Originally published as JCO Early Release 10.1200/JCO.2006.07.0250 on November 13 2006

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Prognostic Significance of Human Epidermal Growth Factor Receptor Positivity for the Development of Brain Metastasis After Newly Diagnosed Breast Cancer

Zsolt Gabos, Richie Sinha, John Hanson, Nitin Chauhan, Judith Hugh, John R. Mackey, Bassam Abdulkarim

From the Department of Oncology, Cross Cancer Institute and University of Alberta; and the Departments of Radiation Oncology, Statistics and Epidemiology, Laboratory Medicine and Pathology, and Medical Oncology, University of Alberta, Edmonton, Alberta, Canada

Address reprint requests to Bassam Abdulkarim, MD, PhD, Department of Oncology & Experimental Oncology, Cross Cancer Institute & University of Alberta, 11560 University Avenue, Edmonton, AB, Canada T6G 1Z2; e-mail: bassamab{at}cancerboard.ab.ca

	ABSTRACT

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PURPOSE: As survival in breast cancer patients is improving, brain metastases are becoming increasingly prevalent. The risk of brain metastases in newly diagnosed human epidermal growth factor receptor 2 (HER-2) –overexpressing breast cancer patients is not yet fully defined. We aimed to analyze the risk of brain metastasis in newly diagnosed HER-2–positive breast cancer patients in comparison with HER-2–negative patients.

PATIENTS AND METHODS: To determine the incidence of brain metastases in HER-2–overexpressing patients, we analyzed a cohort of newly diagnosed 301 HER-2–positive and 363 HER-2–negative patients identified between January 1998 and December 2003. The association between histologic features and the occurrence of brain metastases was evaluated with univariate and multivariate Cox regression analysis.

RESULTS: Median follow-up was 3.9 years. Brain metastases were identified in 9% (27 patients) with HER-2–overexpressing breast cancer compared with only 1.9% (7 patients) in the HER-2 negative patients (hazard ratio 4.23 [1.84-9.74], P = .0007). HER-2 overexpression, tumor size larger than 2 cm, at least one positive node, and grade 2/3 disease were predictors of brain metastases in univariate analysis. In multivariate analysis, HER-2 overexpression, tumor size larger than 2 cm, and hormone-receptor negativity were independent prognostic factors for the development of brain metastases, whereas hormone-receptor expression was protective.

CONCLUSION: Our study shows that newly diagnosed HER-2–overexpressing breast cancer patients are at increased risk for brain metastases. Because most brain metastases occur after the development of systemic disease, these findings prompt consideration of brain prophylaxis strategies with HER-2–inhibiting small molecules able to cross the blood-brain barrier and/or radiologic screening to detect asymptomatic brain metastases.

	INTRODUCTION

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Human epidermal growth factor receptor 2 (HER-2, ErbB-2) overexpression defines an aggressive subtype of breast cancer characterized by rapid cell proliferation, increased angiogenesis, deficient apoptosis, and increased metastasis formation.^1,2 HER-2 amplification or/and overexpression occurs in 25% of invasive breast cancers.^1-3 Activation of HER-2 tyrosine kinase receptor triggers a complex array of signaling pathways that regulates normal cell growth and promotes tumorigenesis via cell proliferation, survival, migration, differentiation, and angiogenesis.^1,4-6

Numerous prognostic factors are established in breast cancer, including tumor size, nodal status, hormone-receptor status, grade, and lymphovascular invasion. HER-2 overexpression is a negative prognostic factor affecting the outcome of breast cancer patients.¹ Population-based studies and retrospective analyses have shown that HER-2 overexpression is an unfavorable prognostic factor that is associated with high-grade tumors, high rate of cell proliferation, and lymph node involvement.⁷ As well, HER-2 overexpression is associated with relative resistance to tamoxifen because the level of steroid receptor in these tumors is lower than in HER-2–negative tumors, and possibly with reduced sensitivity to nonanthracycline chemotherapy.^8-10 All these factors contribute to the greater risk of distant recurrence with a significantly worse overall survival among women with HER-2 overexpression than in those with HER-2–negative breast cancer.¹¹

The brain is a common sanctuary site for metastatic disease in patients with breast cancer, and systemic therapy has limited efficacy in control of intracranial metastases. However, improvements in systemic therapy are substantially prolonging survival in the setting of extracranial metastatic disease. Consequently, brain metastases from breast cancer are becoming increasingly evident, and control of extracranial disease may no longer be the limiting factor determining the outcome in breast cancer patients.¹²

