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Int J Colorectal Dis (2011) 26:1127–1134DOI 10.1007/s00384-011-1213-9 β-catenin and Her2/neu expression in rectal cancer:association with histomorphological response to neoadjuvanttherapy and prognosis Uta Drebber & Martin Madeja & Margarete Odenthal & Inga Wedemeyer &Stefan P. Mönig & Jan Brabender & Elfriede Bollschweiler & Arnulf H. Hölscher &Paul M. Schneider & Hans P. Dienes & Daniel Vallböhmer Accepted: 11 April 2011 / Published online: 3 May 2011 contained less than 50% vital tumor cells (n=14) and by Background Neoadjuvant treatment strategies have been Cologne grading system when resected specimens developed to improve survival of patients with advanced contained less than 10% vital tumor cells (n=15). Intra- rectal cancer. Since mainly patients with major histopath- tumoral β-catenin (nuclear/membranous) and Her2/neu ological response benefit from this therapy, predictive and (cytoplasmatic/membranous) expression was determined prognostic markers are needed. We examined the associa- by immunohistochemistry in pre- and post-therapeutic tion of β-catenin and Her2/neu protein expression with specimens and correlated with clinicopathologic parameters.
histopathologic response to neoadjuvant radiochemotherapy Results A significant association was detected between pre- and prognosis in patients with locally advanced rectal therapeutic membranous β-catenin levels and response: patients with a lower β-catenin protein expression showed Methods Fifty-four patients (33 male; 21 female; median significantly more often a major response compared with age 60.4 years) with locally advanced rectal cancer were patients having high intratumoral protein levels (p=0.011).
included in this study. All patients received a neoadjuvant In addition, patients with a higher Her2/neu protein radiochemotherapy (50.4 Gy, 5-FU) followed by surgical expression showed a significant survival benefit compared resection. Histomorphologic regression was evaluated by with patients having low intratumoral protein levels (5-year Dworak and Cologne staging system. Major response was survival rate: 81% vs. low 41%; p=0.023).
defined by Dworak classification when resected specimens Conclusions The pre-therapeutic β-catenin and Her2/neuprotein expression seem to be valuable predictive andprognostic markers in the multimodality treatment of U. Drebber (*) M. Madeja M. Odenthal I. Wedemeyer H. P. DienesInstitute of Pathology, University Hospital Cologne,Kerpener Str. 62, Keywords Rectal cancer . Neoadjuvant therapy . Response prediction . Prognosis . β-catenin . Her2/neu S. P. Mönig J. Brabender E. Bollschweiler A. H. HölscherD. Vallböhmer Department of General, Visceral and Cancer Surgery,University Hospital Cologne, Rectal cancer has an incidence of over 70,000 patients every year in Germany and leads to a mortality rate of nearly 30,000 patients a year. A neoadjuvant “short-term” or conventional chemoradiation is usually applied in Department of Visceral and Transplantation Surgery, rectal cancer patients falling into UICC (international union against cancer) stages II and III [ with postoperative treatment, preoperative chemoradio- Int J Colorectal Dis (2011) 26:1127–1134 therapy is associated with improved local control and study. There were 33 male and 21 female with a median age reduced toxicity ]. Histopathological evaluation of of 60.4 years. None of the included patients received prior tumor regression in the surgical specimen after preopera- radiotherapy and/or chemotherapy. All patients received a tive chemoradiotherapy is believed to be an objective neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed prognostic factor allowing the identification of patients, by surgical therapy. Restaging was done 2 to 3 weeks who have minor or major benefit from multimodal therapy following completion of radiochemotherapy, and surgical –In fact, patients with major histological response therapy was performed in all study patients. Pathological to therapy have a significantly improved overall survival examination before surgery comprised tumor typing and ]. However, only a subgroup of patients treated with grading. The scientific protocol was approved by the local preoperative chemoradiotherapy responds to treatment ]. The other subgroup consists of non-responders, who donot benefit from the therapy and who might be treated Histomorphologic grading of tumor regression differently. Currently, the selection of patients for neo-adjuvant preoperative therapy mainly depends on clinical Morphologic assessment of tumor regression was per- parameters including the stage of the disease. However, formed by an objective histopathologic examination as most of these parameters do not have a predictive impact described previously by a staff pathologist who was blinded on the therapy response. Thus, one major issue is the for all other clinical data (U.D.) ]. The resected speci- implication of prognostic molecular factors predicting mens were fixed in formalin (10%), embedded in paraffin, histopathological response to treatment.
