2 negative-like, 6.2 % Luminal B/HER2 positive-like, 5.0 % HER2-type, and 12.3 % Triple negative. The Luminal A-like subtype showed the best outcome: LCR was 99.1 % (95 % CI 98.5; 99.7); DFS was 92.1 (95 % CI 90.5; 93.9); DDFS was 92.9 % (95 % CI 91.3; 94.5); OS was 95.1 % (95 % CI 93.7; 96.5) and ROS was 100.0 % (95 % CI 98.5; 101.5). The Triple negative subtype had the worst outcome: LCR at 5 years was 89.6 % (95 % CI 85.8; 93.4); DFS was 69.1 % (95 % CI 64.1; 74.1); DDFS was 72.2 % (95 % CI 67.3; 77.1); OS was 78.5 % (95 % CI 73.8; 83.2); and ROS was 80.1 % (95 % CI 75.1; 85.1). Outcome measures for the whole cohort, with or without inclusion of CIS cases, and for all clinico-pathological subtypes at 5 years are presented in Tables 2 and 3. The corresponding Kaplan-Meier plots are shown in Figs. 1 and 2.
Table 2

Five-year outcomes of 5 different endpoints for all female patients with primary, non-metastatic, unilateral breast cancer treated at the Heidelberg Breast Care Unit between 01 January 2003 and 31 December 2012

 

All patients (including in-situ) n = 4102 (including 499 in-situ cases)

Patients with invasive cancer (excluding in-situ) n = 3603

LCR [%] (95 % CI)

96.1 (95.3; 96.9)

96.1 (95.3; 96.9)

DFS [%] (95 % CI)

84.9 (83.6; 86.2)

83.7 (82.2; 85.2)

DDFS [%] (95 % CI)

86.9 (85.7; 88.1)

85.7 (84.3; 87.1)

OS [%] (95 % CI)

91.3 (90.2; 92.4)

90.5 (89.3; 91.7)

ROS [%] (95 % CI)

95.5 (94.3; 96.7)

94.7 (93.4; 96.0)

CI confidence interval, LCR local recurrence rate, DFS disease-free survival, DDFS distant disease-free survival, OS observed overall survival, ROS relative overall survival

Table 3

Outcome results of 5 different endpoints for all female cases with primary, non-metastatic, unilateral breast cancer treated at the Heidelberg Breast Care Unit between 01 January 2003 and 31 December 2012, (for whom all necessary histological information were available for distinct subtype attribution), differentiated by the invasive clinico-pathological tumor subtype or in-situ tumor (CIS). Results in percent at 5 years (95 % CI)

 

INVASIVE CANCER

CIS

LumA-like

LumB/HER2 neg.-like

LumB/HER2 pos.-like

HER2-type

Triple negative

n = 3454 (100 %) [missing due failed distinct subtype distribution n = 149, i.e. 4.1 % of invasive cohort]

n = 499 (100 %)

n = 1545

n = 1099

n = 215

n = 171

n = 424

 

44.7 %

31.8 %

6.2 %

5.0 %

12.3 %

 

LCR [%] (95 % CI)

99.1 (98.5; 99.7)

95.2 (93.6; 96.8)

95.0 (91.3; 98.7)

90.5 (84.7; 96.3)

89.6 (85.8; 93.4)

96.2 (93.9; 98.5)

DFS [%] (95 % CI)

92.2 (90.5; 93.9)

80.1 (77.2; 83.0)

79.0 (71.9; 86.1)

77.0 (69.4; 84.6)

69.1 (64.1; 74.1)

93.0 (90.2; 95.8)

DDFS [%] (95 % CI)

92.9 (91.3; 94.5)

82.2 (79.5; 84.9)

82.8 (76.0; 89.6)

83.3 (76.6; 90.0)

72.2 (67.3; 77.1)

95.6 (93.5; 97.1)

OS [%] (95 % CI)

95.1 (93.7; 96.5)

88.7 (86.2; 91.2)

92.5 (87.9; 97.1)

85.6 (78.6; 92.6)

78.5 (73.8; 83.2)

96.9 (94.8; 99.0)

ROS [%] (95 % CI)

100.0 (98.5; 101.5)

93.4 (90.7; 96.1)

96.0 (91.2; 100.8)

88.8 (81.5; 96.1)

80.1 (75.1; 85.1)

100.8 (98.6; 103.0)

CI confidence interval, LCR local recurrence rate, DFS disease-free survival, DDFS distant disease-free survival, OS observed overall survival, ROS relative overall survival, CIS carcinoma-in-situ

Fig. 1

LCR, ROS, OS, DDFS and DFS-whole invasive cohort. Kaplan-Meier survival plot for LCR, ROS, OS, DDFS, and DFS for the cohort of invasive cases. Shown are annual survival rates. The table presents the effective sample size for each interval. [LCR: local recurrence rate; DFS: disease-free survival; DDFS: distant disease-free survival; OS: observed overall survival; ROS: relative overall survival]

Fig. 2

Overall Survival for Subtypes. Kaplan-Meier survival plot for overall survival according to molecular subtype (of invasive cancer). The annual survival rates for the following subtypes are shown: LumA, LumB/HER2 neg., LumB/HER2 pos., HER2, and Triple negative (TN). The table presents the effective sample size for each interval

Additional outcome analyses for subtypes subdivided into UICC stages I-IIa (Additional file 3: Table S6) can be found in the supplementary material.

