Chapter 16 - Brain Metastases from Breast Cancer in Patients Receiving Trastuzumab

Abstract

Only 2% of brain metastases from solid tumors originate from breast cancer. However, this occurrence is relatively common in some subsets of breast cancer, including triple-negative and human epidermal growth factor receptor 2 protein (HER2) positive tumors. Among patients with advanced HER2-positive breast cancer, the incidence of brain metastases is in the range of 10–40%. Trastuzumab, a recombinant, humanized monoclonal IgG1 antibody that binds to extracellular subdomain IV of HER2/neu receptor, is used in HER2-positive breast cancer patients in adjuvant and metastatic setting. This therapy is associated with increased response rates, prolonged disease-free survival, and overall survival. Owing to its high molecular weight, penetration of trastuzumab into the central nervous system is extremely low, 1/420th of serum levels. Thus, trastuzumab is ineffective in treating established brain metastases and its preventive effect in the brain is likely indirect, by virtue of combating extracranial disease. New anti-HER2 agents with different mode of action and higher permeability to the central nervous system may have increased efficacy in the brain. The local management of brain metastases originating from breast cancer is dependent on patient performance status, the extent of brain involvement, and the coexistence of progressive extracranial disease, and includes surgery, stereotactic radiotherapy, and whole brain irradiation. There are no uniform recommendations for systemic therapy in HER2-positive breast cancer patients with brain metastases. According to recent ASCO guidelines, patients whose extracranial disease is not progressive at the time of brain relapse should not be switched to another systemic therapy, whereas in patients with progressive extracranial disease, other anti-HER2-targeted agents should be considered. A new area of preclinical and clinical investigations is prevention of brain metastases in high-risk groups of patients with both local and systemic therapies. The development of biomarkers predictive for brain relapse may allow selection of patients for such management and prompt new preventive and therapeutic strategies.