Central nervous system (CNS) metastases are the

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1 o r i g i n a l c o m m u n i c a t i o n Characteristics of Breast Cancer Patients with Central Nervous System Metastases: A Single- Center Experience Hakan Harputluoglu, MD; Omer Dizdar, MD; Sercan Aksoy, MD; Saadettin Kilickap, MD; Didem S. Dede, MD; Yavuz Ozisik, MD; Nilufer Guler, MD; Ibrahim Barista, MD; Ibrahim Gullu, MD; Mutlu Hayran, MD; Ugur Selek, MD; Mustafa Cengiz, MD; Faruk Zorlu, MD; Gulten Tekuzman, MD; and Kadri Altundag, MD The aim of this study was to assess the characteristics of breast cancer patients with central nervous system (CNS) metastases and factors associated with survival after development of CNS metastasis. One-hundred-forty-four patients with brain metastases were retrospectively analyzed. Median age at the time of brain metastasis diagnosis was Median time between initial diagnosis and development of brain metastasis was 36 months. Fourteen cases had leptomeningeal involvement. Twenty-two patients (15.3 %) had single metastasis. Ten percent of the patients had surgery, 94% had radiotherapy and 63% had chemotherapy. Median survival after development of brain metastasis was 7.4 months. Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p=0.0006). Survival of patients who received chemotherapy was significantly longer than those who received radiotherapy alone (9.9 vs. 2 months, p<0.0001). In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p=0.047 and p<0.0001, respectively). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage, grade, hormone receptor or HER2 status individually were not associated with survival. In this study, survival after the diagnosis of CNS metastases appeared to be affected by patient characteristics rather than biologic characteristics of the tumor. This is probably secondary to the lack of effective treatment options in these patients and overall poor prognosis. Key words: breast cancer n brain n metastasis n prognosis From Hacettepe University Institute of Oncology, Department of Medical Oncology (Harputluoglu, Dizdar, Aksoy, Kilickap, Dede, Ozisik, Guler, Barista, Gullu, Tekuzman, Altundag), Department of Radiation Oncology (Selek, Cengiz, Zorlu) Harputluoglu, Department of Preventive Oncology (Hayran), Ankara, Turkey. Send correspondence and reprint requests for J Natl Med Assoc. 2008;100: to: Dr. Omer Dizdar, Department of Medical Oncology, Hacettepe University Institute of Oncology, Sihhiye Ankara 06100, Turkey; phone: ; fax: ; omerdiz@yahoo.com Introduction Central nervous system (CNS) metastases are the most common cause of malignant disease in the brain, affecting up to 25% of cancer patients. With better control of systemic disease, CNS is emerging as a sanctuary site of relapse in patients with otherwise controlled cancer. Therefore, control of CNS disease has become a more vital component of overall disease control and quality of life. Breast cancer is the second most common cause of CNS metastasis, following lung cancer. 1 The incidence of brain metastasis in breast cancer patients is 14 20%, whereas autopsy series reveal another 10% with clinically undetected metastases. 2 CNS metastases are a major cause of morbidity and mortality affecting survival, and quality-of-life issues, including speech, behavior, cognition, pain, etc. CNS metastasis was the cause of death or a major contributing factor to it in 68% of the patients. 3 Treatment consists of radiotherapy, radiosurgery, surgery in selected cases and corticosteroids, along with systemic chemotherapy. 4 Risk factors for the development of CNS metastasis from breast cancer include young age, ductal histology, estrogen receptor negativity and human epidermal growth factor receptor-2 (HER2) overexpression, high tumor grade, epidermal growth factor receptor (EGFR) overexpression and BRCA1 phenotype. 3,5-9 Identification of patients at high risk for CNS metastasis is important, so that early screening and treatment with agents that cross blood-brain barrier or prophylactic cranial irradiation can be considered. Prognosis of patients with brain metastases is generally poor. Median survival ranges between months depending on the performance status (PS), age and primary tumor control. High performance status, younger age, estrogen receptor (ER) positivity, presence of solitary brain metastasis, longer disease-free interval and systemic tumor control were the significant favorable prognostic factors reported. 1,3,10,11 There is much debate over the effect of HER2 status on prognosis of brain metastases. Amplification of the HER2 oncogene is seen in ~25 % of the patients and is associated with poor prognosis. The incidence of JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 100, NO. 5, MAY

