Overall Survival In Colon Cancer Research Articles

Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors

Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets. Here, our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data. A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements. A combined database was set up and integrated into our Kaplan-Meier plotter, making it possible to identify genes with expression changes linked to altered survival. As a demonstration of the utility of the platform, the most powerful genes linked to overall survival in colon cancer were identified using uni- and multivariate Cox regression analysis. The combined colon cancer database includes 2,137 tumor samples from 17 independent cohorts. The most significant genes associated with relapse-free survival with a false discovery rate below 1% in colon cancer carcinoma were RBPMS (hazard rate [HR]= 2.52), TIMP1 (HR= 2.44), and COL4A2 (HR= 2.36). The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R (HR= 2.86), FLNA (HR= 2.88), and TPBG (HR= 2.65). In summary, a new integrated database for colon cancer is presented. A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database (https://www.kmplot.com). The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including, among others, breast, lung, ovarian, gastric, pancreatic, and colon cancers.

Apigenin exerts anti-cancer effects in colon cancer by targeting HSP90AA1

Apigenin, a flavonoid, has shown early promise in colon cancer (CC); thus, exploring potential mechanisms of Apigenin is obligatory. In this study, shared targets of Apigenin and CC were identified through online tools, which were then subjected to functional enrichment analyses, Gene Ontology and KEGG. Further, the protein-protein interaction network of the shared targets was developed (via STRING). The top targets of Apigenin in CC were identified by molecular docking; further investigated for differential gene and protein expression in CC and their influence on CC patient survival (using TCGA data). Out of 13 hub genes, the top 3 targets (HSP90AA1, MMP9, PTGS2) were selected based on docking score. Their expression was significantly elevated and related to poor overall survival in CC (except PTGS2). Molecular dynamics simulation further validated protein-ligand interactions and divulged HSP90AA1 as the best target of Apigenin in CC. Finally, the anti-cancer effects of Apigenin and its major metabolite, luteolin, were investigated in CC, which is involved in the cytotoxicity of CC cells (COLO-205) by reducing HSP90AA1 expression revealed by real-time PCR. Thus, HSP90AA1 was identified as one of the prime targets of Apigenin in CC, and Apigenin could be effective against CC. Communicated by Ramaswamy H. Sarma

A national evaluation of adjuvant chemotherapy in pT4N0M0 colon cancer from the National Cancer Database.

T stage is a prognostic biomarker for overall survival in colon cancer and pathologic T4 disease is a high-risk characteristic. Adjuvant chemotherapy is recommended to improve overall survival in pT4N0M0, but compliance with guidelines is unknown. We aimed to evaluate adjuvant chemotherapy use and impact on overall survival in pT4N0M0 colon cancer. The National Cancer Database was reviewed for pT4N0M0 colon adenocarcinomas undergoing curative surgical resection (2010-2017). Cases were stratified into no adjuvant chemotherapy and adjuvant chemotherapy cohorts. Moderated multiple regression assessed factors associated with no AC. Kaplan-Meier and Cox regression assessed overall survival in propensity-score matched cohorts. The main outcome measures were adjuvant chemotherapy use, factors associated with adjuvant chemotherapy, and impact on overall survival. Of 11 847 cases, 62.4% (n = 7391) received no adjuvant chemotherapy. With private insurance, comorbidities or income do not affect adjuvant chemotherapy use. Medicare cases with a Charlson-Deyo comorbidity index of 0 (odds ratio [OR] = 0.861, 95% confidence interval [CI] = 0.760 to 0.975; P = .019) and Medicare payors with high income (OR = 0.813, 95% CI = 0.690 to 0.959; P = .014) were associated with adjuvant chemotherapy. Medicaid Charlson-Deyo comorbidity index 0 (OR = 1.374, 95% CI = 1.125 to 1.679; P = .002) and uninsured Charlson-Deyo comorbidity index 0 (OR = 1.351, 95% CI = 1.120 to 1.629; P = .002) were associated with no adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved 5-year overall survival (71.7% vs 56.4%; P < .001; adjusted hazard ratio = 0.543, 95% CI = 0.499 to 0.590; P < .001). Although adjuvant chemotherapy is associated with improved overall survival, compliance is low. There is a complex relationship between payor, income, comorbidity, and adjuvant chemotherapy receipt. Medicare patients with no comorbidities or higher income have better adjuvant chemotherapy use. With private insurance, adjuvant chemotherapy compliance is not affected by comorbidities or income, whereas Medicaid and uninsured patients with no comorbidities have poor compliance. Future work could target these disparities for equitable care.

