Risk factors for brain relapse in patients with metastatic breast cancer

K. Slimane, F. Andre*, S. Delaloge, A. Dunant, A. Perez, J. Grenier, C. Massard and M. Spielmann

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer.

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: 1.9–9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7–11, 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There is a body of evidence suggesting that the incidence of brain metastases is rising in patients with breast cancer [1Go, 2Go]. The mechanism usually put forward to explain this phenomenon is the selective destruction of non-brain metastases by new chemotherapy regimens, allowing a later development of brain metastases. It has been shown that the occurrence of brain metastases in patients with breast cancer decreases survival [3Go, 4Go] and alters the quality of life. The possibility of detecting early or preventing the occurrence of brain metastases could therefore lead to survival improvement and better quality of life. Some approaches (prophylactic cranial irradiation, high-dose methotrexate, temozolomide) have been shown to exhibit interesting antitumor activity in brain metastases and could therefore be evaluated as a preventative treatment for brain metastases. Nevertheless, these approaches are usually toxic and could therefore not be applied to all patients. From this situation has emerged the need to identify better the patients with metastatic breast cancer who are at risk of subsequently developing brain metastases, in order to detect early or to prevent brain metastases in a well-selected population. To date, only a few series have reported predictive factors for brain relapse in patients with breast cancer.

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Risk factors for brain metastases were first determined in a series of metastatic breast cancer patients, and then confirmed in a second series. Patients were included in prospective randomized trials for the two series of patients.

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 [5Go]. 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 Kaplan–Meier method. The starting date for Cox and Kaplan–Meier 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 [6Go, 7Go] 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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Figure 1. Patient selection for the first and confirmatory series.

 

    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Characteristics of the patients (first series)
Two hundred and fifteen metastatic breast cancer patients have been included in the present series. The characteristics of the patients are summarized in Table 1. The median follow-up between diagnosis of metastatic relapse and last visit or death was 22 months (range 0–117 months). The median follow-up for living patients was 35 months. Thirty-one patients (14%) presented a brain relapse posterior to the diagnosis of the first metastasis. The 2-year incidence of brain metastases was 13%. The median interval between the first metastatic relapse and the occurrence of brain metastases was 13 months. Twenty-two patients out of 31 (71%) presented with brain relapse more than 5 months after the diagnosis of first metastatic relapse.


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Table 1. Characteristics of patients included in the first series

 
Predictive factors for brain metastases
Lung metastases as the first site of relapse (P=0.0001), negative hormone receptor status (P=0.0001), absence of bone metastases at first relapse (P=0.008) and short disease-free interval (>24 months) (P=0.008) were associated with a higher risk of developing brain metastases in the univariate analysis (Tables 2 and 3). Fifteen out of 50 patients (30%) presenting with lung metastases as the first site of relapse subsequently developed brain metastases during the follow-up. Ten out of 29 patients (34%) with negative hormone receptor status subsequently presented a brain relapse. The 2-year incidence of brain metastases were 24% (95% CI: 12–41%) and 7% (95% CI: 4–13%) in patients with and without lung metastases, respectively (P=0.0001). The 2-year incidence of brain metastases were 6% (95% CI: 3–12%) and 37% (95% CI: 18–62%) in patients with positive and negative hormone receptor status, respectively (P=0.0001). In the multivariate analysis, lung metastases (hazard ratio: 4.3, 95% CI: 1.9–9.3, P=0.0003) and negative hormone receptor status (hazard ratio: 4.2, 95% CI: 1.7–11, P=0.002) were associated with an increased risk of brain metastases.


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Table 2. Predictive factors for brain metastases: univariate analysis in patients included in the first series

 

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Table 3. Predictive factors for brain metastases: multivariate analysis in patients included in the first series

 
Predictive factors for brain metastases in the confirmatory series
The confirmatory series included 199 patients with metastatic disease. The median follow-up was 21 months (range 0–122 months). The median follow-up for living patients was 34 months (range 0–122 months). Lung metastases and negative hormonal receptor status were confirmed as predictive factors for the occurrence of brain metastases. Fourteen out of 48 patients with lung metastases (29%) and six out of 151 patients without lung metastases (4%) presented a brain metastasis (P <0.0001). Eight out of 116 patients with positive hormone receptor status (7%) and eight out of 37 patients with negative hormone receptor status (21%) presented a brain metastasis (P=0.01). The 2-year incidence of brain metastases were 44% and 3% in patients with and without lung metastases, respectively (P <0.0001). The 2-year incidence of brain metastases were 7% and 32% in patients with positive and negative hormone receptor status, respectively (P=0.0005). Ninety-two patients had received adjuvant anthracyclin-based chemotherapy. Of these, nine patients developed brain metastases. At the opposite end of the spectrum, brain metastases occurred in 11 patients who had not received adjuvant chemotherapy (P=0.9). Brain metastases developed in 15% and 9% of patients treated (n=54) or not treated (n=145), respectively, with taxanes (P=0.17). Brain metastases developed in 8% and 11% of patients treated (n=61) or not treated (n=138), respectively, with vinorelbine (P=0.56).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the present study, we report that the presence of lung metastases and negative hormone receptor status are strong predictive factors for the occurrence of a brain relapse in two prospective series of patients with metastatic breast cancer. Previous studies in the same population reported that negative hormonal receptor status [8Go, 9Go] and, more recently, Her2-neu overexpression [10Go, 11Go] may be associated with a higher risk of developing brain metastases. The present study confirms that negative hormone receptor status is a predictive factor for brain metastases in two sets of homogeneously treated, prospectively assessed metastatic breast cancer patients. Her2-neu was not performed in our series since most of the patients relapsed before the introduction of trastuzumab in daily practice. Only a few studies specifically evaluated the correlation between the first sites of metastases and the subsequent development of brain metastases. Crivellari et al. [1Go] reported that 11 out of 28 breast cancer patients presenting a brain relapse had lung metastases as the first site of relapse. The presence of lung metastases was associated with a higher risk of further developing brain metastases in this series. Miller et al. [11Go] reported that the presence of lung metastases was associated with a 2.4-fold increased risk of brain metastases (P=0.07) in a series of 155 consecutive patients with metastatic breast cancer. In the present series, the presence of lung metastases was strongly associated with the occurrence of brain metastases. Indeed, 30% of the patients presenting lung metastases as the first site of relapse subsequently developed a brain relapse. These data raise questions regarding the management of breast cancer patients at the time of metastatic relapse: (i) Should a screening of brain metastases be performed in patients with lung metastases and/or negative hormone receptor status? (ii) Should a prophylactic treatment of brain metastases be evaluated in these subsets of patients?