and cut into slices (5 μm). The sections were stained with Mutation and inactivation of the adenomatous polyposis hematoxylin and eosin and used for both histopathological coli tumor suppressor gene is a major event in early staging according to the tumor–node–metastasis classifica- colorectal carcinogenesis leading to stimulation of the Wnt/ tion system (Union Internationale Contre Le Cancer, 6th β-catenin pathway which plays a central role in colorectal edition, 2002 [and histomorphologic evaluation of the tumor development ]. Overexpression of β-catenin leads to stimulation of the Wnt/β-catenin pathway and The extent of histomorphologic regression was evaluated aberrant target gene expression with increase of cell by two classification systems by using all available tumor The proto-oncogene Her2/neu encodes a transmembrane tyrosine kinase receptor and is normally expressed in 1. Grading system by Dworak: This grading system epithelial cells –Overexpression has been described divides into five categories: grade 0, no regression; in various different tumors, including breast, lung, and grade 1, dominant tumor mass with obvious fibrosis colorectal cancer. This is a consequence of amplification of and/or vasculopathy in 25% or less of the tumor the Her2-gene which normally presents as a single copy in mass; grade 2, dominantly fibrotic changes with few normal cells. Amplification and overexpression result in tumor cells or groups in 26–50% of the tumor mass cellular proliferation. The significance of Her2/neu over- (easy to find); grade 3, very few (difficult to find expression and its impact on progression and prognosis of microscopically) tumor cells in fibrotic tissue with or without mucous substance; i.e., more than 50% of In the present study, we determined the protein tumor regression; grade 4, no tumor cells, only expression of β-catenin and Her2/neu in advanced rectal fibrotic mass (total regression or response). Regres- cancer before and after multimodality treatment and sion grades 3 and 4 were combined to major correlated the intratumoral protein expression with histomorphologic response (MaHR) and grades 0–2 clinicopathological parameters including the histopatho- constituted minor histopathologic response (MiHR) logical response in order to characterize molecular 2. Cologne grading system: This grading system divides into four categories: grade 1, >50% vital residual tumorcells (VRTC); grade 2, 10% to 50% vital residual tumor cells; grade 3, near complete regression with <10%VRTC; grade 4, complete regression (pathologic complete remission and ypT0) according to the classi-fication described by Schneider et al. [Regression Between 1996 and 2006, 54 patients with locally advanced grades 3 and 4 were combined to MaHR and grades 1 rectal cancer (uT3/4Nx) were included in this retrospective and 2 constituted MiHR as reported previously ].
Int J Colorectal Dis (2011) 26:1127–1134 staining, stromal staining was not considered. The degree ofexpression of all the markers was estimated by semiquan- The investigation comprises immunohistochemical analyses titative evaluation and described in percentage. The scores of tumor tissue of pre-therapeutic biopsies and post- used were 0, 0–5%; 1, 5–30%; 2, 30–60%, and 3, >60%. β- catenin staining was analyzed in case of a positive nuclear Immunohistochemical stainings were performed apply- or membranous signal and Her2/neu in case of membranous ing the DAKO EnVision System (DAKO, Hamburg, Germany) according to manufacturer's instructions. β-catenin was detected by the β-catenin-specific monoclonalantibody from Becton-Dickinson Transduction Laboratories (Heidelberg, Germany) (dilution, 1/100). Her2/neu wasdetected by a polyclonal antibody (DAKO, Hamburg, Correlation analysis between the β-catenin or Her2/neu protein expression and outcome parameters was assessed Formalin-fixed and paraffin-embedded tissue was cut using non-parametric tests using SPSS for Windows, and deparaffinized according to standard histological version 17.0G (Chicago, Illinois, USA). The Wilcoxon test techniques. Pretreatment was performed in a microwave was used for paired samples in the comparison of pre- and using citrate buffer (pH 6.0) for 2×4 min at 600 W.
