Breast Cancer Metastasis to the Central Nervous System

Abstract

Clinically symptomatic metastases to the central nervous system (CNS) occur in Natural History of CNS MetastasisOf the nearly 1.3 million people diagnosed with cancer in the United States each year, ϳ100,000 to 170,000 will develop brain metastases, for an annual incidence of ϳ4.1 to 11.1 per 100,000 population (American Cancer Society Cancer Facts and Figures 2005, available at http://www.cancer.org). 1 Large autopsy studies suggest that between 20% and 40% of all patients with metastatic cancer will have brain metastases (http://www.cancer. org). [1][2][3][4] Given their overall greater frequency, lung and breast cancer are by far the most common tumors to present with brain metastases. 2,4 The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges from 10 to 16%. 5 On average, the median latency between the initial diagnosis of breast cancer and the onset of brain metastasis is ϳ2 to 3 years. 1,2 In most cases, breast cancer patients develop brain metastases after metastases have appeared systemically in the lung, liver, and/or bone. 6 For the purposes of this review, central nervous system (CNS) and brain are used interchangeably.Several risk factors for brain metastases have been reported. Young age appears to correlate with elevated risk. 5,7 In a study of 1015 women with metastatic breast cancer, brain metastases occurred in 9% of women with estrogen receptor-negative (ERϪ) primary tumors, compared to 5% of patients with ERϩ primary tumors. 8 Many human breast cancers (25 to 33%) express Her-2, also known as the epidermal growth factor receptor erbB2 or the neu oncogene [Online Mendelian Inheritance in Man (OMIM) accession number 164870; http://www.ncbi. nlm.nih.gov/entrez/dispomim.cgi?id ϭ 164870, accessed 2.25.05]. Amplification or overexpression of Her-2 correlates with a shorter disease-free and overall survival time 9 and also appears to associate with a higher incidence of brain metastases. 10 -12 The metastasis of breast cancer to the CNS, either the brain parenchyma or the leptomeninges, is generally a late feature of metastatic disease. Metastases to the brain parenchyma are thought to be hematogenous in origin. In a retrospective survey of breast cancer patients with brain metastases, 78% had multiple intracerebral metastases, 14% had a solitary intracerebral metastasis, and the remaining 8% had leptomeningeal metastases. 7 Breast cancer is the most common solid tumor to exhibit leptomeningeal colonization. 13 Within the three membranous coverings, or meninges, that surround the brain, leptomeningeal metastases arise on the innermost covering (pia) and the middle membrane (arachnoid) or in the cerebral spinal fluid (CSF)-filled space between the arachnoid and the pia (subarachnoid space). 4 Spread to the leptomeninges may occur via multiple routes including hematogenous, direct extension, transport through

Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer

“…1,17 Only a limited number of patho-anatomical studies on the brainmetastasizing type of breast cancer has been undertaken and even fewer studies of human CNS metastases are available because only a small percentage of affected patients undergo surgery. 8,18,19 Lear-Kaul et al 19 investigated Her-2/neu expression/ amplification in nine paired cases of brain-metastasizing breast cancer and showed CNS metastases to reflect widely the status of the primary tumour. In contrast, EGFR expression exhibited a higher degree of diversity between primary cancer and brain metastasis with concordance in only 8 out of 11 patients (73%).…”

“…Another prognostic adverse feature is provided by Her-2/neu overexpression or amplification, which 8 or by a high intrinsic propensity of amplified cancers to metastasize in the CNS. 27 In the current series, only one patient who received antibody therapy was included.…”

“…2,3,5,6 In addition, the higher incidence may be caused by clonal selection induced by novel therapeutic agents like Herceptin. [7][8][9][10] Because diagnostic imaging procedures will usually only be performed after clinical symptoms have become manifest, identification of risk factors for CNS involvement could enable specific surveillance and management of patients at risk. Indicators of an increased risk for CNS metastases have been described such as young age at diagnosis, diseasefree interval less than 1 year, oestrogen receptor (ER) or progesterone receptor (PR) negativity, 11 and Her-2/neu amplification.…”

Brain Tumor Imaging: Live Imaging of Glioma by Two-Photon Microscopy

“…Despite progress in treating primary tumors in the periphery, tumors that initiate in the central nervous system (CNS) or that preferentially migrate from peripheral primary or secondary metastatic sites into the brain remain refractory to treatment (King et al 2005;Lin et al 2004;Weil et al 2005). Neurons and the supporting glial cells of the brain create a distinct microenvironment for primary brain tumors, and metastastic tumor cells must adapt to this unique environment (Weil et al 2005).…”

“…Neurons and the supporting glial cells of the brain create a distinct microenvironment for primary brain tumors, and metastastic tumor cells must adapt to this unique environment (Weil et al 2005). Furthermore, to enter the brain, tumor cells and therapeutics must cross the blood-brain barrier.…”