Toward customized trastuzumab in HER-2/neu-overexpressing non-small-cell lung cancers.

Abstract

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