Herceptest: Her2 expression and gene amplification in non-small cell lung cancer

Abstract

HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. HER2 (c-erbB-2 or neu) is a member of the erbB/HER type 1 tyrosine kinase receptor family. This family of receptors mediates proliferation and differentiation in normal epithelial cells. Inappropriate over-expression may contribute to tumour growth and invasion. 1 Over-expression of HER2 has been demonstrated in many epithelial tumours, including breast cancer. 2,3 Over-expression of HER2 on the surface of a tumour cell makes this protein a potential target for the anti-HER2 monoclonal antibody (MAb) construct Herceptin. 4 Herceptin, when combined with cytotoxic chemotherapeutic agents, enhances their anti-tumour activity and significantly prolongs survival in metastatic breast carcinoma. 5,6 Potentially, non-small-cell lung cancer (NSCLC) tumours over-expressing HER2 may also be treated with Herceptin.Previous studies of HER2 expression in NSCLC varied in use of antibodies and immunohistochemical technique as well as the definition of positive cases. Studies on paraffin sections vary in data on membranous and cytoplasmic expression. Membranous staining has been demonstrated in 2% to 40% of NSCLC cases 7,8 and associated with a poor prognosis for adenocarcinoma. 8 Other studies have reported cytoplasmic immunostaining in 10% to 60% of NSCLC cases. 9 -13 Although only membranous expression would be expected to be functionally important, several of these studies have shown cytoplasmic HER2 expression, especially in adenocarcinoma, to be associated with a poor prognosis. 9 -11 One study has shown that NSCLC tumours containing higher levels of HER2 protein have a worse outcome. 14 Another study showed HER2 expression in 17/138 (12%) localised lung adenocarcinomas, with only 1 of these immunopositive cases demonstrating gene amplification. 15 This suggests that, unlike breast carcinoma, HER2 gene amplification in NSCLC is uncommon.The HercepTest was designed as a semi-quantitative immunohistochemical assay to determine HER2 protein over-expression in routinely processed breast cancer tissue, to aid the assessment of patients for whom HER2 antibody treatment with Herceptin is being considered. Cases with a HercepTest staining intensity of 2ϩ or 3ϩ may benefit from Herceptin therapy. 4,16,17 Our aim was to evaluate HER2 expression in NSCLC using the HercepTest and to correlate the results with clinicopathological findings and gene amplification. MATERIAL AND METHODSThis was a retrospect...

Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas

“…Based on the clinical experience from the breast cancer studies, it might be of interest to focus on NSCLC patients with 3+ IHC results and/or those having tumours with gene amplification. Data from the current and other studies (Cox et al, 2001) show that these conditions seem to be limited to adenocarcinomas and LCC. Thus, the number of patients who might be candidates for trastuzumab treatment seems to be more limited in the NSCLC population than in the breast cancer population, and such prospective clinical trials in NSCLC will require multicenter studies.…”

“…Other studies, such as Hirashima et al (2001) and Cox et al (2001) also detected clustered amplification only in rare cases of NSCLC. Disomic status for chromosome 17 was only found in 16% of the NSCLC tumours included in our study.…”

“…However, because of the strong intensity of the staining pattern, we classified these tumours as having 2+ results (Figure 1). This could give a slightly higher frequency of positive adenocarcinomas compared to other studies (Cox et al, 2001;Hirashima et al, 2001). However, the clinical significance of this scoring may not be relevant because 2+ tumours do not have a worse prognosis and may not have a significant benefit from HER-2/neu targeted therapy.…”

Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non‐small cell lung cancer

“…The present study confirmed that the same phenomenon exists in clinical specimens, but no clear association between protein overexpression and polysomy of chromosome 17 could be confirmed. Cox et al 25 screened 344 NSCLCs for HER2 overexpression by IHC and found that only 4.3% of tumors overexpressed HER2. They further analyzed the 21 IHCpositive cases identified by FISH and reported that 3ϩ tumors possessed gene amplification but not 2ϩ or 1ϩ tumors, except 1 case of polyploidy.…”

Treatment of non-small-cell lung cancer: state of the art and development of new biologic agents

“…In lung cancer cell lines, dosedependent growth inhibition occurred only in cell lines with cell-surface HER-2/neu expression Cox et al, 2001). HER-2 antibodies also mediate complement-dependent cytotoxicity and/or antibodydependent celular cytotoxicity (Lewis et al, 1993).…”