Brain Metastases from Breast Cancer in Patients Receiving Trastuzumab

Introduction

HER2 Receptor

The HER2/neu proto-oncogene is located in chromosome 17q11-q21 ( ). In physiological conditions, this gene encodes a glycoprotein with molecular mass of 185 kDa (p185), named HER2 receptor or HER2 protein. HER2 and three structurally related tyrosine kinase receptors—HER1 (epidermal growth factor receptor (EGFR)), HER3 (ErbB3) and HER4 (ErbB4)—constitute the ErbB family. HER2/neu gene amplification and/or overexpression, which occur in 15–20% of invasive breast cancers and in up to 60% of intraductal breast carcinomas, play(s) an important role in signal transduction during cell growth ( ). Tumors with HER2/neu gene aberrations, compared to HER2/neu negative tumors, have a more aggressive clinical behavior, characterized by more frequent recurrences and shorter survival ( ). Upon activation, HER2 forms homodimers and/or heterodimers with EGFR, HER3, and HER4. This triggers a network of signaling cascades mediated mainly by AKT and MAPK, which regulate cell proliferation, angiogenesis, migration, and survival ( ). Some studies suggest a dominant role for EGFR and HER3 as key coreceptors driving HER2-amplified breast cancers ( ).

HER Family Receptors and Brain Metastases

Several studies demonstrated that breast cancer patients who developed brain metastases have a higher proportion of HER2-positive tumors, and that alterations of HER2 family receptors occur more frequently in brain metastases than in primary breast cancers or other metastatic sites ( ). In animal models, the overexpression of HER2 in human MDA-MB-231 breast carcinoma subline selected for in vivo brain tropism increased experimental brain metastases 2.5–3-fold, suggesting that HER2 positivity influences the natural history of breast cancer to promote brain colonization ( ). In another study, HER3 overexpression and its downstream pathway activation were found to be implicated in colonization of the brain by breast cancer cells ( ). Notably, in that study, brain metastases from breast and other cancers contained more somatic mutations in EGFR, HRAS, KRAS, NRAS, PIK3CA , and PTEN genes than matched primary tumors. Furthermore, reactive astrocytes driven by activation of the EGFR pathway under pathological conditions appear to be destructive to neurons in the mature brain ( ). These data indicate that pathways driven by HER2 family receptors play an important role in pathogenesis of brain metastases from breast cancer and may be potential therapeutic targets.

Trastuzumab

Trastuzumab (Herceptin, Hoffman La Roche) is a recombinant, humanized monoclonal IgG1 antibody that binds to extracellular subdomain IV of HER2/neu receptor and inhibits the growth of tumor cells. Additionally, this substance is a strong mediator of antibody dependent cellular cytotoxicity, selectively directed against HER2-positive tumor cells ( ). Trastuzumab was also demonstrated to inhibit angiogenesis via modulation of proangiogenic factors, such as vascular endothelial growth factor. Trastuzumab is widely used in combination with chemotherapy or endocrine therapy in adjuvant and metastatic setting in HER2-positive breast cancer patients, and 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, this compound is ineffective in treating established brain metastases. Approximately 14% of patients with breast cancer undergo conversion of HER2 status in brain metastases (at a similar rate in both directions), and trastuzumab does not seem to affect the incidence of this phenomenon ( ).

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