post-therapeutic protein expressions. The significance of Endogenous peroxidase activity was blocked by methanol the association between the dichotomized protein expres- hydrogen peroxide (1 ml H2O2 30% ad 100 ml methanol).
sion and the clinical and histopathologic parameters was Subsequently, primary antibodies were incubated in a computed with the χ2 test and the Fisher's exact test when humidity chamber overnight at 6°C. Secondary antibody necessary. Kaplan–Meier analysis was used to determine was incubated for 30 min at room temperature followed by the probability of survival stratified for the histopathologic DAKO Envsion and horseradish peroxidase 3-amino-9- tumor regression and the post-therapeutic protein expres- ethylcarbazole system for signal detection. Finally, the sion. The level of significance is given for two-sided testing nuclei were counterstained with hematoxylin and the tissues Semiquantitative analysis All slides were evaluated by a pathologist who had no access to patient data and clinicalstatus. Scoring was exclusively restricted to tumor cell Clinical data of the study patients are summarized in Table Int J Colorectal Dis (2011) 26:1127–1134 Histomorphologic regression grading and survival Resected tumor tissues of 54 patients were evaluated. Fortypatients (74%) showed a minor histologic response and 14(26%) showed a major histologic response when using thegrading system by Dworak. In addition, 39 patients (72%)showed a minor histologic response and 15 (28%) showed amajor histologic response when using the Cologne gradingsystem. Kaplan–Meier survival curves demonstrated nocorrelation between major and minor histopathologicresponse (p=0.699; p=0.776; Table There were 54 pre-therapeutic endoscopic biopsies andsurgical specimens available for the evaluation of nuclearand membranous β-catenin expression.
Fig. 1 Membranous β-catenin-expression within tumor cells in pre-therapeutic biopsies before neoadjuvant chemotherapy. Tumor regres- Pre-therapeutic nuclear β-catenin expression Twenty two sion is shown according to Cologne grading, data for Dworak grading (40.7%) biopsies showed β-catenin expression grade 0, 22 (40.7%) biopsies showed grade 1, 6 (11.1%) biopsiesshowed grade 2, and 4 (7.4%) biopsies showed grade 3.
grade 0, 10 (20.4%) surgical specimens showed grade 1, 13 Pre-therapeutic membranous β-catenin expression Five (26.5%) surgical specimens showed grade 2, and 12 (9.3%) surgical specimens revealed grade 0, 14 (25.9%) (24.5%) surgical specimens showed grade 3.
revealed grade 1, 13 (24.1%) revealed grade 2, and 22surgical specimens showed grade 3 membranous β-catenin Post-therapeutic membranous β-catenin expression Twenty (40.8%) surgical specimens revealed grade 0, 7 (14.3%)grade 1, 6 (12.2%) revealed grade 2, and 16 (32.7%) Post-therapeutic nuclear β-catenin expression Fourteen surgical specimens showed grade 3 membranous β-catenin (28.6%) surgical specimens showed β-catenin expression Table 2 Pre- and post-therapeutic membranous β-catenin protein expression and clinicopathological parameters (data of the nuclear β-cateninexpression is not shown) Int J Colorectal Dis (2011) 26:1127–1134 Regulation of β-catenin and Her2/neu protein expressionduring neoadjuvant therapy There were 54 pre-therapeutic endoscopic biopsies andsurgical specimens available for the evaluation of cytoplas- β-catenin and Her2/neu protein expression levels 0 to 3 matic and membranous Her2/neu expression.
were dichotomized into two categories: low-protein expres-sion (grades 0 and 1) and high-protein expression (grades 2 Pre-therapeutic cytoplasmatic Her2/neu expression Ten and 3). There were 49 paired pretreatment biopsies and (18.5%) biopsies showed Her2/neu expression grade 0, 9 (16.7%) biopsies showed grade 1, 12 (22.2%) biopsiesshowed grade 2, and 23 (42.6%) biopsies showed grade 3 Nuclear β-catenin expression Twelve (24.5%) cases expressed downregulation, 24 (49.0%) expressed upregula-tion, and no difference in β-catenin protein expression was Pre-therapeutic membranous Her2/neu expression Twenty observed in 13 (26.5%) cases, respectively. The change in seven (50.0%) biopsies revealed grade 0, 12 (22.2%) nuclear β-catenin protein expression during neoadjuvant revealed grade 1, 8 (14.8%) revealed grade 2, and 7 therapy was not statistically significant (p=0.075).
