|Year : 2012 | Volume
| Issue : 4 | Page : 542-548
The factors that have an impact on the development of brain metastasis in the patients with breast cancer
Adem Dayan1, Dogan Koca1, Tulay Akman1, Ilhan Oztop1, Hulya Ellidokuz2, Ugur Yilmaz1
1 Department of Internal Diseases, Dokuz Eylül University, Medical Faculty, Division of Medical Oncology, Inciralti, Turkey
2 Department of Preventive Oncology, Dokuz Eylül University, Institute of Oncology, Izmir, Turkey
|Date of Web Publication||29-Jan-2013|
Department of Internal Diseases, Dokuz Eylül University, Medical Faculty, Division of Medical Oncology, Inciralti 35340,Izmir
Source of Support: None, Conflict of Interest: None
Background: To evaluate the factors that have an impact on the development of brain metastasis in patients with breast cancer.
Materials and Methods: Among the patients who were followed-up and treated for breast cancer between January 2000 and January 2010, the ones with brain metastasis were included to the analysis. Metastatic breast cancer patients without brain metastasis, which had similar duration of follow-up and median age were included as the control group. Both group were compared for prognostic and predictive factors in terms of relationship between with or without brain metastasis and survival.
Results: There were a total of 63 female patients with metastatic breast cancer who had brain metastasis and the researchers enrolled the same number of female patients as the control group. In the univariate analysis, as a significant finding, it was found that, the patients with breast cancer who had brain metastasis had vascular invasion positivity, human epidermal growth factor receptor-2 (HER-2) positivity, a rare detection of invasive lobular carcinoma component in the tumor, estrogen receptor negativity, and no bone and liver metastasis and they did not receive chemotherapy due to several reasons after the detection of metastasis in any organ. In the multivariate analysis, HER-2 positivity, no bone and liver metastasis and not receiving chemotherapy due to several reasons after the detection of metastasis in any organ were detected as significant findings.
Conclusions: As the prognostic and predictive factors showing the development of brain metastasis in breast cancer patients may be identified, follow-up also including the brain is important in order to take preventive measures.
Keywords: Breast cancer, brain metastasis, prognostic and predictive factors, survival
|How to cite this article:|
Dayan A, Koca D, Akman T, Oztop I, Ellidokuz H, Yilmaz U. The factors that have an impact on the development of brain metastasis in the patients with breast cancer. J Can Res Ther 2012;8:542-8
|How to cite this URL:|
Dayan A, Koca D, Akman T, Oztop I, Ellidokuz H, Yilmaz U. The factors that have an impact on the development of brain metastasis in the patients with breast cancer. J Can Res Ther [serial online] 2012 [cited 2019 Dec 7];8:542-8. Available from: http://www.cancerjournal.net/text.asp?2012/8/4/542/106531
| > Introduction|| |
Breast cancer, an important health problem for women, is the most common cancer among women in USA with an incidence rate of 26%. It is the second leading cause of cancer-related death with a rate of 15%.  Moreover, breast cancer is the second most common brain metastasis-leading cancer among all types. In patients with breast cancer, brain involvement is approximately 10%-16% and this percentage increases to 30% in the autopsy series.  The solid tumor, which most commonly leads to leptomeningeal involvement in the brain, is breast cancer.  In patients with breast cancer, brain metastasis is a condition that is seen in later stages after the metastasis of other organs.  If detected, it is difficult to treat and shows adverse effects on the prognosis and severely shortens the life expectancy. , At present, the prediction of such an important condition and the precautions to be taken are being investigated. 
As, in breast cancer, development of brain metastasis rapidly impairs the general status of the patient and leads to serious morbidity and mortality therefore early diagnosis is very important. Currently, data about development of brain metastasis in breast cancer patients are quite inadequate and approaches, such as prophylactic radiotherapy (RT) similar to that used in small cell lung cancer and an established risk classification, are lacking.
Therefore, we planned to conduct this study to evaluate the factors that have an impact on the development of brain metastasis in breast cancer patients.
| > Materials and Methods|| |
Among the patients who were followed-up and treated with a diagnosis of breast cancer between January 2000 and January 2010, the ones with brain metastasis were included to the analysis. The medical files of the patients were retrospectively examined and prognostic and predictive factors, information about the therapy and survival data were extracted from them.
