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BMC Cancer

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Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer – results from the HER-OS patient registry

  • Isabell Witzel1Email author,
  • Volkmar Müller1,
  • Wolfgang Abenhardt2,
  • Manfred Kaufmann3,
  • Winfried Schoenegg4,
  • Andreas Schneeweis5 and
  • Fritz Jänicke1
BMC Cancer201414:806

https://doi.org/10.1186/1471-2407-14-806

Received: 5 August 2013

Accepted: 20 October 2014

Published: 4 November 2014

Abstract

Background

In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.

Methods

268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.

Results

Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.

Conclusions

HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.

Keywords

HER2Metastatic breast cancerTrastuzumab

Background

Although the majority of breast cancer patients can be cured of their disease, up to 20% will develop metastatic breast cancer (MBC). The Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed or amplified in 15% of breast tumors [1] and is associated with a more aggressive tumor behavior, shorter disease-free and overall survival [24]. Trastuzumab (Herceptin®), a monoclonal antibody directed against HER2, has shown to improve survival in combination with chemotherapy compared to non-trastuzumab-based treatment [57]. It has therefore become the standard treatment in adjuvant and metastatic HER2-positive breast cancer. Although the majority of patients with MBC treated with trastuzumab-based regimens progress within one year [5, 8], few patients experience prolonged remission [9, 10]. Limited data have been published on long term remission under treatment with trastuzumab and are usually based on case reports or small patient numbers [1113]. Aspects such as clinical predictive factors of long-term response to trastuzumab or the optimal duration of trastuzumab therapy in MBC patients achieving stable response remain to be reported. The primary goal of this study was to assess the long-term outcome of patients with durable response to trastuzumab. In addition, factors that could be associated with long-term tumor remission under trastuzumab were identified in an exploratory analysis.

Methods

Selection of patients

Patients with HER2 positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under continuous trastuzumab therapy (complete or partial response or stable disease) met the inclusion criteria to be documented in the HER-OS database. Positive HER2 status was defined as immunohistochemistry (IHC) staining of 3+ or immunohistochemistry staining of 2+ and positive fluorescence in-situ hybridization (FISH, HER2/CEP17 ratio >2.2). Between December 2006 and September 2010, 447 patients under trastuzumab treatment were documented in 71 German medical centers within the HER-OS database, an online- documentation platform for patients with advanced HER2 positive breast cancer. The database for the register was set up by an review board (see Authors’ contributions) as a collection of case reports. The project fulfilled the criteria of a non-interventional study according to the European Community and German legislation, and therefore required no ethical committee vote [14]. Patients gave informed consent to have their medical records reviewed according to the review board guidelines. The not publicly available HER-OS database (owner: Roche Pharma AG, Germany) included documentation of demographic data, clinico-pathological data of the primary tumor, treatment strategies and concomitant diseases. Treatment with trastuzumab, further antineoplastic therapies and tumor status were documented every 6 months after treatment initiation with trastuzumab. Retrospective as well as partial retro-/prospective documentation was allowed. Patient data was anonymized.

The study end point was time to tumor progression (TTP). The HER-OS database was closed in September 2010. The observation period until disease progression or end of study was 41.2 months (median; range: 24.3–117.1 months).

Only 268 of 447 patients (60.0%) had complete documentation of prior treatments, met the inclusion criteria, were without progression for at least 2 years after the initiation of trastuzumab treatment, and were therefore considered eligible for further analyses.

Treatment

Since this study was non-interventional, patients were treated at their physician’s choice. The physicians chose trastuzumab treatment intervals and dosages as well as combination of trastuzumab with other chemotherapeutic or endocrine treatments. The physicians also determined cardiac monitoring intervals, which were mostly performed in 6-monthly intervals.

Statistical methods

Statistical analysis focused on the summary and detailed description of the data. Unless otherwise stated, percentages were displayed as adjusted values, so that patients with missing data were not taken into account.

Primary outcome variable of the study was time to tumor progression (TTP). Nonparametric estimates of survivor functions were calculated by the Kaplan-Meier method. Differences in time distributions were analyzed using Peto’s logrank test. In a multivariate analysis including all parameters of the univariate analysis, forward selection was performed with an entry of 0.25 and a stay of 0.15. Results were regarded as statistically significant at a p-value ≤0.10. Analyses in subgroups were made post-hoc and should be seen as exploratory. The statistical analysis was performed with the program SAS™ version 9.2.

Results

Patients’ characteristics

The median age at diagnosis of breast cancer was 53.8 years (range 29–86 years). 27.2% of patients (n = 64) had metastases at first diagnosis of breast cancer. 37.5% of patients (n = 94) were hormone receptor negative. Of those patients with non-metastatic disease at diagnosis, 76.6% (n = 131) had received chemotherapy in the adjuvant setting, 42.7% (n = 73) a taxane containing regimen. 50.9% (n = 87) had received adjuvant endocrine treatment, 8.2% (n = 14) adjuvant trastuzumab treatment. The median disease-free survival for 131 patients with non-metastatic disease at diagnosis amounted to 3.3 years (range: 1 month – 15.5 years).