(13.0%) biopsies showed grade 3 membranous Her2/neuexpression.
Membranous β-catenin expression Twenty-six (53.1%)cases expressed downregulation, 9 (18.4%) expressed upre- Post-therapeutic cytoplasmatic Her2/neu expression Eigh- gulation, and no difference in β-catenin protein expression teen (36.7%) surgical specimens showed Her2/neu ex- was observed in 14 (28.5%) cases, respectively. The change in pression grade 0, 8 (16.3%) surgical specimens showed membranous β-catenin protein expression during neoadju- grade 1, 10 (20.4%) surgical specimens showed grade 2, vant therapy was not statistically significant (p=0.637).
and 13 (26.5%) surgical specimens showed grade 3(Table ).
Cytoplasmatic Her2/neu expression Twenty-five (51%)cases demonstrated downregulation, eleven (22.4%) dem- Post-therapeutic membranous Her2/neu expression Thirty onstrated upregulation, and no difference in Her2/neu six (73.5%) surgical specimens revealed grade 0, 8 (16.3%) protein expression was observed in 13 (26.6%) cases, showed grade 1, 2 (4.1%) showed grade 2, and 3 (6.1%) respectively. The change in cytoplasmatic Her2/neu protein surgical specimens showed grade 3 membranous Her2/neu expression during neoadjuvant therapy was not statistically Table 3 Pre- and post-therapeutic cytoplasmatic Her2/neu protein expression and clinicopathological parameters (data of the membranous Her2/neu expression is not shown) Int J Colorectal Dis (2011) 26:1127–1134 Membranous Her2/neu expression Twenty (40.8%) cases biopsies and clinical/histopathologic parameters including demonstrated downregulation, 10 (20.4%) demonstrated histologic type, cT, ypT, ypN, grading, and histomorpho- upregulation, and no difference in Her2/neu protein logic regression grade and survival did not show any expression was observed in 19 (38.8%) cases, respectively.
significant association (data not shown).
The change in membranous Her2/neu protein expressionduring neoadjuvant therapy was not statistically significant(p=0.131).
In this study, we performed a comprehensive analysis in 54 Pre-therapeutic β-catenin and Her2/neu protein expression rectal cancer patients undergoing preoperative radiochemo- therapy followed by surgical resection. We analyzed thepathological and clinical implications of tumor regression Analysis of the correlation between dichotomized protein and expression of β-catenin and Her2/neu before and after expression of β-catenin and Her2/neu in pre-therapeutic biopsies and clinical/histopathologic parameters including Grading of histological changes in the resected specimen histologic type, ypT, ypN, and grading did not show any is a method to assess treatment response to preoperative therapy. These changes include cytologic alterations of However, a significant association was detected between residual tumor and fibrotic changes at the site of previous pre-therapeutic membranous β-catenin levels and response: tumor. Whether regression grading is a prognostic factor in patients with a lower β-catenin protein expression showed rectal cancer has still to be clarified and is discussed significantly more often a major response compared with controversially. In our study, we used 4-point grading patients having high intratumoral protein levels (p=0.04; systems to assess the extent of tumor regression to Table ; Fig. using the Cologne grading system while discriminate major responders from minor responders [ there was a trend with the Dworak grading (p=0.09).
