A simple and reproducible scoring system for EGFR in colorectal cancer: application to prognosis and prediction of response to preoperative brachytherapy

Zlobec, Inti; Vuong, T.; Hayashi, S.; Haegert, David G.; Tornillo, Luigi; Terracciano, Luigi; Lugli, Alessandro; Jass, Jeremy R.

doi:10.1038/sj.bjc.6603619

Cited by 67 publications

(56 citation statements)

References 61 publications

(72 reference statements)

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“…On the basis of our previous findings, 11 of these markers were identified as significant and independent prognostic factors in MMR-proficient CRC and, thus, were selected for the current investigation. [10][11][12][13][14][15][16][17] uPA and uPAR also were included in FIGURE 1. Receiver-operating characteristic curves for protein markers that had discriminatory power for survival in lymph node-negative mismatch repairproficient colorectal cancer, namely, urokinase-type plasminogen activator (uPA) (A), uPA receptor (uPAR) (B), p27 (C), and CD8+ tumor infiltrating lymphocytes (D).…”

Section: Discussionmentioning

confidence: 99%

“…The reproducibility of this scoring method between pathologists has been demonstrated previously for TMAs. 16,17,21 uPA and uPAR were evaluated by 2 independent pathologists, and the average of their scores was used in subsequent analyses. MLH1, MSH2, and MSH6 were considered negative for the protein when 0% of the tumor cells were stained.…”

Section: Evaluation Of Ihcmentioning

confidence: 99%

“…Of the protein markers that were chosen for this study, 11 were identified previously that had significant and independent prognostic value in MMR-proficient CRC. [10][11][12][13][14][15][16][17] …”

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confidence: 99%

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Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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BACKGROUND. The heterogeneity of stage II colon cancer underlines the need for identifying high‐risk, lymph node‐negative patients. The objective of this study was to define a multimarker prognostic model of 5‐year survival in patients with lymph node‐negative, mismatch repair (MMR)‐proficient colorectal cancer (CRC). METHODS. Immunohistochemistry for 13 tumor markers was performed on 587 lymph node‐negative, MMR‐proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver‐operating characteristic‐based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed. RESULTS. In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase‐type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267). CONCLUSIONS. The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node‐negative, MMR‐proficient CRC. The current findings suggested that a subgroup of patients with high‐risk, lymph node‐negative pT3 tumors should be considered for adjuvant therapy. Cancer 2008. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Section: Evaluation Of Ihcmentioning

confidence: 99%

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Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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“…The proportion of immunoreactive tumour cells over the total number of tumour cells by 5% increments (0, 5, 10, and so on up to 100%) was determined by three pathologists (A Lugli, JR Jass, S Hayashi) for EGFR and by four pathologists (CC Compton, A Lugli, JR Jass, RP Michel) for p53, Bcl-2, VEGF and APAF-1. This scoring method was previously found to be highly reproducible between pathologists (Zlobec et al, 2006a(Zlobec et al, , 2007c. Only areas of invasive carcinoma were analysed.…”

Section: Evaluation Of Immunohistochemistrymentioning

confidence: 99%

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

et al. 2008

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The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis proteaseactivating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value ¼ 0.009; odds ratio (OR) (95% CI) ¼ 0.24 (0.08 -0.69)) and positive EGFR (P-value ¼ 0.01; OR (95% CI) ¼ 3.82 (1.37 -10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative-and VEGFpositive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.

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“…The reproducibility of this scoring method between pathologists has previously been demonstrated for TMAs. 31 …”

Section: Evaluation Of Immunohistochemistrymentioning

confidence: 99%

HOX D13 expression across 79 tumor tissue types

Cantile

Franco

Tschan

et al. 2009

Intl Journal of Cancer

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HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. ' UICCKey words: HOXD13; HOX and multitumor tissue microarray; HOXD13 and pancreas Class I Homeobox genes (Hox, mice; HOX, human) are transcription factors mostly involved in embryonic development. 1 They display an unique genomic network organization: 4 compact chromosomal loci (HOXA at 7p15.3, HOXB at 17q21.3, HOXC at 12q13.3 and HOXD at 2q31 2 ) where 39 sequence corresponding genes can be aligned with each other into 13 antero-posterior paralogous groups. The HOX gene network, the most repeat-poor regions in the human genome, 3 is also expressed in normal adult human organs. 4 HOX genes appear to regulate phenotype cell identity, 5,6 cell differentiation 7,8 and control primary cellular processes, as proven by the description of congenital, 9 somatic 10 and metabolic 11 diseases involving these genes. Furthermore, besides the already established role of the HOX network in hematopoiesis and leukemogenesis, 12 HOX genes are implicated in the neoplastic alterations of human solid tissues and organs such as kidney, colon, lung, skin, bladder, liver, breast and prostate. 13,14 New crucial functions have recently been ascribed to HOX genes and homeoproteins mostly related to their interaction with miRNAs and ncRNAs to guarantee transcription and export of specific mRNAs. 15,16 Locus D HOX genes are localized on chromosome 2q31-32 and play a role, with its posterior paralogous genes, in limb and digit generation during embryonic development 1...

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A simple and reproducible scoring system for EGFR in colorectal cancer: application to prognosis and prediction of response to preoperative brachytherapy

Cited by 67 publications

References 61 publications

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

HOX D13 expression across 79 tumor tissue types

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