Breast cancer already accounts for the second most common cause of brain metastasis.¹³ Approximately 80% of CNS metastases occur only after other systemic lesions have been diagnosed. In the series of Stefano et al, ¹⁴ the median time to the development of CNS metastases from the diagnosis of breast cancer and from the diagnosis of systemic disease was 34 months and 16 months, respectively. Brain metastases are clinically associated with a significantly detrimental impact on survival.^15,16 Several factors are reported to increase the risk of brain metastasis, including poor performance status, lung metastases, estrogen receptor (ER) –negative tumors, and high burden of metastatic disease.^17,18 Several studies suggest an increased risk of brain metastasis in HER-2–overexpressing tumors, but this may be a consequence of patient selection because these studies do not have a control group without HER-2 overexpression.^12,19 Available studies suggest that women with HER-2–overexpressing metastatic breast cancer (MBC) treated with trastuzumab (a monoclonal antibody targeting HER-2) are still at substantial risk for brain metastases.^20-23 However, the relationship between HER-2 overexpression and the risk of brain metastasis in newly diagnosed breast cancer patients has not been examined systematically in a population-based series.

In our population-based study, we investigated the relationship between HER-2 overexpression and the risk of brain metastasis in newly diagnosed breast cancer patients treated in our center between January 1998 and December 2003, comparing patients with and without HER-2 overexpression. We have shown that HER-2–overexpressing breast cancer patients are at an independently higher risk to develop brain metastasis compared with HER-2–negative patients, and we have confirmed that HER-2–overexpressing MBC patients represent a high-risk group for brain metastasis.

	PATIENTS AND METHODS

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Patient Selection
Ethics approval was obtained from Alberta Cancer Ethics Review Board. Patients were identified from the provincial cancer registry and clinical laboratory. The goal of our selection process was to identify a population of newly diagnosed breast cancer patients with HER-2 overexpression. Our center began prospective HER-2 testing in a single laboratory on all breast cancer patients in January 1998, using a standardized testing procedure. Patients were considered HER-2 positive if they were 3+ on immunohistochemistry (IHC) testing or 2+ on IHC with gene amplification identified by fluorescence in situ hybridization (FISH) testing. We identified a population of patients treated at Cross Cancer Institute (Edmonton, Alberta, Canada) between January 1998 and December 2003 with HER-2 screening and no prior cancer diagnosis. A total of 460 patients were identified with HER-2 overexpression. Chart reviews were conducted and 159 patients were excluded if there was a breast cancer diagnosis preceding January 1998 (recurrent cancer), ductal carcinoma in situ, or other cancer other than breast. A total of 301 patients with HER-2–overexpressing newly diagnosed breast cancer were included for analysis. For the HER-2–negative population, a random sample of 500 patients from the same time period were identified. After chart review, 363 patients were eligible for analysis. Data collected from each chart included date of surgery, date of last follow-up, date of death, treatment received and standard prognostic factors including ER and progesterone receptor (PR) status, tumor grade, time and site of first recurrence, and time and site of subsequent metastatic progression.

Patient Management
All patients treated were reviewed by a multidisciplinary group and offered guideline-based staging, surgery, and adjuvant treatments as per published Canadian recommendations.^24-28 The Cross Cancer Institute is the only tertiary cancer center, the only facility for delivery of radiotherapy, and the only testing center for hormone-receptor status and HER-2 status in Northern Alberta; breast cancer diagnoses within this population are pathologically reviewed and referred to this center. Staging investigations did not include CNS imaging studies in asymptomatic patients. The variety of treatments administered (Table 1) reflects the population-based nature of this study. Adjuvant chemotherapy was offered to all node-positive and high-risk, lymph node–negative patients. Adjuvant hormonal therapy used tamoxifen, with anastrozole used in postmenopausal patients with tamoxifen contraindications. Radiation therapy to the breast was offered to all patients after segmental resection. Patients with one to three positive nodes were offered the MA.20 protocol (National Cancer Institute of Canada [NCIC] study comparing irradiation to the breast only v breast and lymph nodes). Patients with four or more positive nodes were offered regional nodal irradiation. Postmastectomy patients were offered chest wall and regional nodal irradiation if they had node-positive disease or locally advanced disease (ie, greater than T3 tumor). Follow-up was provided as per Canadian guidelines, and CNS screening to detect asymptomatic brain metastases was not employed. Diagnosis of brain metastases was made by computed tomography or magnetic resonance imaging of symptomatic patients.

