Breast Cancer Unit, Departments of Medicine and Biostatistics, Institut Gustave-Roussy, Villejuif, France
* Correspondence to: Dr F. Andre, Breast Cancer Unit, Institut Gustave Roussy, 39 rue C. Desmoulins, 94805 Villejuif, France. Tel: +33-1-42-11-43-71; Fax: +33-1-42-11-52-74; Email: fandre{at}igr.fr
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Abstract |
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Patients and methods: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting.
Results: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.99.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.711, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases.
Conclusion: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.
Key words: brain metastases, breast cancer, chemotherapy, hormone receptor, lung metastases, radiotherapy
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Introduction |
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In the present study, we have searched for predictive factors of brain metastases in patients with metastatic breast cancer, in order to propose a targeted strategy aimed at screening or preventing brain relapse in these patients.
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Patients and methods |
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Patient selection for the first series
Two hundred and fifteen patients were included in the present study. These patients were selected from the database of a randomized trial that compared post-operative castration versus no castration in pre-menopausal patients with breast cancer. It included 557 patients at the Institut Gustave Roussy between 1989 and 1998. The results of this trial have been reported elsewhere [5]. Among the 557 patients, 220 patients developed a metastatic relapse of breast cancer before August 2003. The follow-up of the trial did not include any systematic brain CT scan, nor brain MRI. The characteristics of the patients were available in the database of the clinical trial. The clinical files of these 220 metastatic patients were reviewed in August 2003 in order to determine which patients had presented brain metastases. Five patients presenting brain metastases as first relapse were excluded from the analysis. The predictive factors for brain metastasis were therefore analysed in the remaining 215 patients.
Variables
The age, tumor size, lymph node status, tumor grade, interval between primary and first metastatic relapse, first sites of metastases, loco-regional treatment and adjuvant medical treatment were extracted from the database of the clinical trial. Hormone receptor status was extracted from the clinical charts. These variables were tested for their association with the occurrence of brain metastases.
Statistical analysis
The association between the characteristics of the patients and the occurrence of brain metastases was evaluated with a Cox model in univariate and multivariate analyses. The incidence of brain metastases was determined using the KaplanMeier method. The starting date for Cox and KaplanMeier analyses was the date of the first metastatic relapse. All reported P values are two-sided. The data were analysed with SAS software. Differences were considered statistically significant when P <0.05. Exact P values were reported only when P was 0.0001.
Patient selection for the confirmatory series (Figure 1)
In order to confirm the results provided by the first series of 215 patients, predictive factors for brain metastases were determined in an independent cohort. One hundred and ninety-nine breast cancer patients with metastatic relapse were included in the confirmatory series. These patients were selected from two randomized trials [6, 7
] that evaluated post-operative chemotherapy in node positive, post-menopausal patients and node negative pre-menopausal patients. As in the first series, they represented all patients with metastatic relapse as of 1 August 2003. These trials had included a total of 938 patients at the Institut Gustave Roussy between 1989 and 1996.
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Results |
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Discussion |
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The development of brain metastases is usually associated with neurological symptoms that alter the quality of life. The possibility of detecting early and treating occult brain metastases may avoid the occurrence of neurological symptoms. The current staging procedure of patients presenting a metastatic relapse from breast cancer does not include systematic brain CT scan. Based on the present data, we propose to perform a brain CT scan at the time of relapse to patients presenting lung metastases and/or negative hormone receptor status. Since 30% of breast cancer patients with lung metastases will present a brain relapse, there is a rationale to evaluate a prophylactic treatment in these selected patients. Prophylactic cranial irradiation is currently performed in patients with small cell lung cancer who respond to induction therapy, and was shown to be associated with increased survival [12]. This approach has also been reported to efficiently prevent the occurrence of brain metastases in patients presenting lung adenocarcinoma [13
, 14
]. Prophylactic cranial irradiation could therefore be evaluated in patients with metastatic breast cancer and lung metastases and/or negative hormone receptor status. The use of a systemic drug able to penetrate across the unaltered meningo-cerebral barrier could be another strategy to prevent the occurrence of metastases. Methotrexate is currently used to prevent brain metastasis in acute lymphoid leukemia [15
]. It has been shown that intravenous, high-dose methotrexate provides cytotoxic concentrations of the drug in the cerebrospinal fluid [16
]. Since methotrexate has shown antitumor activity in breast cancer [17
], there may be a rationale to evaluate the use of high-dose methotrexate after induction therapy in patients presenting lung metastases in order to prevent the development of brain relapse. Since 71% of the brain metastases were detected more than 5 months after the diagnosis of the first metastasis, there is a rationale to propose these treatments following six courses of conventional induction chemotherapy.
A greater understanding of the biological processes involved in brain metastases would probably allow better targeting of preventive treatments. The finding that brain metastases occur mainly in patients presenting with lung metastases is in line with the seed and soil theory. This theory has been developed to illustrate the fact that the site of metastasis is not random with respect to the site of the primary tumour [18]. This theory has supported the hypothesis that the homing of tumor cells is determined by biological factors of the environment. It has been suggested recently that the interaction between chemokines and chemokine receptors could drive the homing of tumor cells and be the biological basis of the seed and soil theory [19
]. CXCR4 is a chemokine receptor that leads to metastases in the lung [19
]. This chemokine receptor is expressed in tumor tissues, including breast and lung tumors [20
, 21
]. Of interest, the ligand for CXCR4 (SDF1) is widely expressed in the brain where it plays a role in the migration of astrocytes [22
]. The association of lung and brain metastases is a striking event that could be explained by a discrete expression of chemokine receptors in breast cancer patients. This deserves further exploration with potential treatment implications.
In conclusion, we have shown that patients with lung metastases and/or negative hormone receptor status present a high risk for brain metastases. Based on these data, we propose: (i) that patients with metastatic breast cancer with lung metastases and/or negative hormone receptor status may be screened for the presence of brain metastases; (ii) that the mechanism underlying the preferred association between lung and brain metastases and the potential implication of CXCR4 should be investigated; and (iii) that prophylactic cranial irradiation or drugs with intracerebral activity should be evaluated as part of the preventive strategies for brain metastases.
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Acknowledgements |
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Received for publication May 1, 2004. Revision received June 18, 2004. Accepted for publication June 21, 2004.
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References |
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