Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not <i>HER2/neu</i>‐positive breast cancer

Yonemori, Kan; Tsuta, Koji; Ono, Makiko; Shimizu, Chikako; Hirakawa, Akihiro; Hasegawa, Tadashi; Hatanaka, Yutaka; Narita, Yoshitaka; Shibui, Soichiro; Fujiwara, Yasuhiro

doi:10.1002/cncr.24735

Cited by 119 publications

(103 citation statements)

References 25 publications

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“…In our study, the immunohistochemical profiles for ER, PR and HER2 differed between the primary tumors and the brain metastases in 29.3% of the patients. Prior hormone therapy or chemotherapy exerted an effect on this discordance phenomenon (1)(2)(3)(4)(5)32,33). All the patients with ER or PR alterations (positive-negative and negative-positive) had received hormone therapy prior to the development of brain metastases.…”

Section: Discussionmentioning

confidence: 99%

Extended trastuzumab therapy improves the survival of HER2-positive breast cancer patients following surgery and radiotherapy for brain metastases

Okita

Narita²,

Suzuki

et al. 2013

Molecular and Clinical Oncology

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Abstract. Brain metastases usually present late during the course of breast cancer and are associated with an unfavorable prognosis. It was previously demonstrated that the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) may be altered in the time window between the emergence of the primary breast tumor and the development of metastases. The aim of this study was to compare the expression of ER, PR and HER2 in pathology samples of primary breast cancer and brain metastases in order to evaluate whether previously administered therapy was able to modify this status and determine whether biomarker alterations affect prognosis after the development of brain metastases. Data were collected from 62 patients who were initially diagnosed with breast cancer that had metastasized to the brain. The ER, PR and HER2 status of the samples from the primary tumors and the brain metastases was determined. Differences in the immunohistochemical profiles of ER, PR or HER2 between the primary tumors and the brain metastases in 17 patients (29.3%) were identified. The patients with HER2-positive brain metastases who received trastuzumab had no leptomeningeal metastases and exhibited a longer survival time after brain metastases compared to the HER2-positive patients who did not receive trastuzumab and the patients with HER2-negative brain metastases (P=0.0005). Our results suggested that the patients treated with trastuzumab following surgery and radiotherapy for brain metastases exhibited a better prognosis. Thus, the HER2 status in brain metastases requires re-evaluation and extended trastuzumab therapy is recommended after brain metastases.

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Section: Discussionmentioning

confidence: 99%

Extended trastuzumab therapy improves the survival of HER2-positive breast cancer patients following surgery and radiotherapy for brain metastases

Okita

Narita²,

Suzuki

et al. 2013

Molecular and Clinical Oncology

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“…The existence of the blood-brain barrier, with efflux pumps in brain endothelium capable of preventing the penetration of many therapeutic agents (especially natural products such as anthracyclines and taxanes), has long been recognized, but also debated as a cause of therapeutic failure, given its disruption in the setting of brain metastasis (9). One recent clinical report has suggested that disruption of the blood-brain barrier is common in triple-negative breast cancers but rare in HER2-positive brain metastases (10).…”

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confidence: 99%

Heading in a New Direction: Drug Permeability in Breast Cancer Brain Metastasis

Sledge

2010

Clinical Cancer Research

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Systemic therapies for breast cancer brain metastasis are largely unsuccessful. Mouse models of brain metastasis show significant heterogeneity in uptake of paclitaxel and doxorubicin, with average levels more than those seen in normal brain tissue, but significantly less than in metastases to other organs. Clin Cancer Res; 16(23); 5605-7. Ó2010 AACR.Brain metastasis may be the most devastating, and is certainly the most feared, consequence of breast cancer. It not only robs the patient of her life, it has the potential to rob her of her self, of her essence as a human being. It is also poorly studied. In the clinic, this dearth of research has been a function of the difficulty of obtaining tissue in those who suffer from it, and the lack of dedicated trials. In the laboratory, researchers have lacked model systems that allow them to dissect the mechanisms and effects of brain metastasis. This situation is now changing, as shown in the report by Lockman and colleagues in the current issue of Clinical Cancer Research (1).What we know about brain metastasis in breast cancer is easily summarized. Although not the most frequent of clinical presentations, numerous autopsy studies have shown that occult brain metastases are exceptionally common (2). As many as 15% of patients with advanced breast cancer will have asymptomatic brain metastases visible on screening MRI or computer assisted tomography (CAT) scans (2).Brain metastasis occurs relatively more commonly in patients with HER2-positive and triple-negative (basal) breast cancers than in patients with estrogen receptorpositive breast cancers (3, 4). Among patients with HER2-positive tumors, the frequency of brain metastasis may have increased recently as a function of the use of trastuzumab, of which the inability to penetrate the central nervous system, even as it controls other metastases, allows clinical brain metastases time to emerge (4).Therapy for brain metastases has been divided into local control measures (both surgery and radiation therapy) and systemic therapy. Local control measures are palliative and generally ineffective, with median survivals following diagnosis generally fewer than 12 months (5, 6). More targeted radiation techniques (e.g., stereotactic radiation) have improved palliation and (in combination with whole brain radiation for patients with few lesions) modestly improved survival (6). Systemic therapies [both chemotherapy, hormonal therapy, and more recently HER2-targeted therapy with the small molecule receptor tyrosine kinase (RTK) inhibitor lapatinib] produce occasional responses of short duration (7, 8). All told, it is a gloomy story.Why have we failed so miserably? Part of the failure, of course, represents our larger failure to cure metastatic breast cancer, a failure rooted in the development of drug resistance to all existing systemic therapy modalities. But there has always been a sense that brain metastasis poses specific challenges, rooted in normal neurophysiology, which must be addressed if we are to improve outcome. The...

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“…Little is known about the pharmacokinetics of trastuzumab in the CNS and its ability to pass the intact BBB [8]. Stemmler and colleagues measured trastuzumab levels in the serum and in CSF of HER2+ MBC patients with brain metastases and systemic trastuzumab treatment, before and after WBRT.…”

Section: Discussionmentioning

confidence: 99%

“…HER2+ breast cancer has an increased risk of central nervous system (CNS) metastases [2] but there are little data on LC frequency in these tumors [3]. Trastuzumab, a monoclonal antibody against the extracellular domain of the HER2 receptor, is highly effective in systemic control of HER2+ metastatic breast cancer [4] but it is not clear if it can penetrate the intact blood brain barrier (BBB) [5]. We report the case of a patient who received weekly intrathecal (IT) trastuzumab for LC from HER2+ breast cancer for 18 months, with impressive neurological benefit.…”

Section: Introductionmentioning

confidence: 99%

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

Oliveira¹,

Braga

Passos‐Coelho³

et al. 2011

Breast Cancer Res Treat

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Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after leptomeningeal carcinomatosis diagnosis.A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule and duration of treatment.

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Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

Cited by 119 publications

References 25 publications

Extended trastuzumab therapy improves the survival of HER2-positive breast cancer patients following surgery and radiotherapy for brain metastases

Extended trastuzumab therapy improves the survival of HER2-positive breast cancer patients following surgery and radiotherapy for brain metastases

Heading in a New Direction: Drug Permeability in Breast Cancer Brain Metastasis

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

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