Electronic Letters to:
|
|
E-letters: Electronic letters published:
-
![[Read eLetter]](/icons/misc/sectionDOWN.gif)
Role of Her-2/neu on extra-hepatic cholangiocarcinoma prognosis: myth or reality ?
- Raphael Marechal, Alain Hendlisz, Virginie Meurant, Nathalie Nagy, Marianna Arvanitakis, Jean-Luc Van Laethem (2 July 2007)
|
|
|||
|
Raphael Marechal, Gastroenterologist Erasme Hospital, 808 Route de Lennik,1070 Brussels, Belgium, Alain Hendlisz, Virginie Meurant, Nathalie Nagy, Marianna Arvanitakis, Jean-Luc Van Laethem
Send e-letter to journal:
|
We noted with interest the article by Kim HJ et al. in the March 1, 2007, issue of the Annals of Oncology, entitled gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in node-positive patients (1). The authors have evaluated Her-2/neu protein expression using immunohistochemistry and gene amplification by CISH on tumor paraffine embedded slides. Fifty-five patients were retrospectively evaluated. Her- 2/neu gene amplification was detected in 10 (26%). CISH and IHC were well correlated. They realised a multivariate analysis to identify independent prognostic factors for survival. They use multivariate analysis with 11 covariates although the study contained maximally 55 events. Many problems arise for a too-small number of events per variable (EPV) in proportional hazards analysis. At EPV < 10, the regression coefficients become increasingly biased; confidence intervals may not have the proper coverage; the test statistics may not be valid for the model; the loss of power to identify important associations may lead to underfitting and the frequency of paradoxical associations may increase. The same comment can be made for the multivariate analysis focusing the subgroup of lymph node positive patients. It is questionable to observe that all the 4 variables that have been used are statistically significant. The number of lymph node positive patients (n=6) with Her-2/neu overexpression is limited and alters the validity of the statistical analysis. Taking into account these statistical considerations, in our opinion the study of Kim HJ et al. provides inadequate information about the impact, the influence of Her- 2/neu overexpression in predicting EHC outcome in lymph node positive patients. Furthermore the small number of patients evaluated, the lack of information concerning rate of R0-resection and treatment at relapse hampers evaluation of Her-2/neu overexpression relevance. Data available in the literature are very conflicting with Her-2/neu gene amplification (evaluated by CISH or FISH) and protein overexpression (evaluated by IHC) varying from 4% (3) to 100% (4) and 0% (5) to 100% (6) respectively. We retrospectively evaluated Her-2/neu overexpression and gene amplification in 24 patients diagnosed with EHC between1992 and 2005 in Erasme Hospital and Institut Jules Bordet. Paraffin embedded slides were evaluated. CISH was conducted with the Zymed Spot-Ligh HER2CISH and we used a monoclonal anti-Her-e/neu antibody (Clone 316, Dako, dilution 1:100).We used similar Her-2/neu immunostaining scoring system which is used in breast cancer. Only 2 patients presented gene amplification, one patient was 2+ immunostaining and another one 1+ for Her-2/neu protein expression. These results contrast with those presented by Kim HJ et al. Many factors can partially explain this difference. We used a primary mouse monoclonal antibody and Kim HJ et al. a primary rabbit polyclonal antibody. By contrast with polyclonal antibodies, monoclonal antibodies have an excellent practical sensitivity and give less non specific background than polyclonal antibodies. The antigen retrieval technique that has been used has not been mentioned in the article. The small number of patients in the 2 series and a different physiopathology of EHC in Caucasian and Asiatic patients could also be confounding factors. It seems premature to propose clinical study targeting Her-2/neu because its incidence and contribution in pathogenesis/development of EHC is still unclear and require much convicting studies. Finally ethnical considerations should be taken into account for the analyses of results. References 1. Kim HJ, Yoo TW, Park DI et al. Gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in node-positive patients. Ann Oncol 2007;18:892-897. 2. Peduzzi P, Concato J, Feinstein AR, Holford TD. Importance of events per independent variable in proportional hazards regression analysis II. Accuracy and precision of regression estimates. J Clin Epidemiol 1995;48:1503-1510. 3. Altimari A, Fiorentino M, Gabusi E,et al. Investigation of Erb1 and Erb2 expression for therapeutic targeting in primari liver tumours. Dig Liver Dis 2003;35:332-338. 4. Ukita Y, Kato M, Terada T. Gene amplification and mRNA and protein overexpression of c-erb-2 (HER-2/neu) in human intrahepatic cholangiocarcinoma as detected by fluorescence in situ hybridisation, situ hybridisation, and immunohistochemistry. J Hepatol 2002;36:780-785. 5. Collier JD, Guo K, Mathew J, et al. C-erB-2 oncogene expression in hepatocellular carcinoma and cholangiocarcinoma. J Hepatol 1992;14:377- 380. 6. Benckert, Jonas S, Cramer T, et al. Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells, Cancer Res. 2003 Mar 1;63(5):1083-92. Conflict of Interest:None declared |
|||