Identification of Hypoxia-Associated Signature in Colon Cancer to Assess Tumor Immune Microenvironment and Predict Prognosis Based on 14 Hypoxia-Associated Genes.

Colon cancer is the main malignant tumor of the digestive tract. Hypoxia is highly related to the occurrence, progression and tumor immune microenvironment (TIME) of cancer. The aim of this study was to identify a hypoxia-associated signature with high accuracy for predicting the prognosis and TIME of colon cancer. Download colon cancer data from the GEO and TCGA databases. A novel hypoxia risk model was identified to predict the prognosis of colon cancer patients. Subsequently, GSEA, TIME and mutation analysis were performed in the hypoxia high and low risk score groups. Finally, the signature gene ANKZF1 was selected for functional verification at the cellular level. A novel hypoxia risk model was identified. The risk score was significantly associated with poorer overall survival in colon cancer, and could be used as an independent prognostic factor for colon cancer. GSEA analysis found that the processes related to stimulate tumor proliferation and anti-apoptosis were significantly enriched in the hypoxia high risk score group. The expression of immunosuppressive cells and most immune checkpoints in the high risk score group was significantly higher than that in the low risk score group. In vitro cell experiments showed that knockdown the expression of ANKZF1 could inhibit the proliferation, migration and invasion of colon cancer cells. Hypoxia plays an important role in evaluating the TIME and predicting the prognosis of colon cancer.

Novel prognostic model predicts overall survival in colon cancer based on RNA splicing regulation gene expression

Colon cancer is the third most common cancer and the second leading cause of cancer‐related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2‐like kinase 1(CLK1), CLK2, and A‐kinase anchor protein 8‐like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low‐risk group, and TME‐related pathway gene expression was also higher in low‐risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.

PBXIP1 – An indicator for poor outcome and metastatic spread in colorectal cancer

Tumor cell heterogeneity in colorectal cancers within the same genetic background is a well-described phenomenon. In this work, we investigate the role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in tumor cell subpopulations with differential Wingless-related integration site (WNT) activity as well as its potential associations with epithelial-mesenchymal transition (EMT) and clinical associations in colorectal cancer. We used in situ analyses to identify immunohistochemical expression of PBXIP1 in normal and colorectal cancer tissues and biostatistical approaches to determine its function and regulatory correlations. Clinical associations were analyzed in a case control collection of metastatic and non-metastatic colon cancers and gene expression data sets of colorectal cancers with recorded clinical follow-up data. PBXIP1 was expressed in single epithelial cells from tumor-free colon crypts as well as in tumor cells with high WNT activity. Colorectal cancer cells close to the invasive edge seemed to possess higher PBXIP1 levels indicative of associations with EMT, whereas stromal cells in the tumor microenvironment appeared mostly negative. PBXIP1 expression was associated with local metastasis to lymph nodes as well as distant metastasis to secondary organs in a case-control collection consisting of 91 cases with or without distant metastasis. Furthermore, high expression of PBXIP1 in The Cancer Genome Atlas (TCGA) data set was associated with worse overall survival in colon cancer. PBXIP1 might serve as a novel histological prognostic and regulatory indicator for EMT processes in colorectal cancer that seems to correlate with cancer cell subtypes of high baseline WNT activity.

Adjuvant Chemotherapy Has a Limited Benefit in Terms of Recurrence-free Survival and Overall Survival in Colon Cancer with Solitary Lymph Node Metastasis: A Propensity Score Matching Analysis

Adjuvant Chemotherapy Has a Limited Benefit in Terms of Recurrence-free Survival and Overall Survival in Colon Cancer with Solitary Lymph Node Metastasis: A Propensity Score Matching Analysis

INFORM: INFrared-based ORganizational Measurements of tumor and its microenvironment to predict patient survival.

The structure and organization of a tumor and its microenvironment are often associated with cancer outcomes due to spatially varying molecular composition and signaling. A persistent challenge is to use this physical and chemical spatial organization to understand cancer progression. Here, we present a high-definition infrared imaging-based organizational measurement framework (INFORM) that leverages intrinsic chemical contrast of tissue to label unique components of the tumor and its microenvironment. Using objective and automated computational methods, further, we determine organization characteristics important for prediction. We show that the tumor spatial organization assessed with this framework is predictive of overall survival in colon cancer that adds to capability from clinical variables such as stage and grade, approximately doubling the risk of death in high-risk individuals. Our results open an all-digital avenue for measuring and studying the association between tumor spatial organization and disease progression.

