Annals of Oncology Advance Access originally published online on March 11, 2008
Annals of Oncology 2008 19(7):1242-1248; doi:10.1093/annonc/mdn036
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breast cancer |
Defining prognosis for women with breast cancer and CNS metastases by HER2 status
1 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Medical Oncology, Dubai Hospital, UAE
3 Department of Quantitative Sciences
4 Department of Pathology
5 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
* Correspondence to: Dr S. Dawood, Department of Medical Oncology, Dubai Hospital, UAE. Tel: 832-677-3432; Fax: 8572770918; E-mail: shaheenah_d{at}yahoo.com
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Abstract |
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Background: The purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.
Methods: Five hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.
Results: In the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.
Conclusion: In our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.
Key words: brain metastases, breast cancer, HER2, trastuzumab
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introduction |
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Approximately 100 000–170 000 patients per year, in the USA, are diagnosed with metastases to the central nervous system (CNS), including both parenchymal and leptomeningeal metastases [1, 2], with the bulk of cases arising from patients with primary lung and breast carcinomas. Studies have reported that
10%–15% of patients with breast cancer will develop CNS metastases [3], although autopsy data indicate that this rate may be as high as 30% [4]. CNS metastases generally tend to occur late in the course of metastatic breast cancer and are associated with 1- and 2-year survival rates of only 20% and <2%, respectively [3, 5], with most patients dying of systemic disease progression [6]. With the introduction of more efficacious chemotherapeutic and targeted agents for metastatic breast cancer, control of systemic disease has improved leading to concerns that the incidence of CNS metastasis may increase [7]. This phenomenon may be particularly true for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Amplification of HER2, which occurs in 25%–30% of human breast cancers, is known to be associated with reduced disease-free and overall survival [8] compared with patients with HER2-negative disease. With the introduction of trastuzumab (Genentech, San Francisco, CA), a mAb directed against the HER2 receptor, both progression-free and overall survival have improved [9] essentially changing the natural history of HER2-positive metastatic breast cancer. Several studies evaluating patients with metastatic HER2-positive breast cancer receiving front-line trastuzumab-based therapeutic regimens have reported high incidences of CNS metastases ranging from 28% to 43% [10–13], much higher than those reported historically.
The purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and CNS metastasis, the effect of trastuzumab in patients with HER2-positive disease and to compare this with that of patients with HER2-negative disease.
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patient and methods |
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patient population
After obtaining institutional review board approval for this retrospective study, we searched our prospectively collected database, maintained in the Breast Medical Oncology Department of the University of Texas MD Anderson Cancer Center, to identify patients with histologically confirmed invasive breast cancer who had developed CNS metastases and had known HER2 status. Medical charts for all patients were reviewed to confirm accuracy of variables recorded within the database. Excluded from the analysis were patients who were male and patients who had more than one primary or bilateral disease or had unknown HER2 status. CNS metastasis was defined as the presence of either leptomeningeal disease and/or metastases in the brain parenchyma. Variables recorded included patient demographics, tumor characteristics, sites of first metastases, number of brain metastases, presence of leptomeningeal disease, first-line treatment of CNS metastases and whether patients were treated with trastuzumab. First site of metastases was categorized as visceral only, bone only, other sites only and multiple sites. Patients whose first site of metastases was the CNS were classified under visceral-only metastases. Patients with more than three lesions in the brain were considered to have multiple brain metastases.
division of groups by HER2 and trastuzumab treatment
Patients were considered to have HER2-positive disease if the primary or metastatic lesion had strong overexpression (3+) on immunohistochemistry (IHC) or had gene amplification by FISH technique. Patients were considered to have HER2-negative disease if they either had negative expression by IHC or did not have gene amplification by FISH. Due to the wide variability of timing of trastuzumab treatment relative to the date of first metastases and the date of brain metastases, we considered patients who received trastuzumab within 6 weeks of a metastases diagnosis as receiving trastuzumab as first-line treatment of that diagnosis. Accordingly, we classified patients with HER2-positive disease into five groups: patients who had (i) never received trastuzumab, (ii) received trastuzumab as first-line treatment of any first site of metastases, (iii) received trastuzumab after first-line treatment of first site of metastatic disease, but before diagnosis of CNS metastases, (iv) received trastuzumab as first-line treatment at diagnosis of CNS metastases and (v) received trastuzumab after diagnosis of CNS metastases.
outcome measures and statistical analysis
Patient characteristics were tabulated by HER2 status and compared between groups with the chi-square test and Wilcoxon's rank sum test as appropriate. Time to CNS metastases was defined as the time from the date of first metastases (either locoregional or distant recurrence) to the date of diagnosis of CNS metastases. Overall survival after CNS metastases was defined as the time from diagnosis of CNS metastases to the date of death from any cause or last follow-up. Median follow-up was calculated as the median observation time, from the date of diagnosis of CNS metastases, for all patients and for patients still alive at their last follow-up. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier product limit method and compared between groups with the log-rank statistic.
