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

Abstract

HER-2/neu gene amplification and cell surface overexpression are important factors in breast cancer for prognosis and prediction of sensitivity to anti-HER-2/neu monoclonal antibody therapy. In lung cancer, the clinical significance of HER-2/neu expression is currently under evaluation. We investigated 238 non-small lung carcinomas for HER-2/neu protein overexpression by immunohistochemistry using the HercepTest. We found 2+ or 3+ overexpression in 39 patients (16%), including 35% in adenocarcinomas and 20% in large cell carcinomas, but only 1% of squamous cell carcinomas. Marked (3+) overexpression was uncommon (4%). The association between protein expression and gene copy number per cell, as determined by fluorescence in situ hybridisation assay, was investigated in 51 of these NSCLC tumours. Twenty-seven tumours (53%) were negative by both tests. Marked (3+) protein expression and gene amplification were present in only 4% of samples. In 11 tumours (21%), gene gain was accompanied by chromosomal aneusomy and did not result in high protein levels while in 7 (14%) the score 2+ was associated with maximum number of signals per cell 59. The prognostic implication of HER-2/neu protein expression was studied in 187 surgically resected tumours. No statistical difference in survival was observed comparing patients with positive (2+/3+) and negative tumours (0/1+), although 3+ patients showed a tendency to shorter survival. The therapeutic implications of protein expression and gene amplification in lung cancer need to be examined in prospective clinical trials.

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

“…The frequency observed in our study is in the range (1-5%) of other studies performing ERBB2 FISH in lung cancer. 11,13,15,16 The predilection of adenocarcinomas for ERBB2 amplification is in line with the results from earlier studies showing a correlation of HER2 expression with this histologic subtype. 11 We did not observe significant associations with tumor stage or presence of metastases but found a significant link between ERBB2 amplification and poor prognosis although in univariate analysis only.…”

“…9 HER2 overexpression in adenocarcinoma and squamous cell carcinoma of the lung as assessed by immunohistochemistry is found in 2.5-43% of cases with a clear tendency toward higher rates of positivity in adenocarcinoma than in squamous cell carcinoma. [10][11][12][13] Studies assessing ERBB2 amplification found a similar variability but usually with a much lower frequency of amplified tumors. The different analytical methods such as PCR, Southern blot or fluorescence in-situ hybridization (FISH) used and the varying definitions of amplification have resulted in a wide range (1-23%) of cases reported to be amplified.…”

The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature

“…The inconvenience of ELISA is the requirement of fresh or frozen tissue and calculation of an average c-erbB-2 content of tumour and normal tissue, but the availability for measuring the circulating levels of this protein is an interesting opportunity to assess its overexpression in patients with tumours that are not easily accessible for biopsy. Finally, Hirsch et al (2002) found a good correlation between the IHC and FISH results in twothirds of the 51 tumours investigated. Demonstration of HER-2/neu overexpression in NSCLC using a standardised method is essential for establishing clinical trials for anti-HER-2 drugs.…”

“…A total of 39 studies, published between 1990 and 2002, were found eligible (Kern et al, 1990(Kern et al, , 1994Tateishi et al, 1991Tateishi et al, , 1994Volm et al, 1992Volm et al, , 1993aHarpole et al, 1995aHarpole et al, , b, 1996Giatromanolaki et al, 1996a, b;Pfeiffer et al, 1996;Koukouraki et al, 1997Koukouraki et al, , 2000MacKinnon et al, 1997;Pastorino et al, 1997;Visscher et al, 1997;Yu et al, 1997;Graziano et al, 1998;Greatens et al, 1998;Hsieh et al, 1998;Kim et al, 1998;Kwiatkowski et al, 1998;Nemunaitis et al, 1998;Cantero et al, 1999Cantero et al, , 2000D'Amico et al, 1999;Fu et al, 1999;Moldvay et al, 2000;Schneider et al, 2000;Ardizzoni et al, 2001;Brabender et al, 2001;Liao et al, 2001;Shou et al, 2001;Carbognani et al, 2002;Han et al, 2002;Hirsch et al, 2002;Potti et al, 2002;Selvaggi et al, 2002). Nine of the articles were excluded because identical cohorts of patients were used (studies that were excluded and included were, respectively, references (Cantero et al, 1999) and (Cantero et al, 2000), (Giatromanolaki et al, 1996b;…”

TRAF4 overexpression is a common characteristic of human carcinomas

“…However, genetic gains of chromosome 17q have also been reported in lung adenocarcinomas but the nature of the genes concerned by this genetic alteration remains poorly investigated (Balsara and Testa, 2002). ERBB2 is expressed in about 30% of Non-Small Cell Lung Carcinomas (NSCLC), especially adenocarcinomas, although gene amplification is not usually the underlying mechanism (Hirsch et al, 2002). In our analysis, TRAF4 overexpression was most commonly detected in this cancer type with 60% of lung adenocarcinomas concerned and it is due to gene amplification in about 38% of the cases.…”