Breast Cancer DOI 10.1007/s12282-013-0513-z
ORIGINAL ARTICLE
Brain metastases in HER2-positive metastatic breast cancer patients who received chemotherapy with or without trastuzumab Muhammet Ali Kaplan • Hamza Ertugrul • Ugur Firat • Mehmet Kucukoner • Ali I˙nal • Zuhat Urakci • Zafer Pekkolay Abdurrahman Isikdogan
•
Received: 29 July 2013 / Accepted: 18 December 2013 Ó The Japanese Breast Cancer Society 2013
Abstract Objective The aim of this study was to assess whether trastuzumab usage is a risk factor for the development of brain metastasis (BM) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and factors affecting survival after development of BM. Materials and methods One hundred thirty-two patients treated with (treatment group) or without trastuzumab (control group) with brain metastasis were retrospectively analyzed. Results Ninety of the 132 HER2-positive MBC patients were in the treatment group and 42 were in the control group. BM was significantly increased in patients who were treated with trastuzumab in two or more lines (58.5 vs 24.1 %, p \ 0.001). Trastuzumab and lapatinib usage after BM and age were independent prognostic factors for overall survival in univariate and multivariate analysis. Conclusion The risk for BM was increased in patients who were treated with trastuzumab in two or more lines. Using trastuzumab and lapatinib after BM and age were independent prognostic factors for time to death from BM.
M. A. Kaplan (&) M. Kucukoner A. I˙nal Z. Urakci A. Isikdogan Department of Medical Oncology, Dicle University School of Medicine, Diyarbakir, Turkey e-mail: [email protected] H. Ertugrul Z. Pekkolay Department of Internal Medicine, Dicle University School of Medicine, 21280 Diyarbakir, Turkey U. Firat Department of Pathology, Dicle University School of Medicine, Diyarbakir, Turkey
Keywords Breast cancer Brain metastasis Trastuzumab
Introduction Breast cancer is one of the most common tumors in adults [1]. Approximately 20–25 % of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive [2]. Over-expression of HER2 in primary breast cancer has been associated with decreased patient survival [2]. Trastuzumab is a humanized monoclonal antibody directed against the HER2 oncoprotein. This protein is encoded by the HER2 gene and has been characterized as a transmembrane growth factor receptor belonging to the epidermal growth factor receptor family [3]. The combination of trastuzumab and chemotherapy has yielded an overall response rate of up to 71 % in patients with metastatic breast cancer (MBC) [3–5]. However, it is a large protein that does not cross the blood–brain barrier [6]. The incidence of clinically evident BM among women with MBC is estimated to be between 10 and 16 % [7–10]. The incidence of BM at autopsy ranges from 18 to 30 % [10, 11]. Younger age, ethnicity, presence of visceral metastases, tumor size, hormone receptor-negative disease, and HER2 over-expression are associated with an increased risk of developing central nervous system (CNS) metastases [12]. The incidence of BM in patients with HER2positive breast cancer range from 30 to 53 % [13–18]. Several studies have reported that trastuzumab treatment is associated with increased brain metastasis in patients with MBC, but other studies contradict this statement [19–22]. When trastuzumab is considered as a standard treatment in the metastatic first step, it is not possible, ethically, to search whether or not trastuzumab increases brain
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metastasis frequency prospectively in HER-2 positive MBC patients. Therefore, it is essential to strengthen the study with a wide range of series carried out retrospectively in this field. Previously, the lack of persistence for CNS control was not a problem for most patients because BM occurred late in the course of illness, and progression of systemic disease was the dominant cause of mortality [22– 24]. However, as systemic treatments improve, the control of CNS disease seems to be increasingly important for overall disease management [22]. The first aim of this study was to determine whether trastuzumab was a risk factor for the development of BM in HER2-positive MBC patients. The second goal of the study was to analyze the efficacy of systemic treatment in patients with breast cancer and BM.
Materials and methods We conducted a retrospective analysis of medical records from patients with metastatic or recurrent HER2-positive breast cancer who received palliative chemotherapy at Dicle University Medical Oncology Department between 1995 and 2011. Patients with BM at the time of diagnosis were excluded from the study. Paraffin tumor tissue blocks (from the primary breast cancer) obtained from the hospital archive were reevaluated for HER2positivity by Ugur Firat (pathologist). The HER2 status was evaluated using the polyclonal rabbit anti-human c-erbB-2 oncoprotein, code-number: A 0485 antibody (DAKO, Glostrup, Denmark) and fluorescence in situ hybridization (FISH). Immunohistochemical scoring by a pathologist was based on a 0–3? intensity point scale. Tumors with HER2 scores of 0 or 1? were considered as negative and those of 3? were considered as positive. For the borderline positive (2?) staining, HER2 amplification was confirmed by FISH. This assessment was performed according to the ASCO/CAP guideline [25]. Most of the patients received trastuzumab between 2003 and 2010 after it was approved for the treatment of MBC. We classified the patients in this period as the ‘‘treatment group’’. Other patients who did not receive trastuzumab because it was unavailable before 2003 in our country were classified as the ‘‘control group’’. Brain imaging was performed in patients with symptoms suggestive of brain metastasis, not at diagnosis and not regularly after diagnosis. The patients’ age, sex, menopausal status, histological subgroup, stage at diagnosis, estrogen receptor (ER) status, progesterone receptor (PR) status, metastatic sites, and absence of BM were evaluated from patients’ charts. The study was approved by an institutional Ethics Committee.
