Toward Customized Trastuzumab in HER-2/neu-Overexpressing Non-Small-Cell Lung Cancers

摘要: Amplification or overexpression of the HER-2/neu gene in breast cancer is associated with aggressive behavior and resistance to systemic local radiation therapies. The phosphatidylinositol 3-kinase (PI3K) Akt signaling cascade that results from HER-3 heterodimerization overexpressed receptors cells, promoting cell survival enhanced tumor aggressiveness. Trastuzumab a recombinant DNAderived monoclonal antibody selectively binds p185, protein product extracellular human epidermal growth factor oncogene, HER-2/neu, HER-2/ neu expression predictor trastuzumab response. was approved by US Food Drug Administration for treatment metastatic cancer, based on superior compared conventional therapy. Until recently, role lung has been largely marginalized. In this issue Journal Clinical Oncology, Langer et al present evidence as feasibility combining chemotherapy advanced non–small-cell (NSCLC). A seminal study showed mRNA expression, quantified Northern blotting twenty NSCLC lines, intrinsic multidrug resistance. More Bunn found synergy between cisplatin gemcitabine even greater HER-2/neu-positive lines than lines. Breast because amplification, but amplification occurred infrequently Only Calu-3 line had true amplification. greatest inhibition seen expressing high levels HER-2/neu. One problems faced clinical investigators using patients define patient HER-2/neu-positive. Traditionally, status assessed at least one three following methods: immunohistochemistry (IHC), ranking negative, 1 , 2 3 ; fluorescence situ hybridization (FISH), reflecting positivity negativity; enzyme-linked immunoabsorbent assay (ELISA), where serum concentration 15 ng/mL considered positive. Several studies have demonstrated women IHC demonstrate FISH obtain benefit trastuzumab. Various whole tissue microarray sections Administration-approved HercepTest (Dako Corp, Carpinteria, CA) consistent level detected cancers (19% 30%; ). majority cases abnormalities are adenocarcinomas. (average ratio chromosome 17 copy numbers 2) substantially less frequently (ranging 2% 22%) cancer. recent meta-analysis involving more 4,500 not better those overexpressing hazard 1.46. tumors account only 11% all also show significantly shorter survival. targets small subgroup patients, can be expected greatest. However, may good candidates treatment. Furthermore, it well documented receptor absence addition, reliable assessment JOURNAL OF CLINICAL ONCOLOGY E D I T O R L VOLUME 22 NUMBER 7 APRIL 2004