For the analyses of time to CNS metastases, our primary comparisons were between HER2-negative patients, HER2-positive patients who did not receive trastuzumab before the diagnosis of brain metastasis (groups i, iv and v) and HER2-positive patients who received trastuzumab as first-line treatment of their first site of metastases (group ii). For overall survival after brain metastases, our primary comparisons were between the HER2-negative patients, HER2-positive patients who did not receive any trastuzumab (group i) and patients who received trastuzumab before or at the time of diagnosis of CNS metastases (groups ii–iv).
We also considered the association of other patient characteristics with each outcome and fit Cox proportional hazards models to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics. Analyses were carried out with S-plus 7.0 (Insightful Corp., Seattle, WA). P values <0.05 were considered statistically significant.
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results |
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patient and tumor characteristics
From 1994 to 2006, 598 women with breast cancer diagnosed with CNS metastases were identified, fit eligibility criteria and were included in the analyses. Patient characteristics tabulated by HER2 status are summarized in Table 1. Three hundred and eighteen (53%) patients had HER2-negative disease and 280 (47%) had HER2-positive disease. Patients with HER2-positive breast cancer tended to have higher initial disease stage and multiple sites of first metastases more frequently than patients with HER2-negative disease. Median age at diagnosis of the entire cohort was 45 years (21–79 years). Five hundred and forty-six (91%) patients developed parenchymal brain metastases, 13 (2%) patients developed leptomeningeal disease and 39 (7%) patients had both brain and leptomeningeal disease with no differences observed in frequencies between HER2-positive and -negative groups. CNS was the first site of metastases for 146 (24%) patients of whom 84 patients had HER2-negative disease and 62 patients had HER2-positive disease. Two hundred and seventy-two (45%) patients had three lesions or less in the brain and 326 (55%) patients had multiple metastases with no difference in frequency observed between HER2-positive and -negative groups. Of the 280 patients with HER2-positive disease, 20 received trastuzumab as part of early breast cancer treatment and were excluded from the main analyses of time to brain metastases. Of the remaining 260 patients who had HER2-positive disease, 32 patients (group i) did not receive trastuzumab, 100 patients (group ii) received trastuzumab treatment as first-line treatment of metastases, 92 patients (group iii) received trastuzumab after first-line treatment of metastases but before CNS metastases diagnoses, 22 patients (group iv) received trastuzumab at the time of CNS metastases diagnoses (including 12 patients who had CNS metastases as the first site of metastases and were included in group ii) and 26 patients (group v) received trastuzumab after a CNS metastases diagnoses.
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time to CNS metastases
Median time to CNS metastases for the whole cohort was 11.3 months (range 0–153.7 months). Median time to CNS metastases for HER2-negative patients, HER2-positive patients who did not receive trastuzumab before the diagnosis of CNS metastases (groups i, iv and v) and HER2-positive patients who received trastuzumab for first-line treatment of first site of metastases (group ii) was 8.9, 2.1 and 13.1 months, respectively (Figure 1). Time to CNS metastases was significantly different between the two HER2-positive groups (P = 0.0008), between HER2-negative patients and HER2-positive patients who did not receive trastuzumab before the diagnosis of CNS metastases (P = 0.0004) but not between HER2-positive patients who received first-line trastuzumab and HER2-negative patients (P = 0.97). Other characteristics significantly associated with decreased time to CNS metastases included higher stage of primary tumor, hormone receptor (estrogen receptor/progesterone) -negative status, higher nuclear grade, <10 lymph nodes removed at surgery and visceral and multiple sites as the first site of metastases. In a multivariable model (Table 2) that included terms for age at diagnosis of metastases, nuclear grade, hormone receptor status, initial stage and site of first metastases, patients who had HER2-negative breast cancer [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003) and those who had HER2-positive disease (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) but did not receive trastuzumab before the diagnosis of CNS metastases had shorter times to CNS metastases compared with patients who had HER2-positive disease and received trastuzumab as first-line therapy for metastases.
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survival from CNS metastases
At the time of the analysis, 486 (81%) patients have died. Median follow-up from the date of diagnosis of CNS metastasis among all patients was 7.4 months (range 0.1–95.9 months) and among all patients still alive at the last follow-up was 12.2 months (range 0.3–91.8 months). Table 3 summarizes the overall survival estimates after the diagnosis of CNS metastases. Median survival for the whole cohort was 8.5 months (95% CI 7.5–9.9). Median survival (Figure 2) was 6.3, 6.1 and 11.6 months for patients with HER2-negative disease, patients with HER2-positive disease who did not receive trastuzumab (group i) and patients with HER2-positive disease who received trastuzumab (groups ii–iv) before or at the time of CNS metastases diagnosis, respectively. On univariate analyses, survival after CNS metastases was significantly different between the two HER2-positive groups (P = 0.03), between HER2-negative patients and HER2-positive patients who received trastuzumab before or at the time of CNS metastases diagnosis (P < 0.001) but not between HER2-positive patients who did not receive trastuzumab and HER2-negative patients (P = 0.95). Other characteristics significantly associated with decreased survival included multiple brain metastases, presence of both brain metastases and leptomeningeal disease and observation as first-line treatment of CNS metastases. In a multivariable model (Table 4), after adjusting for clinical and tumor characteristics, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and those who had HER2-positive disease and had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.