Discussion

The 5-year OS for all patients with primary invasive breast cancer was 90.5 % (95 % CI 89.3; 91.7), and the ROS was 94.7 % (95 % CI 93.4; 96.0) (Table 2). This confirms the favorable prognosis of primary non-metastatic breast cancer receiving adequate treatment. In this study, we focused on a well-defined and homogenous patient cohort. The outcomes seen here can be expected at any specialized BCU. Most of the outcomes statistics published in the literature derive from clinical trials with the exclusion of certain types of patients commonly seen in routine care, e.g. the elderly patients with comorbid conditions. Thus, it is important to assess outcomes among a complete, unselected patient population seen in a routine clinical setting. On the basis of the favorable outcome results reported here, additional quality-of-life aspects might be brought more into focus for outcome quality for specific subgroups in the future.

In the face of unavailable gene expression profiles in clinical routine, the BC surrogate classification according to the St. Gallen Consensus 2011 [11] allows a differentiation of five molecular subtypes with distinct prognoses. Although the management of BC patients according to these subtypes has gained importance, it is beyond controversy that the traditionally assessed tumor characteristics, e.g. nodal status and tumor size, still have independent prognostic impact [22]. Because the St. Gallen subtype classification is widely accepted as a surrogate for subtyping according to intrinsic signatures [9], we used this classification for subtype-specific outcome analysis as they are distinct and well applicable in the context of outcome assessment. Standard pathological assessments seem adequate to define useful groups such as TN, HER2-type, and LumB/HER2 pos.-like tumors, for which treatment recommendations are seldom controversial [23]. In contrast to other studies (e.g. [24]), the Ki-67 score was available for the vast majority of cases, enabling us to differentiate the Luminal-like HER2 negative tumors. Nevertheless, the validity and robustness of Ki-67 is still controversial, although it has been widely accepted as a cell proliferation marker that is widely available [25]. Especially the St. Gallen 2011 cut-off recommendation of 14 % for Ki-67 (which was proposed and validated by Cheang et al. [26]) has been viewed critically due to a substantial inter-observer and intra-observer variability, especially for mid-range Ki-67 scores [2729]. This discordance is highly problematic because a recommendation for or against chemotherapy for hormone receptor positive, HER2 negative, grade 2 tumors depends mainly on the Ki-67 threshold in the St. Gallen Consensus 2011.

Because of this ambiguity in defining exact surrogate subtypes it might be difficult to compare subtype outcome results with other studies that used different surrogate definitions. Despite this difficulty in comparison with other study designs the general trend concerning distribution (at least for clear defined subtypes like TN) and outcome in our cohort is in approximate accordance with other results e.g. from Canada [30], USA [31, 32], South Korea [33], Belgium [24], Spain [34, 35], Italy [36] and France [37]: LumA and LumB tumors were the most frequent (LumA was 44.7 %, LumB/HER2 neg. was 31.8 %, and LumB/HER2 pos. was 6.2 %), followed by TN cancers (12.3 %) and HER2 type (5.0 %). For the majority of patients with a Luminal A type a very favorable OS over 5 years of 95.1 % (95 % CI 93.7; 95.5) and an excellent LCR of 99.1 % (95 % CI 98.5; 99.7) was possible. But it becomes also evident that outcome possibilities for HER-2 type and TN cases are still much poorer even in times of more effective systemic treatment (Table 3). Two exemplary studies with large cohorts-the single-hospital report from Broukhaert et al. in Belgium [24] and the population-based report from Minicozzi et al. in Italy [36]-both used similar criteria approximating the St. Gallen 2011 classification. These two studies had quite comparable distributions of BC subtypes (42 % and 56 % for LumA-like, 27 % and 22 % for LumB/HER2 neg.-like, 14 % and 7 % for LumB/HER2 pos.-like, 7 % and 4 % for HER2-type, and 11 % and 10 % for TN). And these two studies also found similar outcomes; the DFS over 5 years was 93.0 % and 94.6 % for LumA-like, 87.4 % and 85.7 % for Lum B/HER2 neg.-like, 86.3 % and 86.8 % for LumB/HER2 pos.-like, 77.9 % and 79.7 % for HER2-type, and 80.5 % and 81.0 % for TN. DFS was somewhat lower for LumB-like and TN in our cohort than in those two other studies. Besides slightly different subtype and endpoint definitions, it must be considered that Broukhaert et al. used tumor grade instead of Ki-67 for defining subtypes, (with the associated problems mentioned above), and Minicozzi et al. studied a retrospective cohort (2003–2005) with a different Ki-67 cut-off and lack of reliable information about how Ki-67 was determined at that time.