As control group, patients with metastatic breast cancer without brain metastasis, which had similar duration of follow-up and median age were enrolled.
The time from the diagnosis to the first detection of a recurrence in any organ was considered as disease-free survival (DFS), the time from the recurrence to the progression was considered as progression-free survival (PFS) and the time from the diagnosis to the death was considered as overall survival (OS).
The statistical analysis of the data was done using Statistical Package for Social Sciences for Windows (SPSS) Version 15.0 software. The mean of two groups was analyzed using t test, the independent group ratios were compared using chi-square test, the analysis between the predictors or independent variables and dependent variables was performed using logistic regression test, OS were analyzed using Kaplan-Meier method and two survival curves were compared using log-rank test. The statistical significance was considered as P<0.05.
| > Results|| |
A total of 63 female patients with breast cancer who had brain metastasis were retrospectively evaluated. As control group, 63 patients with metastatic breast cancer without brain metastasis, which had similar duration of follow-up and median age were enrolled.
Median ages of the patients were similar in both groups, with 49 (21-76) in the patient group with brain metastasis and 50 (29-72) in the control group. Between both the groups it was not found statistically different for menopausal status, to have bilateral breast cancer and body mass index [Table 1].
In the patient group with brain metastasis, histopathological diagnosis was mostly invasive ductal carcinoma (IDC) and majority of the patients had a tumor tissue with vascular invasion (P=0.005), more patients were human epidermal growth factor receptor-2 (HER-2) positive (P=0.001), less patients had invasive lobular carcinoma (ILC) component in their tumor tissue (P=0.043) and more patients were estrogen receptor (ER) negative (P=0.029).
|Table 1: General characteristics of patient groups and the therapies administered to them|
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No significant differences were found between two groups in terms of progesteron receptor (PR) positivity, triple negativity, grade of tumor, the presence of lymphatic invasion of the tumor, the presence of perineural invasion of the tumor, size of the tumor, lymph node involvement and the number of the lymph nodes involved (respectively, P=0.091, P=0.473, P=0.229, P=0.705, P=0.348, P=0.351, P=0.839, P=0.777) [Table 1].
Characteristics of the therapies given
Both patient groups were similar in terms of the neoadjuvant therapies received, the surgical procedures administered and the adjuvant chemotherapy (CT) regimens received (respectively, P=0.348, P=0.771 and P=0.364). Two groups did not show any significant difference in terms of whether they receive anthracycline and taxane-containing regimens as an adjuvant CT regimen or not (respectively, P=0.067 and P=0.489). The patients did not show any difference in terms of whether they receive adjuvant hormonal therapy (HT) and adjuvant RT or not (respectively, P=0.102 and P=0.204). However, median duration of adjuvant HT use was 23.5 (3-60) months in the group with brain metastasis versus 43.5 (3-84) months in the control group (P=0.023) [Table 2].
When both groups were compared in terms of CT application after the detection of the first metastasis in any organ, it was seen that the majority of the patients with brain metastasis did not receive CT (P=0.001). Consistently, very few patients with brain metastasis have received the agents, such as epirubicine (P=0.016), cyclophosphamide (P=0.048), 5-Fluorouracil (5-FU) (P=0.025), docetaxel (P=0.001), paclitaxel (P=0.048) and capecitabin (P=0.004). All patients received steroid therapy and whole brain RT (WBRT) after the detection of brain metastasis, 24 (38.0%) patients were received anticonvulsants therapy, and 3 patients (4.8%) have undergone surgical intervention for metastasis and also these patients received WBRT.
In the adjuvant period, both the groups patients had not received trastuzumab treatment. In the metastatic stage, of these 31 patients with HER-2 positive with brain metastasis, 17 (54.8) patients had received trastuzumab treatment however in without brain metastasis patients group, all HER-2 positive patients (10 patients, 100%) had received trastuzumab treatment. But these data were not statistically significant (P=0.129) [Table 2]. Among patients who received trastuzumab but progressed under this therapy, 2 of 17 (11.7%) brain metastasis patients had received lapatinib treatment; however, 1 of 10 (10%) without brain metastasis patient had received lapatinib treatment.
Median follow-up was 34 (3-212) months in the patient group with brain metastasis and 43 (2-242) months in the control group [Table 1].
