HER-2/neuProtein Expression and Gene Alteration in Stage I-IIIA Nonndash;Small-Cell Lung Cancercolon; A Study of 140 Cases Using a Combination of High Throughput Tissue Microarray, Immunohistochemistry, and Fluorescent In Situ Hybridization

摘要

Regarding HER-2/neuexpression (gene or protein level) in lung cancer, several studies with inconsistent results have been recently reported, partially due to variable techniques used and/or heterogeneous populations examined. The objective of this study was to examine HER-2/neuexpression in a well-defined cohort of nonndash;small-cell lung cancers (NSCLC) and in nonneoplastic lung tissue utilizing a combination of high-density tissue microarray, immunohistochemistry (IHC), and fluorescent in situ hybridization (FISH) under uniform test conditions. One hundred forty stage I-IIIA primary NSCLCs and 38 non-neoplastic lung samples were examined. IHC, using an FDA-approved Hercept monoclonal antibody kit, was performed and HER-2/neugene alteration was assessed by FISH. The association of expression of HER-2/neuwith clinicopathologic parameters was analyzed. Ninety-four percent of tumor samples (131/140) were fully interpretable after tissue processing. Twenty-five of them (19percnt;) overexpressed (2plus;, 3plus;) HER-2/neu, while 106 (81percnt;) had no or weak expression. All thirty-four interpretable non-neoplastic lung samples were negative for HER-2/neualteration at protein and gene level. HER-2/neuprotein overexpression correlated well with HER-2/neugene amplification (r equals;.83,P 0.001). HER-2/neuoverexpression was significantly associated with histologic subtypecolon; 19 adenocarcinomas (19/82, 23percnt;) versus 4 squamous cell carcinomas (4/44, 9percnt;) overexpressed Her-2/neu(Pequals; 0.04). Statistical significance was observed between HER-2/neuexpression and tumor differentiation, with strong positive (3plus;) expression observed more frequently in poorly differentiated tumors (Pequals; 0.01). Patients with HER-2/neuabnormalities, particularly HER-2/neugene amplification, exhibited a shorter survival (Pequals; 0.043). The statistically significant difference (P 0.005) between HER-2/neualteration in tumor samples(25/131, 19percnt;) and in the nonneoplastic tissue (0/34, 0percnt;) implies that HER-2/neumay have a role in the carcinogenesis of NSCLC. The findings provide evidence supporting the hypothesis that the HER-2/neureceptor may represent a useful molecular target in the treatment of NSCLC. The significant association of HER-2/neuexpression and gene amplification with poorly differentiated carcinoma compared with well differentiated carcinoma suggests that HER-2/neumay be involved in NSCLC tumor evolution. Patients with HER-2/neugene amplification and strong positive expression of HER-2/neuprotein showed a strong tendency toward shorter survival.