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

Abstract

BACKGROUNDWomen 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.METHODSUsing 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.RESULTSCentral 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.CONCLUSIONSMetastatic 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. Cancer 2003;97:2972–7. © 2003 American Cancer Society.DOI 10.1002/cncr.11436

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

“…Cumulative 3-year risk of brain relapse of 42% is in the range found in other series of HER2-positive advanced breast cancer patients [11][12][13][14][15][16][17]23]. In this cohort the average annual risk of symptomatic brain relapse for surviving patients during consecutive 7 years of follow-up was 10%, with no apparent plateau.…”

“…Currently HER2-positive breast cancer patients are managed with trastuzumab, a monoclonal antibody against extracellular domain of HER2 receptor. Trastuzumab does not cross through the blood-brain barrier and is ineffective in preventing and treating brain lesions [11][12][13][14][15][16][17]. Recently, Food and Drug Administration (FDA) and European Medicines Agency (EMEA) granted approval to lapatinib, an anti-HER2 small-molecule tyrosine kinase inhibitor, for use in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment.…”

“…With the increased treatment efficacy of extracranial lesions, poor control of brain lesions may largely influence prognosis. For example, in a recent series including metastatic breast cancer patients treated with trastuzumab, nearly half of deaths were due to progressive brain disease [11]. It is hoped that determining tumor and host risk factors for brain metastasis might allow selection of candidates for preventive strategies.…”

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

“…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.…”

Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain

“…13 The percentage of patients where their primary tumor metastasizes to the brain has been increasing over the last two decades, related in part to the increased efficacy of current treatments for primary disease and the associated increased survival. 14,15 We previously established a model of breast cancer brain metastases with intracerebral implantation of human breast cancer cells. Direct intratumoral injection of G207 into intracerebral MDA-MB-435 tumors was efficacious in significantly extending survival.…”