Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases

BACKGROUND: The purpose of the current study was to characterize the outcomes of patients with metastatic triple-negative breast cancers, including the risk and clinical consequences of central nervous system (CNS) recurrence. METHODS: Using pharmacy and pathology records, a study group of 116 patients who were treated for metastatic triple-negative breast cancer at Dana-Farber Cancer Institute between January 2000 and June 2006 was identified. RESULTS: The median survival from time of metastatic diagnosis was 13.3 months. Sixteen patients (14%) were diagnosed with CNS involvement at the time of initial metastatic diagnosis; overall, 46% of patients were diagnosed with CNS metastases before death. The median survival after a diagnosis of CNS metastasis was 4.9 months. The age-adjusted and race-adjusted rate of death for patients whose first presentation included a CNS metastasis was 3.4 times (95% confidence interval, 1.9-6.1 times) that of patients without a CNS lesion at the time of first metastatic presentation. Of the 53 patients who developed brain metastases, only 3 patients were judged to have stable or responsive systemic disease in the face of progressive CNS disease at the last follow-up before death. CONCLUSIONS: Triple-negative breast cancer is associated with poor survival after recurrence. CNS recurrence is common, but death as a direct consequence of CNS progression in the setting of controlled systemic disease is uncommon. Thus, it does not appear that the high rate of CNS involvement is because of a sanctuary effect, but rather is due to the lack of effective therapies in general for this aggressive subtype of breast cancer. New treatment strategies are needed.     

Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives

Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood–brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.     

Chemotherapy for breast cancer brain metastases

Breast cancer is the second most common cause of brain metastases, and 10-15% of patients develop clinically overt central nervous system disease. Radiotherapy is the standard treatment for patients with brain metastases. Surgical resection should be considered in patients with isolated brain metastasis and no extracranial disease. The role of chemotherapy in breast cancer brain metastases is not clearly defined; the results of the 8 trials found in the literature are reported. Most experience has been gained with the CMF (cyclophosphamide, methotrexate and fluorouracil) and PE (cisplatin and etoposide) regimens; here the median survival of 6 months is similar to radiotherapy. The blood-brain barrier, maintained by tight endothelial junctions and active transport mechanisms, is a major reason for the lower activity of most chemotherapeutic agents compared to other sites of metastatic disease. Most substances with good penetration of the blood-brain barrier have limited activity against breast cancer and some of the most active substances in breast cancer - including doxorubicine, the taxanes and trastuzumab - appear not to reach the central nervous system in sufficient concentrations. Approaches to overcome the blood-brain barrier are still experimental, and more research is clearly needed to identify chemotherapeutic agents both active in breast cancer and with good penetration of the blood-brain barrier. With the exception of patients with resectable brain metastases, danger of cranial herniation or poor general condition, chemotherapy should be offered to breast cancer patients with brain metastases that have progressive extracranial metastatic disease or relapse after radiotherapy.     

CNS metastasis: an old problem in a new guise.

It is estimated that 10% to 30% of patients with solid tumors are diagnosed with central nervous system (CNS) metastasis. Common primary sites include lung, breast, melanoma, kidney, and colorectal. Brain metastases are increasing, due to the aging population, detection of subclinical disease, and control of systemic disease. CNS metastases are a major cause of morbidity and mortality affecting survival, neurocognition, speech, coordination, behavior, and quality of life. In pediatric acute lymphocytic leukemia event-free survival rates are >80% and the CNS is an important source of extramedullary relapse. CNS metastases are an increasing problem in solid tumors. In this CCR Focus series, four main topics are reviewed: (a) HER-2-positive breast cancer as a paradigm for the problem; (b) model systems for brain metastasis and mechanistic insights into the pathogenesis of brain metastasis; (c) the unique physiology of the blood brain barrier; (d) and the evolving role of radiotherapy in CNS disease and strategies to improve the therapeutic index. Areas for future research include the need for an understanding of site-specific metastasis, effective anticancer strategies for sanctuary sites, assays to detect drug accumulation in sanctuary sites, prevention of CNS metastasis, improving the therapeutic ratio of systemic and CNS-directed therapies, behavioral tools for anticipating/measuring long-term neurocognitive defects, and quality of life assessment of the long-term effect of systemic and CNS-directed therapies.     