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discussion |
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In our series of patients with breast cancer and CNS metastases, we found that, in addition to clinical and tumor factors, HER2 status and trastuzumab treatment strongly influenced time to development of and survival from diagnosis of CNS metastases. Patients with HER2-positive disease treated with trastuzumab had an increased time to development of and survival from CNS metastases compared with both patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative disease.
A number of studies have examined the association of the development of CNS metastases and HER2 status. In a cohort of 319 patients with known HER2 status, Kallioniemi et al. [14] reported that patients with HER2 overexpression, who had not been treated with trastuzumab, had a significantly increased risk of developing visceral metastases including that to the brain (P = 0.0002). In a larger retrospective study of 9524 women with early-stage breast cancer, who were enrolled on several clinical trials conducted by the International Breast Cancer Study Group and who had not received trastuzumab, Pestalozzi et al. [15] reported a cumulative incidence of CNS metastases as either a first or subsequent event of 6.8% and 3.5% for patients with HER2-positive and -negative disease, respectively (P < 0.01). These studies clearly demonstrate that even in the absence of trastuzumab, women with HER2-positive breast cancer have an increased propensity to develop CNS metastases compared with patients with HER2-negative disease. Results from our study further illustrate that, in the absence of trastuzumab, time to development of CNS metastases is significantly shorter among patients with HER2-positive disease who were not treated with trastuzumab compared with those with HER2-negative disease, which can be explained both by the known aggressive nature and by the increased predilection to CNS metastases of HER2-positive tumors. Interestingly, our results also show that adding trastuzumab to first-line management of HER2-positive metastatic disease increases the time to CNS metastases significantly. As trastuzumab is known not to cross the blood brain barrier [16], one hypothesis to explain these results may be that the level of control of extracranial disease (known to be improved with trastuzumab) is a contributing factor to the timing of development of CNS metastases and may be an important factor to be considered when building predictive models.
CNS metastases in most instances develop late in the natural course of metastatic breast cancer, typically preceded by the involvement of the lungs, liver and bone [3–5, 17] with a resulting median survival ranging from 3 to 6 months [18]. Several retrospective studies have examined the effect of HER2 status on the survival of patients after CNS metastases. In a recent study, Tham et al. [19] described shorter survival times from CNS metastases in patients with HER2-positive disease who had never received trastuzumab compared with patients with HER2-negative disease. In a cohort of 60 patients treated with stereotactic radiosurgery, O'Meara et al. [20] demonstrated superior 1-year survival rates in patients with HER2-positive disease treated with trastuzumab compared with similar patients with HER2-negative disease (78% versus 55%; P = 0.02). Similarly, Kirsch et al. [21], retrospectively studying a cohort of 108 patients with breast cancer and intraparenchymal brain metastases, reported significantly superior median survival in patients with HER2-positive tumors compared with those with HER2-negative tumors (22.4 versus 9.4 months, P = 0.0002). Thus, not surprisingly, our study clearly demonstrated an increased hazard of death in patients with HER2-negative disease and in those with HER2-positive disease not treated with trastuzumab compared with patients with HER2-positive disease who had received trastuzumab either before or at the time of diagnosis of CNS metastases. Interestingly, we also demonstrated similar survival times in patients with HER2-negative disease compared with those with HER2-positive disease who had not received trastuzumab indicating that the course followed by these two groups after the development of CNS metastases may no longer be governed by HER2 status. To evaluate if the timing of trastuzumab administration affected survival, we also demonstrated a significantly superior median survival among patients with HER2-positive disease who had received trastuzumab only at the time of CNS metastases compared with patients with HER2-negative disease (6.3 versus 11.1 months, P = 0.02) (data not shown), indicating the importance of improved control of extracranial disease at any time point during the natural course of metastatic breast cancer.
In summary, to our knowledge this study is the first to report on the effect of trastuzumab in patients with HER2-positive disease and to compare this with that of patients with HER2-negative disease in a large cohort of patients with metastatic breast cancer and CNS metastases. Despite the inherent limitations associated with a retrospective study, the results we generated are important for several reasons. First, it is clear that trastuzumab has changed the natural history of patients with HER2-positive disease improving prognostic outcomes above and beyond that of patients with HER2-negative disease. In addition, most of the improvement seen in the cohort studied is in all likelihood attributed to improved control of extracranial disease. Thus, future studies should focus on prevention and improved treatment of CNS metastases in patients with both HER2-positive and -negative disease.
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The Susan G. Komen Foundation; the Nellie B. Connally Fund for Breast Cancer Research; K23CA121994-01 and ASCO Career Development Award (to A.M.G.-A.).
Received for publication September 9, 2007. Revision received January 22, 2008. Accepted for publication January 24, 2008.
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