DFS was 18.6 (15.1-22.0) months in the patient group with brain metastasis and 21.1 (5.4-36.7) months in the control group. Median OS was 44 (25.8-62.1) months in the patient group with brain metastasis and 99 (73.3-124.6) months in the control group [Figure 1]. The rate of death was more than double in patients with brain metastasis compared to control group and this was statistically significant (P=0.001). Survival-related informations is provided in [Table 3].
In patients with brain metastasis, brain was the first site of metastasis in 22 (34.9%) patients. Median time from diagnosis to brain metastasis was 30.2 (21.5-38.8) months. Time from first (any) metastases to brain metastasis was found to be 8.5 (1.7-16.2) months. Median survival after the detection of the brain metastasis was 6.9 (3.1-10.6) months [Table 3].
|Figure 1: Overall survival of the patients with and without brain metastasis|
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Patterns of metastasis
When the patterns of metastasis were evaluated in patients with brain metastasis, 22 (34.9%) had brain as the first site of metastasis, 57 (90.4%) were symptomatic at diagnosis to brain metastases, 37 (58.7%) were multiple and 26 (41.3%) were solitary. Of the patients, 41 (65.1%) showed other organ metastasis, together with the brain metastasis. Of these 41 patients, 17 had single organ metastasis other than the brain. The locations of other organ metastasis were bone in 30 patients (47.6%), lung in 25 patients (39.7%) and liver in 16 patients (25.4%). While two groups did not show any significant difference for lung metastasis (P=0.188), absence of bone metastasis and liver metastasis were significantly high in the group with brain metastasis (respectively, P=0.002 and P=0.016) [Table 1].
When the univariate analysis was evaluated, it was seen that, in the patients with brain metastasis, the tumor tissue of more patients showed vascular invasion (P=0.005), more patients were HER-2 positive (P=0.001), less patients had a tumor tissue with ILC component (P=0.043), more patients were ER negative (P=0.029), without bone and liver metastasis (respectively, P=0.002 and P=0.016) and higher number of patients that did not receive CT after the occurrence of the first metastasis in any organ (P=0.001) [Table 1].
When the multivariate analysis was evaluated, it was seen that, in the patients with brain metastasis, greater number of HER-2 positive patients (P=0,001), without bone metastasis (P=0.035) and higher number of patients who did not receive CT after the occurrence of the first metastasis in any organ were found to be significant [Table 1].
| > Discussion|| |
The development of brain metastasis in breast cancer is a serious condition which is difficult to treat and an important reason of morbidity and mortality. Therefore, as it is important to predict the patients with breast cancer that may develop brain metastasis, we tried to reveal the risk factors that might have an effect on the development of brain metastasis.
In our study, the positivity of vascular invasion, HER-2 positivity, rare detection of the ILC component in the tumor tissue, ER negativity, without bone and liver metastasis and higher number of patients who did not receive CT after the detection of the first metastasis in any organ were significant in the patient group with brain metastasis compared to the control group.
An important prognostic factor, vascular invasion is a poor risk factor for systemic metastasis. , It is commonly seen in the cases of breast cancer related to germ line mutations.  Especially in lymph node-negative patients, it plays an important role in the decision-making for the administration of adjuvant CT.  It was reported to be a poor prognostic factor for breast cancer , and a risk factor for brain metastasis.  In our study, in the majority of the patients with brain metastasis, we found vascular invasion therefore we think that vascular invasion may be a risk factor. However, the absence of lymphatic drainage in the brain tissue may lead to the use of hematogenous way in the development of metastasis. Vascular invasion may lead to hematogenous-mediated metastasis. This may be caused by vascular invasion being a risk factor but it may also be caused by the obligatory combination of the two.
Approximately 25% of the patients with breast cancer have amplification or over-expression of HER-2. HER-2 positivity is commonly accompanied by high grade and ER negativity.  Especially in the node-positive patients, it appears to be a poor prognostic factor. , In some publications, it is considered to be more important than hormone receptor negativity and lymph node involvement.  In the literature, it is agreed that it shortens DFS and OS. ,,, HER-2 positivity is an absolute risk factor for the brain metastasis as well. ,,,,, In both univariate and multivariate analysis, we found that patients with brain metastasis had a high rate of HER-2 positivity and, consistent with the literature; we predict that HER-2 positivity may be a risk factor for brain metastasis.
