Article Figures & Data
Figures
- Figure 1.
Systematic identification of studies that measured the relationship between expression of selected EMT markers in colorectal cancer primary tumors and patient outcomes.
Tables
- Table 1.
Summary of findings from studies that measured protein expression of selected EMT markers and patient outcomes in colorectal cancer tumorsa
Percent positiveb Survival Effect estimates Marker # Studies Range # Studies # With difference by marker status # Studies # With effect on outcomes β-catenin 5 42%–90% 2 0 1 0 Cytokeratins 2 9%–85% 2 1 1 0 E-cadherin 15 29%–92% 4 3 3 1 Fibronectin 0 — 0 0 0 0 Integrins 2 19%–88% 1 1 1 1 N-cadherin 2 0%–44% 0 0 1 0 Slug 2 30%–37% 2 1 1 1 Snail 5 40%–79% 3 2 2 Mixed TGFβ 2 82%–89% 1 0 0 0 Twist 4 48%–100% 1 1 3 Mixed Vimentin 4 0%–49% 0 0 0 0 ZEB1 1 29% 1 1 0 0 ZEB2 2 48%–90% 1 1 1 Mixed NOTE: Mixed, at least one study of a given marker reported both statistically significant and nonsignificant estimates of the effect of marker expression levels on outcomes.
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↵aThe number of studies under percentage of tumors with positive marker expression, survival, or effect estimates refers to the number of studies that reported values for that measurement for a given marker.
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↵bDefinitions of positive marker expression in a tumor generally varied across multiple studies of a given marker.
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- Table 2.
Summary of findings from studies that measured RNA expression of selected EMT markers and patient outcomes in colorectal cancer tumorsa
Percent positiveb Survival Effect estimates Marker # Studies Range # Studies # With difference by marker status # Studies # With effect on outcomes miRNAs 2 48%–76% 2 2 0 0 Twist 1 86% 1 1 1 1 -
↵aThe number of studies under percentage of tumors with positive marker expression, survival, or effect estimates refers to the number of studies that reported values for that measurement for a given marker.
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↵bDefinitions of positive marker expression in a tumor varied across multiple studies of a given marker.
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- Table 3.
Multivariate modeling performed in included studies
First author EMT markers examined Type of regression Adjustment covariates Bates et al. (45) Integrin α-v-β-6 Cox Age, sex, tumor type (colon vs. rectal), tumor stage Bellovin et al. (34) E-cadherin Cox Age, sex, tumor stage, lymph node status Bellovin et al. (35) E-cadherin Cox Age, sex, tumor stage, lymph node status Fan et al. (20) E-cadherin, N-cadherin, Twist, Snail, β-catenin Logistic Support vector machine, tumor stage, CEA, CA19-9, CA125 Fan et al. (36) E-cadherin, Twist, Snail Logistic Age, sex, histologic grade, tumor class Fujikawa et al. (37) E-cadherin Cox Age, pathologic T category, lymph node metastasis Gomez et al. (48) Twist, Slug (RNA only for both) Cox Age, sex, lymph node metastasis status, tumor stage, treatment protocol (e.g., chemo vs. surgery) Harbaum et al. (30) Cytokeratin-7, E-cadherin Cox Age, sex, T classification, N classification, tumor grade Kahlert et al. (50) ZEB2 Cox Age, sex, tumor stage, grade, type of resection (curative vs. noncurative), microsatellite stability, KRAS mutation status Kevans et al. (23) E-cadherin, β-catenin Cox Age, sex, T-stage, tumor site, tumor differentiation, tumor budding, lymphovascular invasion, neural invasion, microsatellite status Khanh et al. (26) Cytokeratin, TGFβ Cox Tumor grade, tumor depth, node status Knosel et al. (29) Cytokeratins Cox Not listed Knosel et al. (38) E-cadherin Cox Pathologic stage, venous invasion, PITX1 expression Koelzer et al. (31) E-cadherin Cox T-stage, M-stage, N-stage, postoperative therapy Kroepil et al. (39) E-cadherin, Snail Cox Age, sex, T-stage, N-stage, tumor grade Meng et al. (47) miRNA Cox Tumor size, CEA, histologic grade Mesker et al. (24) TGFβ, β-catenin Cox No adjustment covariates reported Saito et al. (41) E-cadherin, vimentin Cox Age, sex, location (colon vs. rectal), tumor size, histological type, lymphatic invasion, venous invasion, invasion of primary tumor, lymph node metastasis Shioiri et al. (42) E-cadherin, Slug Cox Age, distant metastasis, lymph node metastasis, lymphatic invasion, vessel invasion Spaderna et al. (27) E-cadherin, β-catenin, ZEB1, vimentin Cox Not listed Yu et al. (44) E-cadherin, Twist2 Cox Age, sex, T-stage, N-stage, M-stage, tumor differentiation, vascular invasion, tumor location, CEA level Zlobec (28) Cytokeratin Cox Tumor budding, TNM stage, tumor grade, KRAS status, BRAF status, MGMT status, microsatellite instability status, CpG island methylator status Abbreviations: TNM, tumor–node–metastasis; CEA, carcinoembryonic antigen.
- Table 4.
Recommendations for future studies of EMT markers in clinical cancer primary tumors and patient outcomes
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Standardize definitions of positive and negative marker expression status across studies of a given EMT marker measured using the same laboratory technique. To facilitate this for studies of protein expression using immunohistochemistry, score using computer-assisted image analysis to obtain continuous measures of marker staining (e.g., H scores, average intensities) that can be used to develop clinically useful cut points.
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Make study sample sizes as large as possible.
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For every EMT marker measured, present Kaplan–Meier survival curves stratified by marker expression status as well as Cox time-to-event modeling of the association between marker expression and patient time-to-mortality (or other outcomes).
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Develop consensus about what set of covariates should be included in multivariate models to produce valid estimates of the association between EMT marker expression in primary tumor cancer cells and patient time-to-mortality (or other outcomes).
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Measure EMT markers of interest as both RNA and protein in the same set of tumors to clarify which form of marker expression is more clinically useful.
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For studies using immunohistochemistry, report quantitative measures of inter-rater and intra-rater reliability for scoring images.
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To assess marker expression heterogeneity throughout a primary tumor, measure the marker in multiple cores taken from different parts of the tumor, including the invasive front, tumor center, and surface of the tumor away from the invasive front.
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Supplementary Data
Files in this Data Supplement:
- Supplementary Search Terms - PDF file - 98K, This file presents the set of search terms we used as applied to PubMed. It provides information about the structure of the search and how it could be adapted to search for studies of EMT markers and patient outcomes in tumor sites other than colorectal cancer.
Volume 23, Issue 7