Brain metastases in patients with breast cancer: new horizons

Brain metastases occur in as many as one third of patients with disseminated breast cancer. In this article, we discuss various presentations of brain metastases from breast cancer and review evidence that supports different treatment options. Because no prospective, randomized, controlled studies, to our knowledge, have focused solely on patients with brain metastases from breast cancer, we will first review retrospective studies of patients with brain metastases from breast cancer. Randomized studies of patients with brain metastases caused by multiple primary cancers will also be examined, and the conclusions from these studies will be extrapolated to patients with breast cancer. Because brain metastases from breast cancer occur in a variety of different clinical settings, ranging from a single metastasis without extensive extracranial disease to multiple brain metastases with widespread extracranial disease, treatment approaches must be tailored to the specific circumstances of each patient. For different clinical scenarios, neurosurgical resection, radiosurgery, and/or whole-brain radiation therapy may be appropriate treatment options. For patients with brain metastases from breast cancer that overexpresses HER2/neu, trastuzumab could alter the natural history of the non-central nervous system (CNS) disease. Therefore, HER2 status could also influence the treatment of brain metastases from breast cancer. Given the prevalence of brain metastases in patients with metastatic breast cancer in contemporary series, the rationale for clinical trials of CNS screening and prophylactic cranial irradiation will be discussed.     

Breast cancer brain metastases

Breast cancer is the most common malignancy in woman in the USA. Metastasis is a major cause of morbidity and mortality in breast cancer patients. Total incidence of brain metastases of breast cancer is about 30%. Because of the improvements in control of systemic disease, for example the successful use of Trastuzumab, and the consequent prolonged life span, the incidence of brain metastases is increasing in breast cancer patients. The progressive neurological disabilities not only impair the quality of life, but also decrease the survival in patients. However, current treatments are of limited effectiveness. This is partially caused by the unique structure of the blood brain barrier. So far very little is known about the mechanisms how breast cancer metastizes to the brain. Some studies showed that ErbB2 overexpression is associated with the brain metastatic phenotype. Other molecules, like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and chemokine receptor CXCR4 are also involved in the metastasis of breast cancer cell to the brain. The current review will briefly overview the clinical features of brain metastasis of breast cancer and discusses the relationship of blood brain barrier and ErbB2 signal pathway to brain metastasis in breast cancer.     

Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival.

BACKGROUND: As screening central nervous system (CNS) imaging is not routinely performed, the incidence and clinical relevance of occult CNS metastases in advanced breast cancer is unknown. PATIENTS AND METHODS: All patients screened for participation in one of four clinical trials were included; each of the trials excluded patients with known CNS involvement and required screening CNS imaging. A cohort of breast cancer patients with symptomatic CNS metastases was identified from the IU Cancer Center Tumor Registry for comparison. RESULTS: From November 1998 to August 2001, 155 screening imaging studies were performed. Twenty-three patients (14.8%) had occult CNS metastases. HER-2 overexpression (P = 0.02) and number of metastatic sites (P = 0.03) were predictive of CNS involvement by multivariate analysis. Median survival from time of metastasis (1.78 versus 2.76 years; P <0.0001) and from screening (4.67 versus 10.4 months; P = 0.0013) was shorter in patients with than without occult CNS metastasis. Survival among patients with occult CNS metastasis was similar to patients with symptomatic CNS disease. CONCLUSIONS: Patients with CNS involvement, whether occult or symptomatic, have an impaired survival. Occult CNS metastasis is relatively common, but impact on survival of treating occult CNS disease in patients with progressive systemic metastases is questionable.     

Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis

BACKGROUND: Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. METHODS: The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. RESULTS: The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. CONCLUSIONS: The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.     