2 CNS metastases was higher in patients with HER2-positive tumors than those with negative tumors. 12 Various factors account for this higher incidence. HER2-positive tumors have a biological predisposition for visceral metastasis as well as CNS metastasis. Trastuzumab, a humanized monoclonal antibody against HER2, increases overall survival in patients with HER2-positive tumors. Hence, more patients receiving trastuzumab live longer enough to experience brain metastases that would otherwise stay clinically silent. However, trastuzumab does not cross the blood-brain barrier well. Consequently, there is an increase in CNS metastasis in patients with HER2-positive tumors receiving trastuzumab, even in patients with controlled systemic disease. More than two-thirds of patients in various series presented with CNS metastasis at a time when their systemic disease remained either stable or responsive to trastuzumab. 13 On the other hand, patients with HER2- overexpressing breast cancer who received trastuzumab had a significantly longer survival after developing brain metastases compared with patients with tumors that did Table 1. Patient characteristics Characteristics % Age (Median) 45 Menopausal Status Premenopausal Perimenopausal Postmenopausal Stage at Diagnosis I II III IV Grade I II III Estrogen Receptor Unknown Progesterone Receptor Unknown HER2 Unknown CNS involvement Parenchymal Leptomeningeal Histology Ductal Lobular Other not overexpress HER2 (22.4 vs. 9.4 months from date of brain metastasis, respectively). The survival advantage was suggested to result from better control of extracranial systemic disease in patients with HER2-overexpressing tumors who received trastuzumab. 14 Conventional treatment of brain metastases has been whole-brain radiotherapy (WBRT). WBRT generally ameliorates symptoms and improves quality of life, with the cost of neurocognitive detriment secondary to radiation damage in the long run. Younger patients with higher performance status scores and controlled systemic disease have the longest median survival after WBRT, according to the recursive partitioning analysis of Radiation Therapy Oncology Group. 5 There are clinical trials of radiosensitizers which have showed to improve efficacy of WBRT. 15 Radiosurgery is another therapeutic modality which permits delivery of higher doses of radiation to CNS lesions without irradiating normal brain tissue, thus decreasing neurocognitive damage. Systemic treatment options include cytotoxic chemotherapy and targeted therapies. Although blood-tumor barrier is more permissive to chemotherapeutics and WBRT further increases permeability of blood-brain barrier, responses to cytotoxic agents are unsatisfactory. Two targeted agents, i.e., lapatinib and bevacizumab, have demonstrated encouraging activity in HER2-positive patients in clinical trials. 16,17 Many studies evaluating the efficacy of systemic treatments in patients with brain metastasis are ongoing. On this background, we aimed to investigate our single institutional data retrospectively to assess the characteristics of breast cancer patients with CNS metastases and factors associated with survival following detection of CNS metastasis. Patients and Methods This retrospective analysis was performed in Hacettepe University Institute of Oncology, Ankara, Turkey. Onehundred-forty-four (143 female and one male) patients with brain metastases diagnosed between June 1982 and March 2006 at our institution were analyzed in the study. Breast cancer diagnosis was made with core-needle biopsy or excisional biopsy of the breast tumor. CNS metastasis was defined as parenchymal or leptomeningeal involvement with tumor metastasis. The diagnosis was made either by computed tomography (CT)/magnetic resonance imaging (MRI) studies or cerebrospinal fluid cytology. Age and menopausal status of the patients, tumor type, stage, grade, hormonal and HER2 status, local and systemic treatments, interval between first diagnosis and occurrence of CNS metastasis, and survival thereafter were recorded, from the patient files or patient database of our hospital. Statistical analyses were performed using SPSS for Windows, version 10.0 (SPSS Inc., Chicago, IL). Descriptive statistics were reported as proportions. Continuous variables were reported as median (interquartile range). A two-tailed p<0.05 was considered statistically significant. Survival rates were calculated with the Kaplan-Meier 522 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 100, NO. 5, MAY 2008