]. We found that tumor regression did not have a In addition, a significant association was detected significant influence on survival. Rödel et al. described in between pre-therapeutic cytoplasmatic Her2/neu levels and a series of 385 patients that a higher grade of tumor survival: patients with a higher Her2/neu protein expression regression predicted a better survival [Rosenberg et al.
showed a significant survival benefit compared with found a significant improvement of overall survival for patients having low intratumoral protein levels (5-year histopathological tumor responders In contrast to these survival rate: high, 81% vs. low 41%, p=0.023; Fig. results, Jakob et al. did not see a significant influence oftumor regression on disease-free survival, merely an Post-therapeutic β-catenin and Her2/neu protein expression association of tumor regression with early treatment efficacy is described ]. In a recent study, Lindebjerg etal. described that the combined assessment of lymph node Analysis of the correlation between dichotomized protein status and tumor response has a strong prognostic value in expression of β-catenin and Her2/neu in post-therapeutic locally advanced rectal cancer ]. Thus, pathologicallyassessed tumor response may be used as a surrogate endpoint for early determination of treatment efficacy ].
β-Catenin is considered as a potential oncogene in sporadic colorectal cancer [, ]. The intracellulardistribution of β-catenin is of great importance for thedifferent functions of β-catenin and the subsequent behav-ior of tumor cells []. Previous data regarding anassociation of β-catenin expression with clinical andpathological parameters were contradictory. Our studyassessed a possible association of pre- and post- therapeuticnuclear/membranous β-catenin protein expression withhistomorphologic response and survival in patients withadvanced rectal cancer. We were able to demonstrate thatpre-therapeutic membranous β-catenin levels were signifi-cantly associated with major response to treatment. Patients Fig. 2 Kaplan–Meier curves based on cytoplasmatic Her2/neu with low pre-therapeutic intratumoral protein levels showed expression within tumor cells in pre-therapeutic biopsies beforeneoadjuvant chemotherapy significantly more often major response than patients Int J Colorectal Dis (2011) 26:1127–1134 having high protein levels. However, the analysis between our study, the change in membraneous and cytoplasmatic dichotomized protein expression of membranous/nuclear β- Her2/neu expression before and after therapy was not catenin and clinical/histopathologic parameters including histologic typing, cT, ypT, ypN, and grading did not show In conclusion, in our study, a low pre-therapeutic any significant association in our study. Several studies membranous β-catenin protein expression in our cohort of have demonstrated that immunostaining for β-catenin has patients with advanced rectal cancer treated with neo- shown increased membraneous/cytoplasmatic staining in adjuvant radiochemotherapy was associated more often 85% of colorectal cancers and increased nuclear staining in with a major histological response. Patients with a higher 20–26% of tumors [Our study shows similar results cytoplasmatic Her2/neu protein expression showed a with strong membraneous staining in 64% (score 2 and 3) significant survival benefit compared with patients having and strong nuclear staining in 18% (score 2 and 3).
low cytoplasmatic protein expression. There was no Different conclusions have been reached regarding β- correlation of the regulation of β-catenin and Her2/neu catenin expression as a prognostic marker in colorectal protein expression during neoadjuvant therapy with clinical carcinoma. In our study, there was no correlation between and histopathological data. Whether our results represent a β-catenin immunostaining and survival. Fernebro et al.
causal relationship, a surrogate phenomenon, or even a reported a correlation of loss of membranous β-catenin statistical bias can only be determined in larger trials.