Although some subtypes have poor prognosis,  ILC, which is the second most common histopathological type with a rate of 10-15%, shows a low response to CT but has a good prognosis. ,,, It is mostly bilateral and multifocal. , ILC leads less commonly to the development of brain metastasis because it has a good prognosis and it is rarely accompanied by other poor prognostic factors. , Consistent with the literature, we found that the tumor tissue of the patients with brain metastasis did not have the ILC component. In the light of these findings, we can state that the likelihood of brain metastasis development is greater in patients with a tumor tissue that does not contain ILC component.
Estrogen causes breast cancer, by acting on estrogen receptor alpha (ER-α) located on the cells of the breast tissue. ER is over-expressed in approximately 70% of the patients with breast cancer. Today, one of the main targets of the treatment for breast cancer is to prevent ER and thereby to prevent the effects of the estrogen.  ER negativity is considered as a poor prognostic factor. , In addition, ER negativity is commonly accompanied by HER-2 positivity.  Brain metastasis is mostly seen in ER-negative patients. ,,,, Consistent with literature, we found that the majority of the patients with brain metastasis were ER-negative. Therefore, we can suggest that ER negativity is a risk factor for brain metastasis.
In the advanced stage cases, progressive breast cancer-related bone metastasis commonly accompanied by osteolytic lesions  is the most commonly detected site of metastasis, with a rate of 70%.  Especially in lymph node-positive patients, most common metastases are observed in the bones. When compared to other organ metastasis, especially with the progress obtained with the therapies, the presence of bone metastasis in patients with breast cancer is considered among the good factors that slow down the clinical progression.  Bisphosphonates, which are commonly used in the therapy, are the leading important factors that slow down the progression of the bone metastasis.  While it was predicted that brain metastasis would be less frequently seen in the presence of bone metastasis which has a better course compared to other organ metastasis, some studies did support this hypothesis.  In patients with bone metastasis, we found that brain metastasis was less common. We suggest that, in metastatic breast cancer patients, development of brain metastasis will be low in the presence of bone metastasis. The lower rate of brain metastases in patients who had bone metastases is probably due to higher rate of ER and PR positivity rather than HER-2 positivity.
In breast cancer patients, liver is the second most common site of metastasis, with a rate of 15%, following bone metastasis. , In breast cancer patients, brain metastasis is generally seen during the late stages after other organ metastasis  and therefore, these patients commonly had liver metastasis before brain metastasis. Although brain metastasis commonly develops in patients with lung metastasis, it is not the case for liver metastasis.  In our study, we rarely determined the concomitant liver metastasis in patients with brain metastasis. Here, we could not completely explain the cause and effect relationship and, it is still unlikely to conclude that the likelihood of brain metastasis is lower in patients with breast cancer who had liver metastasis.
Although a total cure is not possible in the treatment of metastatic breast cancer,  the main targets of this treatment are to prolong the life expectancy of the patient, to prevent the tumor progression, to reduce the cancer-related symptoms and complications and to provide a higher quality of life for the patient.  For this purpose in metastatic breast cancer patients starting appropriate CT in an early period and continue to be an appropriate time prolong the PFS and OS and increase the quality of life. , In both univariate and multivariate analysis, we found that, among the patients with brain metastasis, the number of patients who received CT after the development of the first metastasis in any organ was very low. It may have resulted from the administration of HT instead of CT to the metastatic patients, especially due to advanced age and impaired general health. Thereby, we can predict that the development of brain metastasis may be more common, if the metastatic patients are not given CT.
In breast cancer, brain metastasis is a condition that is difficult to treat and substantially shortens the life expectancy. We believe that, if we could predict brain metastasis in advance, we could take the necessary precautions for this condition like the prophylactic cranial radiation administered in small cell lung cancer patients. However if a patient with breast cancer has vascular invasion positivity, HER-2 positivity, ER negativity, rare detection of ILC component in the tumor tissue, lack of bone and liver metastasis in metastatic stage and did not receive CT after the detection of the first metastasis in any organ we suggest additional therapies except trastuzumab and lapatinib such as prophylactic cranial radiation or any other treatment to prevent brain metastases.
We can state that the most important limiting factor of our study is its retrospective design. The fundamental critics addressed to retrospective studies apply for our study as well. However, in this study, we aimed to focus on an important subject and pave the road for more qualified prospective studies, by revealing our data.
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[Table 1], [Table 2], [Table 3]