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Time to death (TTD) from BM was defined from the date of BM to death or the last follow-up day. Extracranial disease control was defined by systemic disease status, except for BM, with complete response, partial response (PR), or stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors criteria at the time of BM [26]. Survival rates were estimated by the Kaplan–Meier product-limit method. The log-rank test was used to compare survival rates. The differences in characteristics between the treatment and control groups were estimated by the Chi-square test. A binary logistic regression analysis was used for the multivariate analysis of each potential prognostic variable for development. A Cox proportional hazard regression model was used to assess the effect of each potential prognostic variable on TTD. All potential prognostic variables were included in the model, and variables were removed from this model one at a time in a backward selection process using the likelihood ratio and a significance level of 0.05. Statistical analyses were carried out by using the statistical packages for SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
Results After exclusion of 7 patients with BM at the time of diagnosis, 132 HER2-positive MBC patients were included in the study. There were no patients with leptomeningeal disease in the entire group. Among these patients, 90 patients were treated with trastuzumab (treatment group) and 42 patients were not treated with trastuzumab (control group). Other anti-HER2 therapies except trastuzumab were not used before the diagnosis of brain metastasis. Patient characteristics are summarized in Table 1. The median age was 43 years (22–76) in the entire group, 42.5 years (22–76) in the treatment group, and 44.5 (30–75) years in the control group (p = 0.008). The ER and/or PR positivity was 51.9 % (n = 41) in the treatment group and 77.1 % (n = 27) in the control group (p = 0.011). There was no statistical difference between the two groups in terms of menopausal status, stage at time of diagnosis, grade, prior palliative chemotherapy, histological subgroups, or metastatic sites (except for the brain). Median overall survival after first metastasis was 28.7 [95 % confidence interval (CI) 18.2–31.8] and 25 (95 % CI 23.3–34.2) months in the treatment and control group, respectively (p = 0.871). The median follow-up time was 28 months (5–180 months). There was no statistically difference between BM positive and negative groups (median 28 vs 27 months, p = 0.448) or between treatment and control groups (median 28 vs 25.5 months, p = 0.282) in terms of
Breast Cancer Table 1 Patient characteristics of 132 HER2-positive metastatic breast cancer patients
Patient characteristics
Treatment group (n = 90)
Control group (n = 42)
No
No
%
p value (v2 test)
%
Median age (years)
42.5 (22–76)
44.5 (30–75)
0.008
Median follow up times (months)
28 (5–128)
25.5 (5–180)
0.282 0.520
Menopausal status Postmenopausal
24
27.0
13
32.5
Premenopausal
65
73.0
27
67.5
76 14
84.4 15.6
32 10
76.2 23.8
0.252
ER or PR positivity (n = 114)
41
51.9
27
77.1
0.011
Histological grade high (n = 83)
29
50.0
10
40.0
0.290
Stage I
0
0
1
2.4
0.086
Stage II
14
15.9
11
26.8
Stage III
50
56.8
15
36.6
Stage IV
24
27.3
14
34.1
1 line
46
51.1
24
57.1
C2 line
44
48.9
18
42.9
Histology Ductal Others
Stage at the diagnosis (n = 129)
Prior palliative chemotherapy 0.518
Development of BM
39
43.3
11
26.2
0.059
Presence of extracranial metastasis
77
86.5
37
90.2
0.548
follow up times. There was also no statistical difference between treatment and control groups in terms of number of patients lost to follow up (6.7 % in the treatment group, 9.5 % in the control group, p = 0.563). Brain metastases were observed in 50 of the 132 patients (37.9 %). All 50 patients were treated with steroids and whole brain irradiation, 3 Gy 9 5 per week, with a total dose of 30 Gy. The BM frequency was 43.3 % (n = 39) in the treatment group and 26.2 % (n = 11) in the control group (p = 0.059) with BM being more frequent in patients who were treated with trastuzumab in two or more lines than in patients who were treated in one line or in those not treated with trastuzumab (58.5 vs 24.1 %, p \ 0.001). The disease control rate of systemic extra-cranial lesions (SD ? PR ? CR) at the time of BM was higher in the BM-negative patients than in the BM-positive patients (88.3 vs 69.8 %, p = 0.019). Ninety percent of the patients with brain metastases had two or more extracranial metastases (n = 45), and it was 47.6 % (n = 39) in patients who did not have brain metastases (Table 2, p \ 0.001). The presence of liver metastasis was higher in the BM positive group than in the BM negative group (n = 21, 42 % vs n = 20, 24.4 %, p = 0.034). There was no statistical difference according to age (median 42.5 vs 44, p = 0.169), menopausal status (postmenopausal patients 24 vs 31.6 %, p = 0.350), ER/ PR positivity (54 vs 63.4 %, p = 0.284), stage at the