激素受体阳性乳腺癌脑转移药物治疗研究进展

目的 乳腺癌是仅次于肺癌最易发生脑转移的原发肿瘤.激素受体阳性乳腺癌是转移性乳腺癌的主体,脑转移是该类患者的主要死亡原因,但目前对于激素受体阳性乳腺癌脑转移(breast cancer brain metastases,BCBM)的有效治疗报道较少.本研究旨探讨激素受体阳性BCBM药物治疗的相关研究进展.方法 应用PubMed及CNKI期刊全文数据库检索系统,以"乳腺癌、脑转移和激素受体阳性乳腺癌"等为,检索2005-01-2016-06相关文献,共检测到中文文献128条,英文文献55条.纳入标准:1)BCBM的危险因素及其预后;2)BCBM的当前治疗选择;3)激素受体阳性BCBM药物治疗.根据纳入标准,符合分析的文献25篇.结果限制BCBM药物治疗进展的主要原因是血脑屏障的存在.激素在BCBM治疗中的疗效尚不明确,但有大量个案报道他莫昔芬等内分泌药物对BCBM治疗有效.非对照试验表明某些细胞毒类药物,如卡培他滨、替莫唑胺(temozolomide,TMZ)和卡莫司汀晶片植入剂,对激素受体阳性BCBM有效,但没有足够证据支持具体的治疗方案.免疫抑制剂abemaciclib在激素受体阳性BCBM患者中的应用正处于Ⅱ期临床试验阶段.虽然高分子药物难以通过完整的血脑屏障,但研究证实部分单克隆抗体,如曲妥珠单抗和贝伐单抗,对BCBM治疗有效.纳米药物传递系统能提高中枢神经系统药物转移,有较好发展前景.由纳米颗粒包裹的多柔比星和etirinotecanpegol对治疗激素受体阳性BCBM有一定的疗效.结论尽管目前没有专门批准用于激素受体阳性BCBM系统治疗的药物,但有大量的临床试验正在进行中,将为临床治疗带来启示.     

Identification of brain- and bone-specific breast cancer metastasis genes

In breast cancer, metastases are relatively widely distributed, with the most common sites being bone, regional lymph nodes, lung, liver, and brain. The detailed mechanism of organ-specific metastasis is poorly understood. In this study, we initiated a search for genes that are implicated in brain or bone metastasis of primary human breast cancer. We generated gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors. We identified 73 genes differentially expressed between brain and bone metastases. Visualization of the differential gene expression profiles by correspondence and cluster analyses shows that the metastases clearly separate into two distinct groups as an exact reflection of their site of metastasis. Moreover, the analysis of this gene set in primary breast tumors relapsing to either bone or brain allowed accurate categorization of the tumors according to their metastatic site. The identified genes may prove to be excellent markers to predict the site of metastasis in breast cancer patients and could lead to tailor-made therapy to an individual patient.     

The changing treatment of metastatic her2-positive breast cancer

Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been historically associated with an aggressive disease course with common distant metastasis and poor prognosis. HER2-targeting therapies have significantly changed treatment and drastically improved outcomes for this group of patients. However, primary or acquired resistance to anti-HER2 regimens leads almost universally to disease progression, often with difficult to treat central nervous system (CNS) metastases. The current review summarized the existing therapeutic options for HER2-positive metastatic disease in the first, second and further line setting. Furthermore, novel agents currently under development were presented, which have demonstrated encouraging results in heavily pretreated patients or specific subgroups, such as HR-positive/HER2-positive tumors and CNS disease.     

Systemic chemotherapy,intrathecal chemotherapy,and symptom management in the treatment of leptomeningeal metastasis

Metastasis to the leptomeninges occurs in many common cancers, including leukemia; lung, breast, and gastrointestinal cancers; and tumors of the brain. By way of the flow of cerebrospinal fluid, leptomeningeal metastasis spreads throughout the neuraxis. Consequently, therapy for leptomeningeal metastasis must be directed to the entire central nervous system (CNS). Treatment often consists of involved-field radiotherapy, systemic chemotherapy, and intrathecal chemotherapy. However, because meningeal spread occurs most often in advanced disease, treatment is mainly palliative, except in childhood leukemia, where durable remission has been reported. This article outlines the role of systemic and intrathecal chemotherapy in patients with leptomeningeal metastases. Strategies for symptom management in these patients are also described.     

