The ErbB signaling network is known to influence a wide range of cellular processes, including proliferation, motility, and survival [
19]. It is known that overexpression of EGFR often portends a worse prognosis [
20,
21]. The frequency of positivity appears to increase with clinical stage of disease. Her-2-neu positivity may thus represent a late event in the natural history of colorectal cancer and is associated with a worse prognosis. Overexpression of the HER-2/neu receptor is detected in 25–35% of human breast cancer [
4,
7] but the level and incidence of HER-2 overexpression in primary colon tumours appears to be different than those observed in breast cancer. Conflicting data exist about the prevalence of HER-2/neu overexpression in colorectal cancer which ranges from 0 to 83 % [
12‐
16]. In our study, we examined 77 colorectal cancer tumour samples for the presence of Her-2/neu oncoprotein by immunhistochemistry. Out of these 77 samples, 56 (70%) were negative. Strong membranous HER-2 staining was only detected in 2 cases (3%). No correlation could be found between clinicopathological features and the HER-2/neu overexpression. Similar results are described in the study of Nathason et al [
22]; they examined HER-2/neu gene amplification in 169 colon cancer specimens and HER-2/neu protein expression in 139 specimens, where they found HER-2/neu to be overexpressed in 5 cases (3.6%) and the gene to be amplified in 4 of these cases (2.4%). The HER-2/neu overexpression or the gene amplification was also not associated with any specific clinicopathological features [
22]. In another study, strong membranous HER-2 staining was detected in only 5% of tumors in 96 primary human colorectal adenocarcinomas that also showed HER-2 gene amplification [
23]. In contrast to these results are four studies who did report an association between Her-2/neu overexpression and advanced stage, decreased survival or both [
14,
15,
24,
25]. One of the studies by Kapitanovic et al [
15] described a significant correlation between the epidermal abnormality degree and clinical parameters including Dukes' stage, relapse-free and postoperative survival.
Our study results indicating a very low rate of HER-2-/neu positivity and no correlation with clinicopathological features might be hampered by the small number of cases (77 specimens), However, the results are in agreement with same other larger patient series. In contrast to these data are the above mentioned four publications. The most likely reason for this divergency is the technical variability in the performance of immunhistochemistry. It is well known that there are pitfalls in immunostaining for HER-2/neu in breast cancer. Another reason may be due to the fact, that different antibodies have been used, stressing the importance of using standardized test systems most notably in case of therapeutic relevance of the results. Our results were all confirmed by a pathologist who is specialized in immunostaining for HER-2/neu and is a well known reference pathologist for this tumour entity. The inclusion of cytoplasmatic positivity in the Hercep-score in earlier papers may also be responsible for the conflicting results regarding the frequency of Her-2neu expression in colorectal cancer in the literature.
The c-erbB-e protein expression was observed in colorectal cancer but rarely in the therapeutic range (2+ and 3+). As known from studies in Her-2/neu metastatic breast cancer, Herceptin
®, a HER-2 neutralizing antibody, is only effective in the therapeutic range. In a study by Ramanathan et al [
26] Her-2/neu positive patients with advanced colorectal cancer should receive trastuzumab (Herceptin
® and irinotecan treatment. Of 138 screened patients Her-2/neu overexpression was only detected in 11 (8%; 2+ in 5 and 3+ in 6 patients), therefore the study was prematurely closed.
These data are similar to ours and indicate that c-erbB-2 is unlikely to play a major role in the therapeutic management of colorectal cancer. Therefore, further investigations of regimens involving trastuzumab seem not be useful.