diagnosis (stage 3–4 at the diagnosis 81.3 vs 79 %, p = 0.759), disease free interval (\24 months 82 vs 79.3 %, p = 0.702), or histological subtypes (ductal histology 78 vs 84.1 %, p = 0.374) between groups with or without brain metastases (Table 2). Trastuzumab was used in 20 of the 50 patients with BM (40 %). Lapatinib was also administered in 12 patients for salvage treatment after BM (24 %). The median duration of trastuzumab treatment was 24 weeks (range 11–54 weeks), and the median duration of lapatinib was 20 weeks (range 10–48 weeks). The median time to brain metastasis was 13.7 months. It was 14.2 and 12.1 months in the treatment and control group, respectively (p = 0.574). The factors affecting brain metastasis were investigated by multivariate analysis. Patients treated with trastuzumab in two or more lines (p = 0.003, OR = 3.43, 95 % CI 1.52–7.75) and those with a presence of two or more extracranial metastatic sites (p \ 0.001, OR = 8.30, 95 % CI 2.62–26.2) were associated with an increased risk of brain metastasis. Age (p = 0.802, OR = 1.01, 95 % CI 0.95–1.08), menopausal status (p = 0.344, OR = 0.63, 95 % CI 0.24–1.64), stage at time of diagnosis (p = 0.971, OR = 0.98, 95 % CI 0.33–2.95), control of systemic disease (p = 0.306, OR = 0.64, 95 % CI 0.28–1.49), histologic subtype (p = 0.208, OR = 1.94, 95 % CI 0.69–5.44), ER and/or PR positivity (p = 0.367, OR = 0.66, 95 % CI 0.27–1.62),
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Breast Cancer Table 2 Univariate analysis of potential risk factors for brain metastases
BM positive (n = 50)
BM negative (n = 82)
No
No
%
p value (v2 test)
%
Median age (years)
42.5 (25–70)
44 (22–76)
0.169
Median follow up (months)
28 (5–180)
27 (5–123)
0.448
Menopausal status Postmenopausal
12
24.0
25
31.6
Premenopausal
38
76.0
54
68.4
Histology ˙Invasive ductal
0.350
39
78.0
69
84.1
11
22.0
13
15.9
ER or PR positivity (n = 114)
27
54.0
52
63.4
0.284
Histological grade high (n = 83)
15
55.6
24
42.9
0.540
Stage at the diagnosis (n = 129) Stages 1–2
9
18.8
17
21.0
0.759
39
81.3
64
79.0
CR/PR/SD
30
69.8
53
88.3
PD
13
30.2
7
11.7
31
62.0
22
26.8
\0.001
Two or more
45
90.0
39
47.6
\0.001
One
5
10.0
43
52.4
21
42.0
20
24.4
0.034
\24 monthsa
41
82.0
65
79.3
0.702
C24 months
9
18.0
17
20.7
Other
Stages 3–4
0.374
Systemic disease status (n = 103)
Trastuzumab use (C2 line)
0.019
Other metastatic site
Liver metastasis (present) Disease free interval (months) a
Patients who have metastasis at the time of diagnosis were included in this group
disease free interval (p = 0.530, OR = 0.71, 95 % CI 0.25–2.10) and presence of liver metastasis (p = 0.223, OR = 1.76, 95 % CI 0.71–4.35) were found to have no effect (Table 3). We analyzed the factors that affect overall survival in HER2-positive patients with brain metastases. The median survival duration was 11.4 months in patients who were treated with trastuzumab, and 4.1 months in patients who were not treated with trastuzumab (p = 0.012). The median survival duration was 15.9 months in patients who were treated with lapatinib after brain metastasis and 5.6 months in patients who were not treated with lapatinib (p = 0.010). The median survival time after brain metastasis was 2.5 months in patients C50 years and 7.5 months in patients \50-year-old (p = 0.013). A Cox regression analysis of the factors affecting survival after brain metastasis revealed the positive effects of trastuzumab [hazard ratio (HR) = 0.46, 95 % CI 0.22–0.96, p = 0.038] and lapatinib (HR = 0.33, 95 % CI 0.14–0.80, p = 0.014) usage after brain metastasis was detected. However, in patients who were C50-year-old, the prognosis was poorer after brain metastasis (HR = 3.27, 95 % CI 1.51–7.10,
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p = 0.003) (Table 4). The presence of two or more extracranial metastatic sites, histological subtype, time to BM and ER/PR positivity were not found to be statistically significant regarding overall survival after brain metastasis (Table 4).