At the time of disease recurrence or onset of metastatic disease, 15.3% (n = 41) of the 268 women suffered from inoperable locoregional recurrent disease, 52.2% (n = 140) from distant metastases and 32.5% (n = 87) from both. Metastases were predominantly found in bone (n = 102; 38.1%), liver (n = 88; 32.8%), and lung (n = 75; 28.0%). Brain metastases were present in only 2.2% of documented patients (n = 6).

In general, patients had a good performance status at the beginning of trastuzumab therapy. 49.8% (n = 115) had Eastern Cooperative Oncology Group (ECOG) performance status 0. 42.2% (n = 108) of patients had normal weight, while 51.6% (n = 132) were overweight or obese, and 6.3% (n = 16) were underweight.

Nearly every fifth patient (19.4%) presented with relevant comorbidities, which were mostly hypertension (10.1% of all patients) or cardiac arrhythmia (2.6% of all patients).

Tables 1 and 2 provide detailed patients’ characteristics at the time of diagnosis of breast cancer and at the start of palliative trastuzumab treatment.
Table 1

Patient characteristics at diagnosis of breast cancer

Characteristics

Number

%

Age, years

  

 Median (Range)

53.8 (29–86)

 

TNM status

  

 T0-T1

77

30.4

 T2

119

47.1

 T3 and T4

57

22.5

 N0

74

31.0

 N1-N3

165

69.0

 M0

171

72.8

 M1

64

27.2

Grading

  

 G1

11

4.4

 G2

121

48.4

 G3

118

47.2

HER2 status

  

 +2 and positive FISH

11

4.1

 +3

257

95.9

Estrogen receptor (ER)/progesterone receptor (PR)

  

 ER positive/PR positive

105

41.8

 ER positive/PR negative

38

15.1

 ER negative/PR positive

14

5.6

 ER negative/PR negative

94

37.5

 ER or PR unknown

17

 
Table 2

Disease status before initiation of trastuzumab treatment

Characteristics

Number

%

Age (years)

  

 Median (Range)

58.5 (31–86)

 

BMI (kg/m2)

  

 Median (Range)

25.1 (16–50)

6.3

 <18

16

42.2

 18–25

108

51.5

 >25

132

 

ECOG performance status

  

 0

115

49.8

 1

108

46.8

 2

8

3.4

Disease-free survival (months)

  

 Median (Range)

37.3 (1–413)

 

Site of disease recurrence

  

 Inoperable locoregional recurrence

41

15.3

 Metastatic disease

140

52.2

 Both

87

32.5

Site of locoregional recurrence

  

 Breast

47

17.5

 Axillary lymph nodes

64

23.9

 Supraclavicular lymph nodes

33

12.3

 Chest wall

23

8.6

 not specified

15

5.6

Site of metastatic disease

  

 Lung

75

28.0

 Liver

88

32.8

 Bone

102

38.1

 CNS

6

2.2

 Other

25

9.3

Trastuzumab treatment

Although the administration of trastuzumab as weekly and three-weekly infusion was balanced at the beginning of palliative treatment, the majority of patients switched to three-weekly intervals during therapy (84.0%).

In 78.4% of women, trastuzumab was started in a combination treatment with chemotherapy (n = 169; 63.1%) or with endocrine treatment (n = 92; 34.3%). The most commonly used chemotherapeutic agents were taxanes (40.3% total; 20.9% paclitaxel; 19.4% docetaxel), vinorelbine (22.4%) and antimetabolites (17.2% total; 12.7% capecitabine; 2.6% gemcitabine; 1.9% fluorouracil). Anthracyclines were also combined with trastuzumab in 2.6% of women (2.2% doxorubicin; 0.4% epirubicin). In case of endocrine therapy in combination with trastuzumab, patients mostly received an aromatase inhibitor or tamoxifen. In 21.6% of women (n = 58), trastuzumab was used as single agent.

Interruption of trastuzumab therapy

17 patients (6.4%) received lower trastuzumab dosages due to therapy interruption, mostly due to other illnesses. The most frequent reasons for interruption of trastuzumab therapy were patient’s wish (1.5%) or cardiac adverse event (1.1%). Patients who experienced progression within 6 months after trastuzumab interruption (n = 3) were excluded from further analyses.

Response to trastuzumab

A clinical response to trastuzumab treatment was required in order to be included in the study. 38.7% of patients (n = 103) had complete remission, 32.0% (n = 85) partial remission, and 29.3% (n = 78) stable disease as best response to trastuzumab treatment. A remission (complete or partial) was documented after a median time of 7.3 months since treatment initiation.