Statistical Analysis
The primary end point of this study was the occurrence of brain metastasis. Brain metastasis (present v absent) was considered a binary response variable. Cox regression was used to identify predictive factors for brain metastasis. Factors found to be significant with the univariate test were then entered in a stepwise multivariate analysis to identify significant independent predictors. A P value of .05 was considered statistically significant for all analyses. ² tests and hazard ratios, along with corresponding 95% CIs, were calculated. Disease-free, overall, and brain metastasis–free survival curves for HER-2–positive and –negative cohorts were constructed according to the method of Kaplan and Meier. All reported P values are two sided, and differences were considered statistically significant when P < .05. The Fisher's exact test procedure was used to calculate the significance of the relationship between the dichotomous variables. The SAS program (version 9.1, SAS Institute Inc, Cary, NC) was used for the statistical analysis. To validate the results found in the multivariate Cox analysis, a matched-pair analysis was carried out. HER-2–positive and –negative patients were matched according to tumor size (0 to 0.9, 1 to 1.9, 2 to 2.9, 3 to 3.9, 4 to 4.9, and > 5 cm) and lymph node involvement (zero, one to three, and four positive nodes) from the overall patient population.

	RESULTS

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Patient Characteristics
Median follow-up of patients from diagnosis to death or last follow-up was 3.9 years. HER-2–positive patients had a greater burden of disease. There were a similar number of lymph node–positive patients in the HER-2–positive and –negative groups (44.2% v 42.4%; P = .42). HER-2–positive patients had tumors with significantly greater size ( 2 cm) and higher disease grade (2/3) compared with HER-2–negative patients (Table 2). HER-2–positive patients were more likely to be ER negative, (38.5% v 22.0%; P = .0001) and PR negative (68.8% v 44.1%; P = .0001).

Patterns of Recurrence
The patterns of recurrence are detailed in Table 3. The cumulative incidence of local recurrence or metastatic disease was 24.1% (160 of 663). More HER-2–positive patients developed disease progression (33.6 v 16.3%; P = .0001). The diagnosis of brain metastases required computed tomographic and/or magnetic resonance imaging confirmation. Among those patients with brain metastasis, there were a total of 27 events (9.0%) in HER-2–positive patients compared with only seven events (1.9%) in the HER-2–negative patients (hazard ratio, 4.23; 95% CI, 1.84 to 9.74; P = .0007). Of all patients who developed CNS metastases in HER-2–positive patients (n = 27), in eight patients (30%) the CNS was the initial site of metastases, and in 19 patients (70%) the CNS metastases were diagnosed subsequent to metastatic disease at other sites. In HER-2–negative patients who developed CNS metastases, it was the initial site of relapse in 29% (two of seven), with 71% occurring after systemic disease progression. The 5-year disease-free survival was 85% and 64% for HER-2–negative and –positive patients respectively (P < .001; Fig 1A). The 5-year overall survival was 87% for HER-2–negative patients versus 73% for HER-2–positive patients (P < .001; Fig 1B). HER-2–positive patients had a 5-year brain metastasis–free survival of 91% versus 97% for HER-2–negative patients (P < .001; Fig 1C).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Recurrence-free survival, (B) overall survival, and (C) brain metastasis–free survival by human epidermal growth factor receptor 2 (HER-2) status using the Kaplan-Meier method. –ve, negative; +ve, positive.

Characteristics of Patients With Brain Metastasis
Over a median follow-up of 3.9 years, 34 patients developed brain metastasis. Of the total HER-2–positive patient population, 9.0% developed brain metastasis compared with 1.9% of the HER-2–negative patients (P = .0001). There was no significant difference in the histologic characteristics, such as lymph node involvement, tumor size, grade, and hormone receptor status, between HER-2–positive and –negative patients who developed brain metastasis. Sixty-two HER-2–positive patients received trastuzumab-based therapy at the time of progression. Of these 62 relapsed patients receiving trastuzumab, 20 (32%) subsequently developed brain metastasis. Of the 30 patients receiving trastuzumab in an adjuvant setting, only one (3.3%) developed brain metastases.

	DISCUSSION

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The relevance of HER-2 positivity as a risk factor for brain metastases in breast cancer has not yet been clearly defined. We characterized the frequency of development of brain metastasis among patients with newly diagnosed HER-2 positive breast cancer and compared them with concurrently diagnosed HER-2–negative breast cancer patients. We found that 9.0% of HER-2–overexpressing breast cancer patients developed brain metastases compared with 1.9% of HER-2–negative patients (P = .0001). In this study, HER-2 overexpression emerges as the most significant prognostic factor for the development of brain metastasis and outperforms all other known prognostic factors in early breast cancer.

Several studies have addressed the incidence of brain metastasis in HER-2–overexpressing MBC.^20,31-33 These trials focused on MBC patients and were limited by the fact that the risk of brain metastasis was not examined independently in a breast cancer cohort without HER-2 overexpression. The weakness of these studies also includes uncertain HER-2 status in a subset of these patients. The incidence of brain metastases in MBC patients receiving trastuzumab-based therapies varied from 28% to 42%.^20-23 At the time of diagnosis of brain disease, 50% of patients were responding to treatment or had stable disease.