Discussion Trastuzumab is a humanized, monoclonal antibody that is used in both metastatic and adjuvant settings to treat HER2-positive breast cancer [27]. In various trials investigating trastuzumab-based therapy in patients with MBC, the incidence of BM ranged from 21 to 48.1 % [14, 19–22, 28–33]. Four of them compared the incidence of BM among patients who had MBC and who were receiving trastuzumab-based therapy with the incidence among patients who were receiving non-trastuzumab-based treatment and reported conflicting results [19–22]. Pinder et al. [21], reported the incidence of BM in patients with MBC who received trastuzumab-based treatment as 41 % at 2 years compared with 20 % in those who did not receive
Breast Cancer Table 3 Multivariate logistic regression analysis of risk factors for brain metastases p value
Trastuzumab use (C2 line)
0.003
Odds ratio (OR)
95 % CI Lower
Upper
3.43
1.52
7.75
Table 4 Multivariate Cox regression analysis on time to death from BM diagnosis p value
Hazard ratio
95 % CI Lower
Upper 0.96
Trastuzumab after BM
0.038
0.46
0.22
Lapatinib after BM
0.014
0.33
0.14
0.80
0.003 0.731
3.27 1.25
1.51 0.35
7.10 4.50
\0.001
8.30
2.62
26.2
Systemic control
0.306
0.64
0.28
1.49
Age (C50) Other metastatic site
Ductal histology
0.208
1.94
0.69
5.44
Histologic subgroups
0.839
1.10
0.42
2.93
ER or PR positivity
0.367
0.66
0.27
1.62
ER or PR positivity
0.540
1.26
0.60
2.62
Age
0.802
1.01
0.95
1.08
0.567
0.81
0.40
1.66
Menopausal status
0.344
0.63
0.24
1.64
Time to BM (\12 vs C12 months)
Stage at the diagnosis
0.971
0.98
0.33
2.95
Liver metastasis
0.223
1.76
0.71
4.35
DFS \24 months
0.530
0.71
0.25
2.10
2 or more metastatic site
DFS Disease free survival
trastuzumab-based treatment. In the trial reported by Lai et al. [19], the incidence of BM in trastuzumab-treated (48.1 %) patients was similar to that in non-trastuzumabtreated patients (46.6 %). However, this study was questioned for bias in patient selection. In another study by Lower et al. [20], the incidence of BM in trastuzumabtreated patients (26 %) was lower than that observed in non-trastuzumab-treated patients (31 %). Finally, in the study by Park et al. [22], the incidence of BM among patients with MBC patients who received trastuzumabbased treatment was 37.8 % compared to 25 % for those who did not receive trastuzumab-based treatment. Although, there is a meta-analysis including adjuvant trastuzumab studies that supports the increased risk of brain metastases in patients with HER-2 positive early breast cancer receiving trastuzumab [34], there is not a single prospective study in metastatic HER-2 positive patients. Regarding the use of trastuzumab in any stage of treatment of HER2-positive breast cancer, this issue, which still has contradictory results, won’t be supported through prospective studies due to ethical drawbacks. Accordingly, wide retrospective series may contribute to the issue. For this reason, we analyzed the effect of trastuzumab on the development of brain metastasis in patients with HER2positive MBC. The rates of brain metastases observed in our study were similar to other studies published in this issue. Our findings also revealed that trastuzumab was associated with increased rate of brain metastasis (43.3 vs 26.2 %) in HER2-positive MBC patients. Furthermore, in patients who were treated with trastuzumab in two or more lines, the frequency of brain metastasis was higher than in patients who were treated in one line or in those not treated with trastuzumab (58.5 vs 24.1 %). Due to the retrospective design of the study, there were differences between the
groups who were treated with trastuzumab-based-therapy and non-trastuzumab-based-therapy according to prognostic factors such as age along with ER and PR statuses. It is well known that younger age and hormone receptor negativity are important risk factors for development of brain metastasis [12]. The fact that hormone receptor positivity and age were both unfavorable in terms of brain metastasis progression for therapy group, may have contributed to the increased brain metastasis in this group. Therefore, a multivariate analysis was performed in order to eliminate the effects of these differences. In the multivariate analysis, trastuzumab usage in two or more lines and the presence of two or more extracranial metastatic sites were significantly associated with increased brain metastasis, while age, menopausal status, stage at time of diagnosis, control of systemic disease, histologic subtype, ER and/or PR positivity, disease free survival time and presence of liver metastasis were not associated with increased brain metastasis. We know that the frequency of brain metastases in metastatic small cell lung cancer is reported to be 40 % in the first year, and prophylactic cranial irradiation has prolonged survival in the patients who have responded well to this treatment [35]. Similarly, prophylactic cranial irradiation may be considered after randomized studies for HER2-positive MBC patients who have been treated with trastuzumab in two or more lines. Another goal of this study was to determine the factors that affect survival after BM in HER2-positive disease. Until recently, the use of chemotherapy to treat BM has been unsatisfactory [12]. However, capecitabine has shown efficacy in the treatment of breast cancer BM [36]. Lapatinib is a small molecule tyrosine kinase inhibitor that binds to the intracellular adenosine triphosphate binding site of both the HER1 and HER2 receptors [12]. The efficacy of lapatinib monotherapy in patients with breast cancer BM has been shown in several studies [37–39]. Retrospective analyses have been performed to evaluate
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the effect of trastuzumab on survival in breast cancer patients with BM. Most of these studies suggest that trastuzumab-based treatment significantly prolonged overall survival after BM [19–22, 24, 40–42]. Furthermore, the efficacy of the use of intrathecal trastuzumab has also been reported in anecdotal reports [43, 44]. In our study, trastuzumab and lapatinib were also shown to prolong survival after brain metastases, which is similar to other findings [37–42]. Besides these two factors, another factor affecting survival was age, which has also been shown in other studies [42]. Survival was shown to be longer in patients younger than 50-year-old. According to these results, we suggest that anti-HER2 treatments should be continued, especially for patients younger than 50-years-old, despite the development of brain metastases. Conflict of interest The authors declare that they have no conflict of interest or funding.