staining and distant metastases and the reduced/absentmembranous β-catenin expression as an independent This work was supported by Cologne University prognostic marker in colorectal carcinoma [In anearlier study, Günther et al. did not find any associationbetween the nuclear overexpression of β-catenin and the development of metachronous metastases ]. Moreover,Baldus et al. did not find correlations between nuclear β- 1. Bosset JF, Calais G, Daban A, Berger C, Radosevic-Jelic L, catenin expression and important clinicopathological vari- Maingon P, Bardet E, Pierart M, Briffaux A (2004) Preoperative ables [Little is known about the regulation of β-catenin chemoradiotherapy versus preoperative radiotherapy in rectal expression before and after neoadjuvant therapy. In our cancer patients: assessment of acute toxicity and treatmentcompliance. Report of the 22921 randomised trial conducted by study, the change in nuclear and membraneous β-catenin the EORTC Radiotherapy Group. Eur J Cancer 40:219–224 expression before and after therapy was not statistically 2. Kim JS, Hur H, Kim NK, Kim YW, Cho SY, Kim JY, Min BS, Ahn JB, Keum KC, Kim H, Sohn SK, Cho CH (2009) Oncologic Her2neu is a therapeutic target in a variety of malignan- outcomes after radical surgery following preoperative chemo-radiotherapy for locally advanced lower rectal cancer: abdomi- cies. Her2 overexpression in breast cancer is known to be noperineal resection versus sphincter-preserving procedure. Ann associated particularly with aggressive disease and poor prognosis [In addition to its well-established role in 3. Minsky BD (2009) Is preoperative chemoradiotherapy still the breast cancer, Her2 overexpression and amplification has treatment of choice for rectal cancer? J Clin Oncol 27:5115–5116 4. Pasetto LM (2005) Preoperative versus postoperative treatment for also been demonstrated in subsets of numerous other locally advanced rectal carcinoma. Future Oncol 1:209–220 human cancers and is associated with poorer prognosis in 5. Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, many of these tumors [Our results with staining for Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, HER 2 in colorectal carcinoma are consistent with other Wolmark N (2009) Preoperative multimodality therapy improvesdisease-free survival in patients with carcinoma of the rectum: reports in the literature. In the pre-therapeutic biopsies, we found a membranous staining in 27% of the biopsies (score 6. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, 2 and 3). Kluftinger et al. detected weak and moderate Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens staining in 38% of the cases ]. Natali and coworkers JH, Liersch T, Schmidberger H, Raab R (2004) Preoperativeversus postoperative chemoradiotherapy for rectal cancer. N Engl demonstrated membranous staining in 29% of colorectal tumors []. In line with Kluftinger et al., our data 7. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, demonstrate no association between positive staining and Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, clinical/histopathologic parameters, including histologic Griffiths G, Thompson LC, Parmar M (2009) Preoperativeradiotherapy versus selective postoperative chemoradiotherapy in type, cT, ypT, ypN, and grading ]. However, we found patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a a significant association between pre-therapeutic cytoplas- multicentre, randomised trial. Lancet 373:811–820 matic Her2/neu levels and survival: patients with a higher 8. Guillem JG, Chessin DB, Cohen AM, Shia J, Mazumdar M, Her2/neu protein expression showed a significant survival Enker W, Paty PB, Weiser MR, Klimstra D, Saltz L, Minsky BD,Wong WD (2005) Long-term oncologic outcome following benefit compared with patients having low intratumoral preoperative combined modality therapy and total mesorectal protein levels. Little is known about the regulation of excision of locally advanced rectal cancer. Ann Surg 241:829– Her2/neu expression before and after neoadjuvant therapy. In Int J Colorectal Dis (2011) 26:1127–1134 9. Rosenberg R, Nekarda H, Zimmermann F, Becker K, Lordick F, 24. Rödel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Hofler H, Molls M, Siewert JR (2008) Histopathological Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind response after preoperative radiochemotherapy in rectal carci- C (2005) Prognostic significance of tumor regression after noma is associated with improved overall survival. J Surg preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 10. Horisberger K, Hofheinz RD, Palma P, Volkert AK, Rothenhoefer 25. Jakob C, Liersch T, Meyer W, Baretton GB, Schwabe W, Hausler S, Wenz F, Hochhaus A, Post S, Willeke F (2008) Tumor response P, Kulle B, Becker H, Aust DE (2006) Prognostic value of to neoadjuvant chemoradiation in rectal cancer: predictor for histologic tumor regression, thymidylate synthase, thymidine surgical morbidity? Int J Colorectal Dis 23:257–264 phosphorylase, and dihydropyrimidine dehydrogenase in rectal 11. Fearon ER, Vogelstein B (1990) A genetic model for colorectal cancer UICC Stage II/III after neoadjuvant chemoradiotherapy.