3 method, and differences between groups were assessed with the log-rank test. Independent variables predicting survival were evaluated by using the Cox proportional hazards model, sharing in all variables with p values <0.20 in the univariate analysis except for HER2 status and biological subtype (both of which have p values >0.05), where high number of unknowns would risk the validity of the model. The 95% confidence interval was calculated for all hazard ratios (HRs) in Cox regression analysis. Results Patient characteristics are presented in Table 1. Sixty percent of the patients were premenopausal. Median time between initial diagnosis and development of brain metastasis was 36 months. Median age at the time of brain metastasis diagnosis was Twenty-two patients (15.3%) had single metastasis. CNS was the first site of metastasis in 21 (14.6%) patients. Leptomeningeal involvement was seen in 14 (10%) cases (three cases with lobular carcinoma and 11 cases with ductal carcinoma). After the diagnosis of brain metastases, surgery was performed in 15 patients, 11 of whom had single metastases and four had multiple metastases. Ninety-four percent of the patients were treated with cranial radiotherapy. Ninety patients (63%) received chemotherapy following radiotherapy. One-hundred-one patients died during follow-up. Median survival was 52.7 months, and median survival after development of brain metastases was 7.4 months (Figure 1). Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p=0.0006). Survival of patients who received chemotherapy was significantly longer than those who received cranial radiotherapy alone (9.9 vs. 2 months, p<0.0001). In univariate analyses, presence of single metastasis (p=0.0006), surgery (p=0.016) and chemotherapy (p<0.0001) were associated with longer survival. Estrogen, progesteron and HER2-receptor status individually did not have a significant impact on survival after brain metastases; however, when the patients were regrouped as having triple-negative tumors versus others, patients with triple-negative tumors had shorter survival than others, with borderline significance (6.6 vs. 13 months, respectively, p=0.06). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage or grade were not associated with survival (Table 2). The male patient was included in all the analyses, and gender was not included as a separate variable in univariate analysis. In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p=0.047 and p<0.0001, respectively) (Table 3). Discussion We retrospectively evaluated prognostic factors of breast cancer patients with brain metastasis in our institution. This Figure 1. Survival of patients after diagnosis of brain metastasis JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 100, NO. 5, MAY

4 study revealed that only the presence of solitary brain metastases and systemic treatment with chemotherapy after the diagnosis of brain metastasis were the significant predictors of survival in contrast to previous studies reporting many significant prognostic factors such as Karnofsky performance status, presence of solitary brain metastasis, younger age, ER positivity, HER2 positivity, ductal histology, systemic tumor control, response to corticosteroid treatment, Table 2. Univariate analyses of factors associated with survival from diagnosis of brain metastasis Median Survival (Months) Age Menopausal Status Premenopausal Perimenopausal Postmenopausal Stage I II III IV Histologic Grade I-II III Estrogen Receptor Progesterone Receptor HER2 Number of Lesions Single Multiple Location of Lesions Parenchymal Leptomeningeal Biologic Subtype Triple negative Other Surgery Performed Not performed Chemotherapy Performed Not performed < p Table 3. Multivariate Cox proportional hazards model results showing the factors associated with survival after development of CNS metastasis HR 95% CI Median Survival (Months) 1-year Survival (%) P Value Number of Metastasis Multiple Single Chemotherapy No Yes % 35 % < JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 100, NO. 5, MAY 2008

5 and longer disease-free interval.4,9,11,14,18 The mechanism of brain metastasis is poorly understood. Alterations were found in expression of various genes and DNA methylation, which have been implicated in tumor cell apoptosis, angiogenesis and energy metabolism. 19 In a study which analyzed protein expression profiles of tumor cells from breast cancer brain metastases, the majority of proteins that were differentially expressed in brain metastatic variant of breast cancer cells were involved in cell metabolism, supporting the hypothesis that adaptation of tumor cell energy metabolism is crucial in breast cancer brain metastases. 20 Clarifying the exact mechanism of brain metastases will generate new therapeutic targets and better treatment options. Overall survival after WBRT is poor (4 6 months). Therefore additional measures to increase survival and quality of life in patients with brain metastasis are investigated. Overall survival improved in patients, particularly with single brain metastasis with the addition of surgery or stereotactic radiosurgery to WBRT. 21 Surgical removal of all lesions in selected patients with multiple brain metastases also resulted in significantly increased survival time. 22 In our study, 94% of the patients received WBRT, and 11 of 20 patients with single metastasis were operated. Surgery was one of the significant factors predicting survival in univariate analysis. Better survival observed in patients with single metastasis in our study can be partially attributed to the high rate of surgery performed in this group. The role of systemic chemotherapy is controversial in patients with CNS metastases. The intact blood-brain barrier precludes the entry of most chemotherapeutic agents into the CNS. Agents that cross blood-brain barrier, such as temozolomide and idarubicin, have limited activity in breast cancer. Disrupted blood-brain barrier by either the tumor itself or radiotherapy permits passage of certain amounts of chemotherapeutics. 