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38. Lin NU, Die´ras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15(4):1452–9. 39. Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011;105(3):613–20 Epub 2011 Jun 26. 40. Church DN, Modgil R, Guglani S, et al. Extended survival in women with brain metastases from HER2-overexpressing breast cancer. Am J Clin Oncol. 2008;31:250–4. 41. Park IH, Ro J, Lee KS, Nam BH, Kwon Y, Shin KH. Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer. Ann Oncol. 2009;20:56–62. 42. Sawrie SM, Meredith RF, Spencer SA, et al. HER2-neu status as a predictor of survival in patients with brain metastases from primary breast adenocarcinoma. J Clin Oncol. 2007;25:36s. 43. Laufman LR, Forsthoefel KF. Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer. 2001;2:235. 44. Platini C, Long J, Walter S. Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol. 2006;7:778–80.
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ORIGINAL ARTICLE
Brain metastases in HER2-positive metastatic breast cancer patients who received chemotherapy with or without trastuzumab Muhammet Ali Kaplan • Hamza Ertugrul • Ugur Firat • Mehmet Kucukoner • Ali I˙nal • Zuhat Urakci • Zafer Pekkolay Abdurrahman Isikdogan
•
Received: 29 July 2013 / Accepted: 18 December 2013 Ó The Japanese Breast Cancer Society 2013
Abstract Objective The aim of this study was to assess whether trastuzumab usage is a risk factor for the development of brain metastasis (BM) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and factors affecting survival after development of BM. Materials and methods One hundred thirty-two patients treated with (treatment group) or without trastuzumab (control group) with brain metastasis were retrospectively analyzed. Results Ninety of the 132 HER2-positive MBC patients were in the treatment group and 42 were in the control group. BM was significantly increased in patients who were treated with trastuzumab in two or more lines (58.5 vs 24.1 %, p \ 0.001). Trastuzumab and lapatinib usage after BM and age were independent prognostic factors for overall survival in univariate and multivariate analysis. Conclusion The risk for BM was increased in patients who were treated with trastuzumab in two or more lines. Using trastuzumab and lapatinib after BM and age were independent prognostic factors for time to death from BM.
M. A. Kaplan (&) M. Kucukoner A. I˙nal Z. Urakci A. Isikdogan Department of Medical Oncology, Dicle University School of Medicine, Diyarbakir, Turkey e-mail: [email protected] H. Ertugrul Z. Pekkolay Department of Internal Medicine, Dicle University School of Medicine, 21280 Diyarbakir, Turkey U. Firat Department of Pathology, Dicle University School of Medicine, Diyarbakir, Turkey
Keywords Breast cancer Brain metastasis Trastuzumab
Introduction Breast cancer is one of the most common tumors in adults [1]. Approximately 20–25 % of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive [2]. Over-expression of HER2 in primary breast cancer has been associated with decreased patient survival [2]. Trastuzumab is a humanized monoclonal antibody directed against the HER2 oncoprotein. This protein is encoded by the HER2 gene and has been characterized as a transmembrane growth factor receptor belonging to the epidermal growth factor receptor family [3]. The combination of trastuzumab and chemotherapy has yielded an overall response rate of up to 71 % in patients with metastatic breast cancer (MBC) [3–5]. However, it is a large protein that does not cross the blood–brain barrier [6]. The incidence of clinically evident BM among women with MBC is estimated to be between 10 and 16 % [7–10]. The incidence of BM at autopsy ranges from 18 to 30 % [10, 11]. Younger age, ethnicity, presence of visceral metastases, tumor size, hormone receptor-negative disease, and HER2 over-expression are associated with an increased risk of developing central nervous system (CNS) metastases [12]. The incidence of BM in patients with HER2positive breast cancer range from 30 to 53 % [13–18]. Several studies have reported that trastuzumab treatment is associated with increased brain metastasis in patients with MBC, but other studies contradict this statement [19–22]. When trastuzumab is considered as a standard treatment in the metastatic first step, it is not possible, ethically, to search whether or not trastuzumab increases brain
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metastasis frequency prospectively in HER-2 positive MBC patients. Therefore, it is essential to strengthen the study with a wide range of series carried out retrospectively in this field. Previously, the lack of persistence for CNS control was not a problem for most patients because BM occurred late in the course of illness, and progression of systemic disease was the dominant cause of mortality [22– 24]. However, as systemic treatments improve, the control of CNS disease seems to be increasingly important for overall disease management [22]. The first aim of this study was to determine whether trastuzumab was a risk factor for the development of BM in HER2-positive MBC patients. The second goal of the study was to analyze the efficacy of systemic treatment in patients with breast cancer and BM.
Materials and methods We conducted a retrospective analysis of medical records from patients with metastatic or recurrent HER2-positive breast cancer who received palliative chemotherapy at Dicle University Medical Oncology Department between 1995 and 2011. Patients with BM at the time of diagnosis were excluded from the study. Paraffin tumor tissue blocks (from the primary breast cancer) obtained from the hospital archive were reevaluated for HER2positivity by Ugur Firat (pathologist). The HER2 status was evaluated using the polyclonal rabbit anti-human c-erbB-2 oncoprotein, code-number: A 0485 antibody (DAKO, Glostrup, Denmark) and fluorescence in situ hybridization (FISH). Immunohistochemical scoring by a pathologist was based on a 0–3? intensity point scale. Tumors with HER2 scores of 0 or 1? were considered as negative and those of 3? were considered as positive. For the borderline positive (2?) staining, HER2 amplification was confirmed by FISH. This assessment was performed according to the ASCO/CAP guideline [25]. Most of the patients received trastuzumab between 2003 and 2010 after it was approved for the treatment of MBC. We classified the patients in this period as the ‘‘treatment group’’. Other patients who did not receive trastuzumab because it was unavailable before 2003 in our country were classified as the ‘‘control group’’. Brain imaging was performed in patients with symptoms suggestive of brain metastasis, not at diagnosis and not regularly after diagnosis. The patients’ age, sex, menopausal status, histological subgroup, stage at diagnosis, estrogen receptor (ER) status, progesterone receptor (PR) status, metastatic sites, and absence of BM were evaluated from patients’ charts. The study was approved by an institutional Ethics Committee.