12. de Lau W, Barker N, Clevers H (2007) WNT signaling in the 26. Lindebjerg J, Spindler KL, Ploen J, Jakobsen A (2009) The normal intestine and colorectal cancer. Front Biosci 12:471–491 prognostic value of lymph node metastases and tumour regression 13. Kitisin K, Mishra L (2006) Molecular biology of colorectal grade in rectal cancer patients treated with long-course preoper- cancer: new targets. Semin Oncol 33:S14–S23 ative chemoradiotherapy. Colorectal Dis 11:264–269 14. Yang VW (1999) The molecular genetics of colorectal cancer.
27. Brabletz T, Kirchner T (2003) Morphogenetic aspects of colorectal 15. Su LK, Vogelstein B, Kinzler KW (1993) Association of the APC 28. Savas B, Ensari A, Percinel S, Kuzu I, Kuzu MA, Bektas M, tumor suppressor protein with catenins. Science 262:1734–1737 Cetinkaya H, Kursun N (2007) The significance of beta-catenin, 16. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, E-cadherin, and P-cadherin expressions in neoplastic progression Masiarz FR, Munemitsu S, Polakis P (1993) Association of the of colorectal mucosa: an immunohistochemical study. Acta APC gene product with beta-catenin. Science 262:1731–1734 17. Ochs AM, Wong L, Kakani V, Neerukonda S, Gorske J, Rao A, 29. Gunther K, Brabletz T, Kraus C, Dworak O, Reymond MA, Jung Riggs M, Ward H, Keville L (2004) Expression of vascular A, Hohenberger W, Kirchner T, Kockerling F, Ballhausen WG endothelial growth factor and HER2/neu in stage II colon cancer (1998) Predictive value of nuclear beta-catenin expression for the and correlation with survival. Clin Colorectal Cancer 4:262–267 occurrence of distant metastases in rectal cancer. Dis Colon 18. Kapitanovic S, Radosevic S, Kapitanovic M, Andelinovic S, Ferencic Z, Tavassoli M, Primorac D, Sonicki Z, Spaventi S, 30. Fernebro E, Bendahl PO, Dictor M, Persson A, Ferno M, Nilbert Pavelic K, Spaventi R (1997) The expression of p185(HER-2/neu) M (2004) Immunohistochemical patterns in rectal cancer: appli- correlates with the stage of disease and survival in colorectal cation of tissue microarray with prognostic correlations. Int J 19. Tsioulias GJ, Muto T, Morioka Y, Yamamoto T, Mori S (1990) 31. Baldus SE, Monig SP, Huxel S, Landsberg S, Hanisch FG, erbB-2 gene expression in colorectal cancer. Jpn J Exp Med Engelmann K, Schneider PM, Thiele J, Holscher AH, Dienes HP (2004) MUC1 and nuclear beta-catenin are coexpressed at the 20. D'Emilia J, Bulovas K, D'Ercole K, Wolf B, Steele G Jr (1989) invasion front of colorectal carcinomas and are both correlated Summerhayes IC: expression of the c-erbB-2 gene product (p185) with tumor prognosis. Clin Cancer Res 10:2790–2796 at different stages of neoplastic progression in the colon.
32. Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy.
21. Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, Schaefer H, Thiele J, Dienes HP, Mueller RP, 33. Kruser TJ, Wheeler DL (2010) Mechanisms of resistance to HER Hoelscher AH (2005) Histomorphologic tumor regression and family targeting antibodies. Exp Cell Res 316(7):1083–1100 lymph node metastases determine prognosis following neoadju- 34. Kluftinger AM, Robinson BW, Quenville NF, Finley RJ, Davis NL vant radiochemotherapy for esophageal cancer: implications for (1992) Correlation of epidermal growth factor receptor and c-erbB2 response classification. Ann Surg 242:684–692 oncogene product to known prognostic indicators of colorectal 22. International Union Against Cancer (UICC) (2002) TNM classi- fication of malignant tumors, 6th edn. Wiley, New York 35. Natali PG, Nicotra MR, Bigotti A, Venturo I, Slamon DJ, Fendly 23. Dworak O, Keilholz L, Hoffmann A (1997) Pathological features BM, Ullrich A (1990) Expression of the p185 encoded by HER2 of rectal cancer after preoperative radiochemotherapy. Int J oncogene in normal and transformed human tissues. Int J Cancer

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