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.

PURPOSE: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. METHODS: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. RESULTS: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. CONCLUSIONS: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.     

Systemic Therapy in the Setting of Central Nervous System (CNS) Metastases in Breast Cancer

Purpose of Review

Over 25% of patients with metastatic breast cancer will develop brain metastases. Recent advances in systemic therapy, especially molecularly targeted agents, have improved control of extracranial disease, but have had limited effect on intracranial disease. In this review, we discuss the barriers and challenges associated with employing systemic therapy to treat brain metastases. We also provide an overview of current systemic therapy used as standard of care in all subtypes of breast cancer that have metastasized to the brain, as well as describe novel agents that are currently under study in preclinical models or clinical trials.

Recent Findings

While there are few systemic therapies that are standard of care for the treatment of breast cancer brain metastases, there are many novel agents currently in development or under active investigation. Detailed genomic analysis has led to a better understanding of the molecular aberrations that drive metastasis in the different subtypes of breast cancer, leading to rational approaches to the development of targeted molecular therapy.

Summary

The most promising systemic therapeutic modalities for treating breast cancer brain metastases utilize targeted molecular agents or molecular exploitation of the blood-brain barrier in combination with cytotoxic chemotherapy to enhance entry into the CNS.

     

Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma

BACKGROUND: Women with HER-2 overexpressing metastatic breast carcinoma benefit from trastuzumab-based therapy, but trastuzumab does not cross the blood-brain barrier. The authors characterized central nervous system (CNS) disease in these women. METHODS: Using pharmacy records, the authors retrospectively identified 153 women treated with trastuzumab alone or with chemotherapy for HER-2-positive metastatic breast carcinoma at Dana-Farber Partners Cancer Care from June 1998 to December 2000. A study cohort of 122 patients was identified after excluding patients without adequate clinical follow-up or who had CNS disease before trastuzumab treatment. Central nervous system disease was defined as one or more brain metastases or as leptomeningeal carcinomatosis. The median follow-up of this cohort was 23 months. RESULTS: Central nervous system metastases were identified in 34% of patients (95% confidence interval, 26-44%) at a median of 16 months after diagnosis of metastatic breast carcinoma and 6 months from the beginning of trastuzumab therapy. Ninety-three percent of patients with CNS disease presented with clinical symptoms. Five percent of patients with CNS disease had leptomeningeal involvement alone, although 14% had leptomeningeal involvement and parenchymal brain metastases. Fifty percent of patients were responding or had stable disease while receiving trastuzumab at other disease sites at the time of diagnosis of CNS metastasis. The median survival period after CNS metastases was 13 months. Fifty percent of patients died of progressive CNS disease. Patients receiving trastuzumab as first-line therapy for metastatic disease frequently developed brain metastases while responding to or stable on trastuzumab at other disease sites. CONCLUSIONS: Metastatic breast carcinoma to the CNS is common among patients receiving trastuzumab-based therapy, including patients responding to therapy outside the CNS. This may be due either to predilection for the CNS by HER-2-positive tumor cells and/or poor penetration of the CNS by trastuzumab or to improved visceral disease control leading to a longer life and onset of late tumor spread to the CNS. Efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted.     