Until the end of the study, 126 patients (47.0%) had progressive disease during continuous trastuzumab treatment with an estimated median time to progression (TTP) of 4.5 years (95% CI: 4.0–6.6 years). It was estimated that 47.1% of patients (95% CI: 39.9–54.1%) remained in remission for more than 5 years, 40.5% (95% CI: 32.1–48.7%) for more than 7 years, and 29.2% (95% CI: 15.1–44.8%) for more than 9 years (Table 3, Figure 1).
Table 3

Time to tumor progression at the end of each year during follow-up

Year

Patients with progression

Patients censored

Product-limit survival estimates

95%-confidence interval of survival estimates

Patients left

Lower limit

Upper limit

1 and 2

0

0

100.0%

  

268

3

72

29

71.6%

65.6%

76.8%

167

4

29

39

57.1%

50.4%

63.3%

99

5

15

29

47.1%

39.9%

54.1%

55

6

3

22

43.9%

36.2%

51.3%

30

7

2

15

40.5%

32.1%

48.7%

13

8

1

4

36.5%

26.0%

47.0%

8

9

1

3

29.2%

15.1%

44.8%

4

10

3

1

0.0%

-

-

0

Figure 1

Probability of progression during palliative trastuzumab treatment.

Factors associated with long-term tumor remission

Patients who were younger (age <50 years) at diagnosis of inoperable locoregional recurrent or metastatic disease and had a good performance status (ECOG 0) exhibited a trend towards longer TTP in the univariate analysis (p = 0.07 and p = 0.08, respectively; Table 4). In addition, best response to trastuzumab treatment had an influence on TTP (p = 0.057; Table 4). Interruption of trastuzumab treatment was associated with shorter TTP (p = 0.0005; Table 4). We could not observe an influence of tumor size, grading, hormone receptor status, nodal status or disease-free survival in univariate analysis. The absence of distant metastases at the onset of trastuzumab treatment or the initial combination of trastuzumab with endocrine therapy or chemotherapy had also no impact on TTP (Table 4).
Table 4

Association of clinicopathological and treatment characteristics with time to tumor progression (univariate analysis)

Parameter

 

Patients (total)

Patients (progressed)

Time to progression (years)

p-value

TNM status at diagnosis

T0-T1

77

28

5.10

4.13- n.e.

0.1423

T2-T4

176

92

4.06

3.56-7.74

 

N0

74

37

4.11

3.30-6.05

0.2813

N1-N3

165

75

5.06

4.05-9.76

 

M0

171

79

5.06

4.05-9.70

0.2367

M1

64

31

4.39

3.51-6.58

Grading

G1-G2

132

63

4.13

3.55-6.05

0.3122

G3

118

55

5.06

4.04-9.53

Disease-free survival

0-5 years

203

91

5.12

4.11-8.72

0.2183

>5 years

56

32

3.46

3.00-4.44

Hormone receptor status

ER negative

109

48

5.96

4.04-9.53

0.1876

ER positive

148

73

4.13

3.55-6.05

 

PR negative

132

61

5.06

4.05-6.58

0.6547

PR positive

120

56

4.11

3.53-9.70

 

ER and PR negative

94

42

5.06

4.04-9.53

0.3789

ER or PR positive

157

75

4.18

3.56-6.58

Age at trastuzumab start

< 50 years

70

32

5.96

4.11-9.76

0.0744

≥50 years

198

94

4.20

3.56-6.05

ECOG status at trastuzumab start

0

115

54

4.61

3.91-9.76

0.0812

1-4

116

59

4.05

3.44-5.96

Site of recurrence at trastuzumab start

locoregional

    

0.1156

recurrent only

55

22

9.70

3.63-9.70

Bone metastases only

41

21

4.05

3.30-n.e.

Visceral metastases

139

69

4.39

3.55-6.58

Initial response to trastuzumab treatment

Complete remission

48

16

8.72

4.46-9.76

0.0571

Partial remission

80

46

4.03

3.50-4.41

Stable disease

82

37

4.66

3.56-n.e.

Interruption of trastuzumab treatment

no therapy interruption

251

109

5.13

4.11-9.53

0.0005

therapy interruption

14

14

3.51

2.36-4.44

In the multivariate analyses, interruption of trastuzumab treatment turned out to be associated with shorter TTP (p = 0.0015; data not shown).

Discussion

In our group of patients responding at least 2 years to trastuzumab treatment for inoperable locoregional recurrent or metastatic breast cancer, long-term tumor remission for several years could be achieved. The median time to progression in our study cohort was 4.5 years. We could identify that younger age (under the age 50) and good performance status (ECOG 0) at the initiation of trastuzumab treatment were associated with longer TTP. An interruption of trastuzumab treatment correlated with shorter TTP in univariate and multivariate analysis.