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Time to death (TTD) from BM was defined from the date of BM to death or the last follow-up day. Extracranial disease control was defined by systemic disease status, except for BM, with complete response, partial response (PR), or stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors criteria at the time of BM [26]. Survival rates were estimated by the Kaplan–Meier product-limit method. The log-rank test was used to compare survival rates. The differences in characteristics between the treatment and control groups were estimated by the Chi-square test. A binary logistic regression analysis was used for the multivariate analysis of each potential prognostic variable for development. A Cox proportional hazard regression model was used to assess the effect of each potential prognostic variable on TTD. All potential prognostic variables were included in the model, and variables were removed from this model one at a time in a backward selection process using the likelihood ratio and a significance level of 0.05. Statistical analyses were carried out by using the statistical packages for SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
Results After exclusion of 7 patients with BM at the time of diagnosis, 132 HER2-positive MBC patients were included in the study. There were no patients with leptomeningeal disease in the entire group. Among these patients, 90 patients were treated with trastuzumab (treatment group) and 42 patients were not treated with trastuzumab (control group). Other anti-HER2 therapies except trastuzumab were not used before the diagnosis of brain metastasis. Patient characteristics are summarized in Table 1. The median age was 43 years (22–76) in the entire group, 42.5 years (22–76) in the treatment group, and 44.5 (30–75) years in the control group (p = 0.008). The ER and/or PR positivity was 51.9 % (n = 41) in the treatment group and 77.1 % (n = 27) in the control group (p = 0.011). There was no statistical difference between the two groups in terms of menopausal status, stage at time of diagnosis, grade, prior palliative chemotherapy, histological subgroups, or metastatic sites (except for the brain). Median overall survival after first metastasis was 28.7 [95 % confidence interval (CI) 18.2–31.8] and 25 (95 % CI 23.3–34.2) months in the treatment and control group, respectively (p = 0.871). The median follow-up time was 28 months (5–180 months). There was no statistically difference between BM positive and negative groups (median 28 vs 27 months, p = 0.448) or between treatment and control groups (median 28 vs 25.5 months, p = 0.282) in terms of
Breast Cancer Table 1 Patient characteristics of 132 HER2-positive metastatic breast cancer patients
Patient characteristics
Treatment group (n = 90)
Control group (n = 42)
No
No
%
p value (v2 test)
%
Median age (years)
42.5 (22–76)
44.5 (30–75)
0.008
Median follow up times (months)
28 (5–128)
25.5 (5–180)
0.282 0.520
Menopausal status Postmenopausal
24
27.0
13
32.5
Premenopausal
65
73.0
27
67.5
76 14
84.4 15.6
32 10
76.2 23.8
0.252
ER or PR positivity (n = 114)
41
51.9
27
77.1
0.011
Histological grade high (n = 83)
29
50.0
10
40.0
0.290
Stage I
0
0
1
2.4
0.086
Stage II
14
15.9
11
26.8
Stage III
50
56.8
15
36.6
Stage IV
24
27.3
14
34.1
1 line
46
51.1
24
57.1
C2 line
44
48.9
18
42.9
Histology Ductal Others
Stage at the diagnosis (n = 129)
Prior palliative chemotherapy 0.518
Development of BM
39
43.3
11
26.2
0.059
Presence of extracranial metastasis
77
86.5
37
90.2
0.548
follow up times. There was also no statistical difference between treatment and control groups in terms of number of patients lost to follow up (6.7 % in the treatment group, 9.5 % in the control group, p = 0.563). Brain metastases were observed in 50 of the 132 patients (37.9 %). All 50 patients were treated with steroids and whole brain irradiation, 3 Gy 9 5 per week, with a total dose of 30 Gy. The BM frequency was 43.3 % (n = 39) in the treatment group and 26.2 % (n = 11) in the control group (p = 0.059) with BM being more frequent in patients who were treated with trastuzumab in two or more lines than in patients who were treated in one line or in those not treated with trastuzumab (58.5 vs 24.1 %, p \ 0.001). The disease control rate of systemic extra-cranial lesions (SD ? PR ? CR) at the time of BM was higher in the BM-negative patients than in the BM-positive patients (88.3 vs 69.8 %, p = 0.019). Ninety percent of the patients with brain metastases had two or more extracranial metastases (n = 45), and it was 47.6 % (n = 39) in patients who did not have brain metastases (Table 2, p \ 0.001). The presence of liver metastasis was higher in the BM positive group than in the BM negative group (n = 21, 42 % vs n = 20, 24.4 %, p = 0.034). There was no statistical difference according to age (median 42.5 vs 44, p = 0.169), menopausal status (postmenopausal patients 24 vs 31.6 %, p = 0.350), ER/ PR positivity (54 vs 63.4 %, p = 0.284), stage at the