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 [12Go]. This approach has also been reported to efficiently prevent the occurrence of brain metastases in patients presenting lung adenocarcinoma [13Go, 14Go]. 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 [15Go]. It has been shown that intravenous, high-dose methotrexate provides cytotoxic concentrations of the drug in the cerebrospinal fluid [16Go]. Since methotrexate has shown antitumor activity in breast cancer [17Go], 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 [18Go]. 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 [19Go]. CXCR4 is a chemokine receptor that leads to metastases in the lung [19Go]. This chemokine receptor is expressed in tumor tissues, including breast and lung tumors [20Go, 21Go]. Of interest, the ligand for CXCR4 (SDF1) is widely expressed in the brain where it plays a role in the migration of astrocytes [22Go]. 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.


    Acknowledgements
 
We thank Yuki Takahashi (Hôpital Saint Louis, Paris) for editing.

Received for publication May 1, 2004. Revision received June 18, 2004. Accepted for publication June 21, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Crivellari D, Pagani O, Veronesi A et al. International Breast Cancer Study Group. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 2001; 12: 353–356.[Abstract]

2. Abali H, Celik I. High incidence of central nervous system involvement in patients with breast cancer treated with epirubicin and docetaxel. Am J Clin Oncol 2002; 25: 632–633.

3. Chang J, Clark GM, Allred DC et al. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 2003; 97: 545–553.[CrossRef][ISI][Medline]

4. Engel J, Eckel R, Aydemir U et al. Determinants and prognoses of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys 2003; 55: 1186–1195.[CrossRef][ISI][Medline]

5. Arriagada R, Le M, Spielmann M et al. Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Proc Am Soc Clin Oncol 2003; 22: A14.

6. Arriagada R, Spielmann M, Koscielny S et al. Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen. Ann Oncol 2002; 13: 1378–1386.[Abstract/Free Full Text]

7. Tursz T, Arriagada A, Koscielny S. Patterns of failure in two randomized trials of adjuvant anthracycline-based chemotherapy in 1,146 patients with early breast cancer. Proc Am Soc Clin Oncol 2003; 22: A36.

8. Samaan NA, Buzdar AU, Aldinger KA et al. Estrogen receptor: a prognostic factor in breast cancer. Cancer 1981; 47: 554–560.[ISI][Medline]

9. Stewart JF, King RJ, Sexton SA et al. Oestrogen receptors, sites of metastatic disease and survival in recurrent breast cancer. Eur J Cancer 1981; 17: 449–453.[ISI][Medline]

10. Bendell JC, Domchek SM, Burstein HJ et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003; 97: 2972–2977.[CrossRef][ISI][Medline]

11. Miller KD, Weathers T, Haney LG et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 2003; 14: 1072–1077.[Abstract/Free Full Text]

12. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341: 476–484.[Abstract/Free Full Text]

13. Stuschke M, Eberhardt W, Pottgen C et al. Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999; 17: 2700–2709.[Abstract/Free Full Text]

14. Umsawasdi T, Valdivieso M, Chen TT et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease nonsmall cell lung cancer. J Neurooncol 1984; 2: 253–259.[ISI][Medline]

15. Clarke M, Gaynon P, Hann I et al. Childhood ALL Collaborative Group. CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 2003; 21: 1798–1809.[Abstract/Free Full Text]

16. Tetef ML, Margolin KA, Doroshow JH et al. Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol 2000; 46: 19–26.[CrossRef][ISI][Medline]

17. Colleoni M, Rocca A, Sandri MT et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002; 13: 73–80.[Free Full Text]

18. Fidler IJ, Yano S, Zhang RD et al. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002; 3: 53–57.[CrossRef][ISI][Medline]

19. Muller A, Homey B, Soto H et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.[CrossRef][ISI][Medline]

20. Kato M, Kitayama J, Kazama S et al. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 2003; 5: 144–150.[CrossRef]

21. Spano JP, Andre F, Besse B et al. Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol 2004; 15: 613–617.[Abstract/Free Full Text]

22. Stumm RK, Zhou C, Ara T et al. CXCR4 regulates interneuron migration in the developing neocortex. J Neurosci 2003; 23: 5123–5130.[Abstract/Free Full Text]





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