Trastuzumab therapy has increased response rates and survival times in the metastatic setting [15]. We can report a complete remission rate of 38.7% in HER2 positive patients receiving trastuzumab treatment for advanced breast cancer. To our knowledge, we are the first to describe a clinical cohort of patients with advanced breast cancer disease who benefit from trastuzumab treatment for several years.

Long-term follow-up, beyond 3 to 5 years, is exceptional in the metastatic breast cancer literature as median survival ranges between 2 and 4 years. While most patients with metastatic breast cancer respond transiently to conventional treatments, the majority develop evidence of progressive disease within 12 to 24 months of first-line therapy [16, 17]. However, some patients who achieve a complete remission after chemotherapy remain in this state for prolonged periods of time, with some even beyond 20 years [18, 19]. Tomiak et al. reported that 20% of metastatic breast cancer patients who achieved complete remission with chemotherapy were alive and without disease progression for more than 5 years [19]. In another retrospective analysis of 147 premenopausal women with metastatic breast cancer receiving chemotherapy, 28% of patients were reported to be alive after a follow-up period of 5 years [20]. In a cohort of 1581 metastatic breast cancer patients treated with anthracycline containing therapy for a maximum of 2 years in the 1970s and 1980s, complete remission rates of 16.6% were described. 3% of patients remained in complete remission for more than 5 years [18]. The long-term survivors described in those studies were usually young, had excellent performance status and limited metastatic disease. In line with these results, we were able to show that of all clinicopathological parameters, age at initiation of trastuzumab treatment (under age 50), good performance status (ECOG 0) and initial response to trastuzumab treatment (complete remission) were associated with longer TTP. However, also patients with only partial or stable disease had long-term tumor remission. Interestingly, in our group of patients, site of disease recurrence was not associated with TTP (inoperable locoregional disease recurrence vs. bone metastases vs. visceral metastases).

As our data base was documented in several institutions, it reflects the reality of medical care of HER2 positive MBC patients between 2006 and 2010. Most of the patients had received trastuzumab in combination with chemotherapy or endocrine therapy while 20% of patients had received trastuzumab only as monotherapy. According to published data, trastuzumab as single-agent first-line treatment in MBC showed efficacy. 57% of responding patients had stable disease longer than 12 months [6]. In HER2 positive MBC patients who progressed under at least one cytotoxic regimen, response rates of 48% (19% complete or partial remission, 29% stable disease) with trastuzumab monotherapy were reported [21]. In this trial, one third of patients lived for more than three years with trastuzumab monotherapy.

We were able to demonstrate that therapy cessation or interruption should be avoided as it was associated with shorter TTP in our patient cohort. Continuous suppression of the HER2 pathway may be important, and was already demonstrated by the benefit of trastuzumab use beyond progression [22]. Our data is supported by a retrospective cohort of 84 patients treated with trastuzumab for MBC in two different institutions. One institution stopped trastuzumab treatment after two years of response, in this institution durable response rates were lower than in the institution that continued trastuzumab treatment after two years of response (durable response rates 6 versus 11%) [10]. Although there might be a benefit of longer trastuzumab treatment in the metastatic setting, the duration of trastuzumab treatment is still unclear.

The study was designed to find new hypotheses regarding long-term remission. Therefore a significance level of p < 0.1 seemed appropriate. A lower p-value of p = 0.05 as used in randomized clinical trials could have led to the exclusion of hypotheses that might be worth to evaluate further. A drawback of our study is that it is a single-arm multicenter study with no comparative cohort, so that we were not able to draw unequivocal conclusions but could only describe parameters influencing long-term remission within a highly selected sample. It is important to note that we report only time to disease progression and that we have not collected data about overall survival. However, overall survival rates can be expected to be significantly longer than the TTP reported here because several anti-HER2 treatment strategies can still be applied in HER2 positive metastatic breast cancer after disease progression.

Conclusions

Although the fraction of metastatic breast cancer patients with long-term tumor remission is small, we provide evidence that HER2 positive patients who initially respond to palliative treatment with trastuzumab can achieve a long-term tumor remission of several years.

Declarations

Acknowledgments

This work was supported by an unrestricted research grant from Roche Pharma AG, Grenzach, Germany. Statistical analysis was performed by Anfomed GmbH, Möhrendorf, Germany.

Authors’ Affiliations

(1)
Department of Gynecology, University Medical Center Hamburg-Eppendorf
(2)
Onkologische Praxis Elisenhof
(3)
Department of Obstetrics and Gynecology, University Hospital
(4)
Breast Center, DRK Hospital
(5)
Department of Obstetrics and Gynecology, University Hospital

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  23. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/806/prepub

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© Witzel et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

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