Extracranial metastatic patterns on occurrence of brain metastases

Extracranial metastases and their frequency by sites have been described as prognostic factors for survival of patients with brain metastasis. However, these factors must be identified and described in more detail for a large series of patients. Using routine data from the largest German health insurance fund, 5,074 patients with brain metastasis who were diagnosed and treated in 2008 were analyzed to identify the frequency and distribution of extracranial metastatic sites concurrent with brain metastasis in relation to age, gender, and tumor type. Brain metastases were observed in males more frequently than in females (56.4 and 43.6% respectively P < 0.001), and were most often from lung (51.2%), breast (12.3%), and unknown (7.5%) primaries. Extracranial metastatic sites were observed in 58.8% of patients; the number of sites was from 1 to 7, with a mean of 1.11. For the 16 most common primary sites the range was from 0.13 to 1.91 . In 11 of these 16 sites, lungs were the most common concurrent metastatic site. Lung cancer, breast cancer, non-Hodgkin’s lymphoma, and testicular cancer most commonly metastasized to bone, and bladder cancer to kidneys. Different primary tumors have different frequencies and patterns of extracranial metastatic sites concurrently with brain metastasis. The lung is the most common metastatic site of most primary tumors, bone for a few tumors, and kidneys for bladder cancer. For the unknown primary tumor type, screening for these most common metastatic sites must be intensified, in particular when molecular assessment is not available.     

Progress in the Biological Understanding and Management of Breast Cancer‐Associated Central Nervous System Metastases

Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%–16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%–5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2‐positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer‐associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.     

Expression of KAI1/CD82 in distant metastases from estrogen receptor-negative breast cancer

The tetraspanin protein superfamily member KAI1 suppresses tumor growth and metastasis in animal models and is downregulated in various human malignancies. In breast cancer, KAI1 is preferentially lost in estrogen receptor (ER)-positive tumors. Interestingly, most ER-negative primary breast cancers retain KAI1 expression. This study aimed to evaluate whether or not KAI1 is downregulated during progression to metastasis of these carcinomas. Expression of KAI1, ER, progesterone receptor, c-ErbB2, and Ki67 was analyzed in tissue microarrays comprising a large collection of distant organ metastases from human breast cancers ( n  = 92) by immunohistochemistry. Results were compared with a previously characterized set of primary breast tumors ( n  = 209). Immunoreactivity for KAI1 was observed in one-third of the metastases and was associated with lack of ER expression ( P  = 0.005). The high frequency of KAI1-positive cases in ER-negative primary tumors was maintained in ER-negative metastases. Expression of KAI1 was also observed in MDA-MB-468 and SK-BR-3, two ER-negative breast cancer cell lines of metastatic origin. Moreover, a reanalysis of independent microarray gene expression data indicated maintenance of KAI1 mRNA expression in metastases from ER-negative breast cancers. Furthermore, in a series of matched pairs of mammary carcinomas and metachronous distant metastases, all metastases from KAI1-positive/ER-negative primary tumors were KAI1-positive as well. Collectively, these findings demonstrate that the expression of KAI1 is maintained during progression to metastasis in a large proportion of ER-negative mammary carcinomas. This has significant implications for the use of KAI1 as a clinical marker and the understanding of the metastatic process in human breast cancer. ( Cancer Sci 2009; 100: 1767–1771)     

Capecitabine Therapy of Central Nervous System Metastases from Breast Cancer

Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994–2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18–165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.     

Clinical and cell line specific expression profiles of a human gene identified in experimental central nervous system metastases

Some cancers, particularly malignant melanomas and carcinomas of the breast and lung, metastasize to the central nervous system (CNS) in advanced stages. In order to develop into clinically manifest metastases, hematogenously disseminated tumor cells must respond to trophic factors within the CNS microenvironment. We have previously identified a nuclearfactor, com1, expressed in human breast carcinoma cells upon formation of experimental metastatic tumors in the CNS. In the present study distinct com1 mRNA expression was detected in cerebral metastases from patients with lung carcinomas, whereas the expression level was generally much lower in glioblastomas (primary brain tumors). In tissue specimens from normal brain and lung, as well as in glioma and lung carcinoma cell lines, com1 expression was barely detectable. One potential mechanism involved in the induction of com1 expression was indicated in the metastatic MCF7/LCC2 breast carcinoma cells. Significant increases in the level of com1 mRNA were observed upon activation of receptor tyrosine kinase signaling, which is known to operate during metastatic tumor cell proliferation within the CNS. The observations in this study strengthen the assumption that com1 may be involved in the tumor cell response to regulatory signals upon metastasis formation.