Our study differs from previously reported studies on three important levels. First, our study population-based cohort included all newly diagnosed early-stage breast cancers with HER-2 overexpression. The patients analyzed here were not routinely administered adjuvant trastuzumab, and were staged without routine brain imaging. This population most closely resembles those treated in daily practice and thus more accurately represents the natural history of HER-2 positive disease. Second, the entire population was rigorously tested prospectively for HER-2 overexpression in a single centralized laboratory. Third, because of the centralized nature of cancer care delivery in our province, all recurrences and treatment delivery were readily captured by the standardized follow-up of these patients.

The proportion of patients with brain metastasis is higher than historic experience would suggest; approximately 40% of HER-2–overexpressing patients with metastatic disease developed brain metastasis at some point in our study, whereas only 15% of HER-2–negative MBC patients developed brain metastases. This suggests that specific factors related to the biology of HER-2 overexpression and the evolving efficacy of breast cancer treatment are likely to contribute to the growing incidence of brain metastasis in breast cancer. Three mechanisms may hypothetically increase the risk of brain metastases in HER-2–overexpressing breast cancer patients: (1) the limitations on drug delivery imposed by the intact blood-brain barrier in early breast cancer treatment, (2) the trends for improved systemic disease control and overall survival in patients with MBC, and (3) the role of chemokine-mediated chemotaxis in breast cancer patients with tropism for brain relapse (organotropism).³⁴ The limited penetration of intravenous trastuzumab through the blood-brain barrier and the improvement of systemic control and overall survival in MBC patients³⁵ underscore the apparent inability of trastuzumab to prevent or treat brain metastases. HER-2 overexpression endows tumor cells with increased metastatic aggressiveness to sites such as the lung and liver, and may similarly augment metastatic propensity to the brain. Recent data have suggested the role of chemokine-mediated movement of malignant cells to specific organs. In particular, the chemokine receptor CXCR4 and its ligand stromal cell–derived factor-1 alpha (SDF-1) are expressed in organs that represent important sites of breast cancer metastasis such as bone marrow, liver, and lung.³⁶ CXCR4 expression is associated with HER-2 overexpression and amplification.³⁷ SDF-1, which is selectively expressed in the developing and mature CNS,³⁸ increases the vascular permeability and the penetration of HER-2–overexpressing breast tumor cells through the human brain microvascular endothelial cells, and has recently been shown to transactivate HER-2 tyrosine kinase signaling.³⁹ Better understanding of CXCR4/SDF-1 chemoattractant pathway for brain metastasis in HER-2–overexpressing breast cancer patients may help to better define the CNS breast cancer phenotype.

The use of trastuzumab appears to have improved the natural history of HER-2–positive breast cancer. Early results from adjuvant trastuzumab trials show improved disease-free survival^37,40,41 and overall survival.⁴⁰ An increased incidence of isolated brain metastases as first site of relapse was reported with adjuvant trastuzumab (33 v 15 events in the control arm).⁴¹ However, the effect of trastuzumab on the rate of brain metastasis cannot yet be defined given the short follow-up.⁴¹

In summary, our study shows that newly diagnosed HER-2–overexpressing breast cancer patients are at significantly increased risk for brain metastasis. Of all patients who developed CNS metastases in HER-2–positive patients (n = 27), in eight patients (30%) the CNS was the initial site of metastases, and in 19 patients (70%) the CNS metastases were diagnosed subsequent to metastatic disease at other sites. Given this extremely high-risk population for brain metastases, studies of serial radiologic screening and/or prophylactic cranial irradiation (PCI) in HER-2–overexpressing MBC patients are warranted; studies looking at the tolerability and efficacy of PCI are already underway. In patients with both early-stage and HER-2–overexpressing breast cancer, evaluation of prophylactic strategies with HER-2–inhibiting small molecules able to cross the blood-brain barrier should be also investigated.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Bassam Abdulkarim Collection and assembly of data: Zsolt Gabos, Richie Sinha, John Hanson, Nitin Chauhan, Bassam Abdulkarim Data analysis and interpretation: Zsolt Gabos, Richie Sinha, John Hanson, Bassam Abdulkarim Manuscript writing: Zsolt Gabos, Richie Sinha, Judith Hugh, John R. Mackey, Bassam Abdulkarim Final approval of manuscript: John R. Mackey, Bassam Abdulkarim Other: Judith Hugh (pathological review and immunostaining for estrogen receptor, progesterone receptor, and HER-2)

 

	NOTES

 
published online ahead of print at www.jco.org on November 13, 2006.

Z.G. and R.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 12, 2006; accepted September 27, 2006.

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