23 By this way, objective responses up to 40 60% were obtained with single or combined use of cisplatin, etoposide, carboplatin, cyclophosphamide, anthracyclines, temozolomide, 24 etc. Capecitabine is another option for brain metastases. Although the passage from intact blood-brain barrier is unknown, there are case reports demonstrating very good clinical and radiological responses to capecitabine. 25 Tamoxifen has been demonstrated to reach brain metastases with similar concentrations to tumor and serum; 26 however, clinical benefit is reported in only few cases. 27 Trastuzumab poorly penetrates blood-brain barrier. Cerebrospinal fluid-to-serum ratio of trastuzumab was found to be 1:420 in breast cancer patients with CNS metastases receiving trastuzumab. Although radiotherapy increased permeability to trastuzumab, CSF levels are generally therapeutically inadequate. 28 Lapatinib is an oral inhibitor of EGFR and HER2. Among 39 patients with progressive HER2-positive breast cancer and CNS metastases, two objective responses in the CNS was reported. 29 In another phase-iii study comparing capecitabine alone versus capecitabine and lapatinib in patients with advanced breast cancer having progression under trastuzumab containing regimens, the number of patients who developed brain metastases under treatment was lower in the lapatinib arm (four patients in capecitabine plus lapatinib arm versus 11 patients in capecitabine arm, p=0.110). 17 Various chemotherapy regimens, including capecitabine, ifosfamide, etoposide, navelbine, mitomycine were used as adjunct to WBRT in our patients, with more or less similar survival times. We know that patients who receive chemotherapy are those who have a good performance status. Therefore, in the light of previous literature, we have interpreted the significant impact of chemotherapy on survival in our study in three ways as a consequence of good performance status of the patients receiving chemotherapy, better control of extracranial systemic disease with chemotherapy and activity (albeit limited) on CNS lesions. Neither ER/progesterone receptor (PR) nor HER2 overexpression individually was associated with the time from initial diagnosis to development of brain metastases or survival after brain metastases in our study. However, triple-negative phenotype was a significant prognostic factor in univariate analysis but not in multivariate analysis. A low number of patients with triple-negative tumors (n=10) may account for this. Nevertheless, triple-negative tumors have been reported to have a more aggressive course, and shorter survival in our series may be secondary to uncontrolled systemic disease in those patients. Expression of ER was previously reported to be associated with favorable prognosis in patients with brain metastases. 11 However, whether the course of triple-negative tumors with brain metastases is different is unknown. A limitation of our study was the relatively small number of patients in subgroups, which might increase the probability of type-ii error. Additionally, performance status data were not included in univariate analyses as they were lacking in most of the patient records obtained from the computer database. Hence, we could not evaluate the individual impact of PS and chemotherapy on survival. In conclusion, prognosis of patients with brain metastases is yet poor, although improving. Survival after the diagnosis of CNS metastases did not seem to be affected by biologic characteristics of the tumor in this cohort, including ER, PR, HER2 or histologic grade. This appeared probably secondary to the lack of effective treatment options in these patients and overall poor prognosis. Understanding the pathophysiology of brain metastases and defining new therapeutic targets, new strategies for the delivery of drugs to CNS, employing additional local treatments such as radiosurgery, improving systemic treatments and identifying subgroups of patients who could benefit most can change the dismal course of these patients. REFERENCES 1. Nussbaum ES, Djalilian HR, Cho KH, et al. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78: Tsukada Y, Fouad A, Pickren JW, et al. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer. 1983;52: JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 100, NO. 5, MAY

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