diagnosis (stage 3–4 at the diagnosis 81.3 vs 79 %, p = 0.759), disease free interval (\24 months 82 vs 79.3 %, p = 0.702), or histological subtypes (ductal histology 78 vs 84.1 %, p = 0.374) between groups with or without brain metastases (Table 2). Trastuzumab was used in 20 of the 50 patients with BM (40 %). Lapatinib was also administered in 12 patients for salvage treatment after BM (24 %). The median duration of trastuzumab treatment was 24 weeks (range 11–54 weeks), and the median duration of lapatinib was 20 weeks (range 10–48 weeks). The median time to brain metastasis was 13.7 months. It was 14.2 and 12.1 months in the treatment and control group, respectively (p = 0.574). The factors affecting brain metastasis were investigated by multivariate analysis. Patients treated with trastuzumab in two or more lines (p = 0.003, OR = 3.43, 95 % CI 1.52–7.75) and those with a presence of two or more extracranial metastatic sites (p \ 0.001, OR = 8.30, 95 % CI 2.62–26.2) were associated with an increased risk of brain metastasis. Age (p = 0.802, OR = 1.01, 95 % CI 0.95–1.08), menopausal status (p = 0.344, OR = 0.63, 95 % CI 0.24–1.64), stage at time of diagnosis (p = 0.971, OR = 0.98, 95 % CI 0.33–2.95), control of systemic disease (p = 0.306, OR = 0.64, 95 % CI 0.28–1.49), histologic subtype (p = 0.208, OR = 1.94, 95 % CI 0.69–5.44), ER and/or PR positivity (p = 0.367, OR = 0.66, 95 % CI 0.27–1.62),
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Breast Cancer Table 2 Univariate analysis of potential risk factors for brain metastases
BM positive (n = 50)
BM negative (n = 82)
No
No
%
p value (v2 test)
%
Median age (years)
42.5 (25–70)
44 (22–76)
0.169
Median follow up (months)
28 (5–180)
27 (5–123)
0.448
Menopausal status Postmenopausal
12
24.0
25
31.6
Premenopausal
38
76.0
54
68.4
Histology ˙Invasive ductal
0.350
39
78.0
69
84.1
11
22.0
13
15.9
ER or PR positivity (n = 114)
27
54.0
52
63.4
0.284
Histological grade high (n = 83)
15
55.6
24
42.9
0.540
Stage at the diagnosis (n = 129) Stages 1–2
9
18.8
17
21.0
0.759
39
81.3
64
79.0
CR/PR/SD
30
69.8
53
88.3
PD
13
30.2
7
11.7
31
62.0
22
26.8
\0.001
Two or more
45
90.0
39
47.6
\0.001
One
5
10.0
43
52.4
21
42.0
20
24.4
0.034
\24 monthsa
41
82.0
65
79.3
0.702
C24 months
9
18.0
17
20.7
Other
Stages 3–4
0.374
Systemic disease status (n = 103)
Trastuzumab use (C2 line)
0.019
Other metastatic site
Liver metastasis (present) Disease free interval (months) a
Patients who have metastasis at the time of diagnosis were included in this group
disease free interval (p = 0.530, OR = 0.71, 95 % CI 0.25–2.10) and presence of liver metastasis (p = 0.223, OR = 1.76, 95 % CI 0.71–4.35) were found to have no effect (Table 3). We analyzed the factors that affect overall survival in HER2-positive patients with brain metastases. The median survival duration was 11.4 months in patients who were treated with trastuzumab, and 4.1 months in patients who were not treated with trastuzumab (p = 0.012). The median survival duration was 15.9 months in patients who were treated with lapatinib after brain metastasis and 5.6 months in patients who were not treated with lapatinib (p = 0.010). The median survival time after brain metastasis was 2.5 months in patients C50 years and 7.5 months in patients \50-year-old (p = 0.013). A Cox regression analysis of the factors affecting survival after brain metastasis revealed the positive effects of trastuzumab [hazard ratio (HR) = 0.46, 95 % CI 0.22–0.96, p = 0.038] and lapatinib (HR = 0.33, 95 % CI 0.14–0.80, p = 0.014) usage after brain metastasis was detected. However, in patients who were C50-year-old, the prognosis was poorer after brain metastasis (HR = 3.27, 95 % CI 1.51–7.10,
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p = 0.003) (Table 4). The presence of two or more extracranial metastatic sites, histological subtype, time to BM and ER/PR positivity were not found to be statistically significant regarding overall survival after brain metastasis (Table 4).
