The development of brain metastases is usually a late event in the natural history of uncontrolled cancer. Despite increased interest during past years there are very few established predictive factors associated with the occurrence of CNS metastatic disease in patients with breast cancer. It is a common clinical experience that brain metastases occur more frequently in young women with large and/or aggressive tumors [4
]. Several studies have also demonstrated that the negative hormonal receptor status and the presence of lung metastases may be associated with a higher risk of developing brain metastases [5
]. In addition, recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen [9
]. There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab [8
The results of the present study demonstrate that the overall incidence of CNS metastatic disease in patients with breast cancer (both early breast cancer and advanced/metastatic breast cancer) is not different from that observed in patients with other types of solid tumors. The multivariate analysis, however, demonstrated that the stage of the disease, the HER2/neu status (grade 2+ or grade 3+ by immunohistochemistry) and the presence of CK-19 mRNA-positive CTCs represent independent predictive factors for CNS relapse. The same parameters emerged as independent predictive factors in the subgroup of breast cancer patients in whom the CNS involvement was the unique site of disease progression.
The predictive value of the HER2/neu status already reported [8
] was further confirmed in the present study. Moreover, it has been shown that the HER2/neu status of the brain metastases is similar and highly concordant (97%) with that of the primary tumor, suggesting that the HER2/neu status of the primary tumor is predictive of the HER2/neu status of the tumors. The time to develop CNS metastatic disease seems to be shorter in patients with HER2/neu-positive brain lesions, demonstrating the importance of evaluating the HER2/neu status early in the diagnosis of breast cancer in order to provide information on the patient's prognosis and to assist clinical decision-making. It has been reported that 25% of metastatic breast cancer patients developed CNS metastatic disease during treatment with trastuzumab [20
], and that nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as the first site of tumor progression [22
]. In addition, almost 15% of patients with disseminated breast cancer had occult CNS metastases and the only predictive factors for this evolution were the number of sites involved and the HER2/neu status [8
A possible explanation for these observations could be a predilection of HER2/neu tumors to developed CNS metastases. Alternatively, we cannot exclude that trastuzumab may control the systemic disease, leading to an improved survival [23
]. Since trastuzumab cannot cross the blood–brain barrier, however, the CNS remains a vulnerable 'sanctuary site'. Irrespective of the reasons for the observed increased incidence of brain metastases in patients with HER2/neu-overexpressing breast cancer, the practical problem remains the development of CNS disease, which has an extremely poor prognosis. It is therefore important to develop a risk assessment and therapeutic strategy in order to prevent and/or control CNS disease, aiming at prolonging patient survival.
We also observed that the incidence of brain metastases was significantly higher in patients with visceral disease than soft tissue disease, despite the fact that this parameter did not emerge as an independent predictive factor in the multivariate analysis. Although we did not discriminate between pulmonary and other visceral localizations of disease, this finding is in agreement with other studies [8
] reporting a higher incidence of brain metastases in patients with lung metastases (nearly 30%). This higher incidence of brain metastases in patients with visceral disease is common evidence in retrospective studies [9
] and should probably be attributed to the more aggressive biologic behavior of these tumors and the higher probability of hematogeneous dissemination of malignant cells in these patients. We have also reported that patients with CK-19 mRNA-positive CTCs have increased incidence for relapse with metastatic disease [17
]. Moreover, our observation that the detection of CK-19 mRNA-positive CTCs was associated with an increased risk of CNS involvement in patients with breast cancer further support the hypothesis.
This finding was not surprising since the detection of CK-19 mRNA-positive tumor cells in the peripheral blood [17
] or in the bone marrow [25
] represents an independent predictive and prognostic factor for early clinical relapse and death from the disease. Indeed, the circulating CK-19 mRNA-positive tumor cells have the possibility, through the blood vasculature, to reach every tissue. The development of clinically overt metastatic disease is not a random phenomenon according to the 'seed and soil' theory, since the homing ability of these circulating tumor cells is determined by their biological characteristics as well as by other biological factors of the local environment [27
]. Maguire and colleagues have reported the detection of cytokeratin-positive cells in bone marrow aspirates in 12 out of 12 cancer patients with CNS relapse; in nine of these patients, bone marrow occult cells were the only evidence for systemic spread [28
]. The validation of the predictive value of CK-19 mRNA-positive cells for CNS relapse, however, requires a prospective study with a higher number of patients, a more prolonged follow-up period and further molecular and biological characterization of peripheral blood CK-19 mRNA-positive occult tumor cells.
In the present study it was also possible to confirm the initial clinical observation that breast cancer patients who receive a taxane-containing chemotherapy regimen have a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen. Nevertheless, this parameter did not emerge as an independent predictive factor in the multivariate analysis. It is important to note, however, that a similar difference was not observed in patients with other types of solid tumor treated or not with a taxane-containing chemotherapy regimen.
Taxanes are highly effective in breast cancer and they prolong the survival of patients with advanced disease. It is also well known that CNS involvement is more frequent in the late stages of the disease. A possible explanation could therefore be that the increase in survival and the prolonged period of advanced disease is correlated with the increased frequency of CNS relapse. It is important to note that such a correlation could represent a confounding factor, in a retrospective analysis. For example, someone can hypothesize that physicians may have chosen more aggressive treatment for patients with aggressive tumors. These patients also showed increased incidence for CNS relapse. Although this observation could be explained with the 'sanctuary site' hypothesis, experimental studies in mice have demonstrated that the blood–brain barrier is intact inside and around brain metastases smaller than 0.2 mm2
but not in larger lesions [29
]. This finding implies that the barrier should not be a major obstacle to using chemotherapy in the treatment of brain metastases, at least in the advanced stages of the disease. In addition, more recent studies have shown that paclitaxel is exported by the p
-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries [15
The aforementioned data suggest that taxanes may not penetrate well into the CNS, and therefore the CNS may represent tumor 'sanctuary' sites for taxane-containing chemotherapy regimens. A difference in the incidence of CNS relapses between patients with breast cancer and other solid tumors treated with taxanes was observed. This difference in the incidence of CNS relapse between patients with breast cancer and other solid tumors could be explained by the higher efficacy of the taxanes in breast cancer which is associated with increased survival in comparison with other solid tumors.
We have previously reported that the use of Transtuzumab could decrease or eradicate CK-19 mRNA-positive CTCs [30
]. Based on these results we have initiated a randomized clinical trial to evaluate the effect of Transtuzumab administration on the disease-free survival of patients with early breast cancer and CK-19 and HER-2 mRNA-positive CTCs. The incidence of CNS relapse in correlation with the detection of CK-19 mRNA-positive CTCs will be prospectively evaluated in this ongoing study.