In our cohort the median age of early breast cancer patients was 57 years compared to 64 years in Germany. Concerning surgical procedures mastectomy was performed in 26.9 % of all patients, which is lower than in a current published report from the SEER database with a mastectomy rate of 34 % showing an increase in the United States especially in women with node-negative and in-situ disease (Table 1) [38]. The widely use of specific anti-HER2 therapy in this cohort could increase outcome for patients with HER2 positive breast cancer [39]. The subgroup of patients with Luminal B/HER2 positive-like reveals a LCR of 95.0 % (95 % CI 91.3; 98.7) and a ROS of 93.4 % (95 % CI 91.2; 100.8) at 5 years. Note, however, that the HER2-type subgroup had the second poorest outcome with a LCR of 90.5 % (95 % CI 84.7; 96.3) and a ROS of 88.8 % (95 % CI 81.5; 96.1) (Table 3). The poor survival of triple-negative tumors reflects the lack of effective and specific therapy for this subgroup of patients.

Strengths and limitations

This study adds recent up-to-date outcomes for the 5 different molecular subtypes from a large prospective cohort with a broad usage of Ki-67 for subtype definition (with a cut-off at 14 %). Unfortunately the subgroups in this study are too small with a favorable outcome and the analysis is underpowered to exhibit further differences in stage distribution as well as surgical and systemic management of primary breast cancer on outcome. The effective disentangling of these and further possible effect would require far larger sample sizes than are present in our data base, and should be pursued within cooperative research projects [40].

In our study, the cohort mirrors the typical, unselected cohort of breast cancer patients treated at a specialized breast cancer unit, as there were no specific exclusion criteria. Unfortunately, we did not systematically document a performance status describing comorbidities. As a prospective, single center study, we cannot exclude any potential center effects that may have confounded the results. Further outcome studies from other clinical settings may help to identify if and to what extent outcomes may vary between different breast units.

Conclusion

If primary BC is managed at a specialized BCU under guideline-adherent conditions, patients with a favorable subtype can expect an OS above 95 % and an LCR of almost 100 % over 5 years. On the other hand the outcome of patients with HER2 and TN subtypes remains poor, thus necessitating more intensified research and care.

Abbreviations

BC: 

Breast cancer

BCU: 

Breast cancer units

CI: 

confidence interval

CIS: 

Carcinoma-in-situ

DDFS: 

Distant disease-free survival

DFS: 

Disease-free survival

ER: 

Estrogen receptor

GEP: 

Gene expression profiles

HER2: 

Human epidermal growth factor receptor 2

IHC: 

Immunohistochemistry

LCR: 

Local control rate

OS: 

Overall survival

PR: 

Progesterone receptor

ROS: 

Relative overall survival

UICC: 

Union Internationale contre le cancer

Declarations

Acknowledgements

We would like to thank Michael Hanna, PhD, for proof-reading the manuscript and we would like to thank Christian Lange, Brigitte Wiegand and Ibrahim Kilic for the medical documentation and data management.

Funding

None

Availability of data and material

The dataset analysed during the current study can be provided under special authorization from Prof. Schneeweiss, Heidelberg University Hospital, Division of Gynecological Oncology on reasonable request.

Authors’ contributions

AH, JH and ASc designed the study, FR, AD conducted the statistical analysis, AH, JH analyzed and interpreted the data, AH, JH, H-PS, PS, FM, DJ H-UK, ASt, KL, JD, MG, FS, CS, ASc were involved in the data acquisition, AH, JH wrote the manuscript, ASc, AG provide conceptual advice, All co-authors revised the manuscript and have given final approval for publication, JH takes final responsibility.

Competing interests

There are no conflicts of interests (e.g. employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, or grants or other funding with regard to this study) for any of the authors.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The study was approved by the ethics committee of the University of Heidelberg and in accordance with the Declaration of Helsinki. Because the study was deemed as without risk, including only anonymized analysis of routinely collected data, the ethics committee of the University of Heidelberg did not request approval for consent.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Gynecology and Obstetrics, University of Heidelberg
(2)
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
(3)
Department of Pathology, University of Heidelberg
(4)
National Center for Tumor Diseases (NCT), University Hospital
(5)
Radiology Department, University of Heidelberg
(6)
Department of Radiation Oncology, University of Heidelberg

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© The Author(s). 2016

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