Discussion Trastuzumab is a humanized, monoclonal antibody that is used in both metastatic and adjuvant settings to treat HER2-positive breast cancer [27]. In various trials investigating trastuzumab-based therapy in patients with MBC, the incidence of BM ranged from 21 to 48.1 % [14, 19–22, 28–33]. Four of them compared the incidence of BM among patients who had MBC and who were receiving trastuzumab-based therapy with the incidence among patients who were receiving non-trastuzumab-based treatment and reported conflicting results [19–22]. Pinder et al. [21], reported the incidence of BM in patients with MBC who received trastuzumab-based treatment as 41 % at 2 years compared with 20 % in those who did not receive
Breast Cancer Table 3 Multivariate logistic regression analysis of risk factors for brain metastases p value
Trastuzumab use (C2 line)
0.003
Odds ratio (OR)
95 % CI Lower
Upper
3.43
1.52
7.75
Table 4 Multivariate Cox regression analysis on time to death from BM diagnosis p value
Hazard ratio
95 % CI Lower
Upper 0.96
Trastuzumab after BM
0.038
0.46
0.22
Lapatinib after BM
0.014
0.33
0.14
0.80
0.003 0.731
3.27 1.25
1.51 0.35
7.10 4.50
\0.001
8.30
2.62
26.2
Systemic control
0.306
0.64
0.28
1.49
Age (C50) Other metastatic site
Ductal histology
0.208
1.94
0.69
5.44
Histologic subgroups
0.839
1.10
0.42
2.93
ER or PR positivity
0.367
0.66
0.27
1.62
ER or PR positivity
0.540
1.26
0.60
2.62
Age
0.802
1.01
0.95
1.08
0.567
0.81
0.40
1.66
Menopausal status
0.344
0.63
0.24
1.64
Time to BM (\12 vs C12 months)
Stage at the diagnosis
0.971
0.98
0.33
2.95
Liver metastasis
0.223
1.76
0.71
4.35
DFS \24 months
0.530
0.71
0.25
2.10
2 or more metastatic site
DFS Disease free survival
trastuzumab-based treatment. In the trial reported by Lai et al. [19], the incidence of BM in trastuzumab-treated (48.1 %) patients was similar to that in non-trastuzumabtreated patients (46.6 %). However, this study was questioned for bias in patient selection. In another study by Lower et al. [20], the incidence of BM in trastuzumabtreated patients (26 %) was lower than that observed in non-trastuzumab-treated patients (31 %). Finally, in the study by Park et al. [22], the incidence of BM among patients with MBC patients who received trastuzumabbased treatment was 37.8 % compared to 25 % for those who did not receive trastuzumab-based treatment. Although, there is a meta-analysis including adjuvant trastuzumab studies that supports the increased risk of brain metastases in patients with HER-2 positive early breast cancer receiving trastuzumab [34], there is not a single prospective study in metastatic HER-2 positive patients. Regarding the use of trastuzumab in any stage of treatment of HER2-positive breast cancer, this issue, which still has contradictory results, won’t be supported through prospective studies due to ethical drawbacks. Accordingly, wide retrospective series may contribute to the issue. For this reason, we analyzed the effect of trastuzumab on the development of brain metastasis in patients with HER2positive MBC. The rates of brain metastases observed in our study were similar to other studies published in this issue. Our findings also revealed that trastuzumab was associated with increased rate of brain metastasis (43.3 vs 26.2 %) in HER2-positive MBC patients. Furthermore, in patients who were treated with trastuzumab in two or more lines, the frequency of brain metastasis was higher than in patients who were treated in one line or in those not treated with trastuzumab (58.5 vs 24.1 %). Due to the retrospective design of the study, there were differences between the
groups who were treated with trastuzumab-based-therapy and non-trastuzumab-based-therapy according to prognostic factors such as age along with ER and PR statuses. It is well known that younger age and hormone receptor negativity are important risk factors for development of brain metastasis [12]. The fact that hormone receptor positivity and age were both unfavorable in terms of brain metastasis progression for therapy group, may have contributed to the increased brain metastasis in this group. Therefore, a multivariate analysis was performed in order to eliminate the effects of these differences. In the multivariate analysis, trastuzumab usage in two or more lines and the presence of two or more extracranial metastatic sites were significantly associated with increased brain metastasis, while age, menopausal status, stage at time of diagnosis, control of systemic disease, histologic subtype, ER and/or PR positivity, disease free survival time and presence of liver metastasis were not associated with increased brain metastasis. We know that the frequency of brain metastases in metastatic small cell lung cancer is reported to be 40 % in the first year, and prophylactic cranial irradiation has prolonged survival in the patients who have responded well to this treatment [35]. Similarly, prophylactic cranial irradiation may be considered after randomized studies for HER2-positive MBC patients who have been treated with trastuzumab in two or more lines. Another goal of this study was to determine the factors that affect survival after BM in HER2-positive disease. Until recently, the use of chemotherapy to treat BM has been unsatisfactory [12]. However, capecitabine has shown efficacy in the treatment of breast cancer BM [36]. Lapatinib is a small molecule tyrosine kinase inhibitor that binds to the intracellular adenosine triphosphate binding site of both the HER1 and HER2 receptors [12]. The efficacy of lapatinib monotherapy in patients with breast cancer BM has been shown in several studies [37–39]. Retrospective analyses have been performed to evaluate
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Breast Cancer
the effect of trastuzumab on survival in breast cancer patients with BM. Most of these studies suggest that trastuzumab-based treatment significantly prolonged overall survival after BM [19–22, 24, 40–42]. Furthermore, the efficacy of the use of intrathecal trastuzumab has also been reported in anecdotal reports [43, 44]. In our study, trastuzumab and lapatinib were also shown to prolong survival after brain metastases, which is similar to other findings [37–42]. Besides these two factors, another factor affecting survival was age, which has also been shown in other studies [42]. Survival was shown to be longer in patients younger than 50-year-old. According to these results, we suggest that anti-HER2 treatments should be continued, especially for patients younger than 50-years-old, despite the development of brain metastases. Conflict of interest The authors declare that they have no conflict of interest or funding.
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