Identification and validation of an immune-related gene signature predictive of overall survival in colon cancer.

The heterogeneity and complexity of tumor-immune microenvironments lead to diverse immunotherapy effects among colon cancer patients. It is crucial to identify immune microenvironment-related biomarkers and construct prognostic risk models. In this study, the immune and stromal scores of 415 cases from TCGA were calculated using the ESTIMATE algorithm. AXIN2, CCL22, CLEC10A, CRIP2, RUNX3, and TRPM5 were screened and established a prognostic immune-related gene (IRG) signature using by univariate, LASSO, and multivariate Cox regression models. The predicted performance of IRG signature was external validated by GSE39582 (n=519). Stratified survival analysis showed IRG signature was an effective predictor of survival in patients with different clinical characteristics. The protein expression level of six genes was validated by immunohistochemistry analysis. Difference analysis indicated the mutation rate, immune cell of resting NK cells and regulatory T cells infiltration and four immune checkpoints of PD-1, PD-L1, LAG3 and VSIR expression levels in the high-risk group were significantly higher than those in the low-risk group. A nomogram incorporating the gene signatures and clinical factors was demonstrated had a good accuracy (1-, 3-, and 5-year AUC= 0.799, 0.791, 0.738). Our study identified a novel IRG signature, which may provide some references for the clinical precision immunotherapy of patients.

Clinicopathological Characteristics of TZAP Expression in Colorectal Cancers.

PurposeThe zinc finger protein, ZBTB48, is a telomere-associated protein. It was renamed as telomeric zinc finger-associated protein (TZAP) binding to elongated telomeres. However, its expression level was not measured in cancers.Patients and MethodsWe analyzed TZAP mRNA levels in 60 colorectal cancers (CRC) and its correlation with telomere length and TERT was studied.ResultsTZAP mRNA in CRC was higher statistically than that in paired non-cancerous tissues (p = 0.033). Higher TZAP was found in carcinoembryonic antigen (CEA)-positive CRCs (>5 ng/mL) (p = 0.012). Shorter telomere was found in CRCs with high TZAP expression than that with low TZAP expression (p = 0.010). According to quantitative correlation analysis, TZAP has a correlation with age (r = −0.349, p = 0.007), TERT (r = 0.279, p = 0.041) and telomere length (r = −0.305, p = 0.021). TZAP expression did not harbor prognostic value in CRC. Inhibition of TZAP expression by siRNA suppresses cell growth in HT29 cells; however, it resulted in increased cell viability in HCT116 cells. TZAP inhibition induces a decrease in mRNA levels of TERT in both HT29 and HCT116 cells. TCGA data analysis showed higher expression of TZAP showed poorer overall survival in colon cancer (p = 0.001); however, it did not have a significance in rectal cancer (p = 0.951).ConclusionWe suggested that TZAP may be a possible biomarker for CRC.

Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer.

Aim: To evaluate the expression pattern of ALDH1 (aldehyde dehydrogenase 1), E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer (CRC) and to study association of their expression with the occurrence of CRC at a young age. Materials & methods: Immunohistochemistry of ALDH1, E-cadherin, Vimentin and Twist was performed on 103 pretreated CRC biopsy samples. Results: ALDH1 expression was found to have strong correlation with early onset CRC (p < 0.0001). Conclusion: High ALDH1 expression correlates with the early onset of CRC. ALDH1 over-expression correlates with poor overall survival in colon cancer.

Identification of an Immune-Related Nine-lncRNA Signature Predictive of Overall Survival in Colon Cancer.

Growing evidence suggests that immune-related genes (IRGs) and long non-coding RNAs (lncRNAs) can serve as prognostic markers of overall survival (OS) in patients with colon cancer. This study aimed to identify an immune-related lncRNA signature for the prospective assessment of prognosis in these patients. Gene expression and clinical data of colon cancer patients were downloaded from The Cancer Genome Atlas (TCGA). Immune-related lncRNAs were identified by a correlation analysis between IRGs and lncRNAs. In total, 447 samples were divided into a training cohort (224 samples) and a testing cohort (223 samples). Univariate, lasso and multivariate Cox regression analyses identified an immune-related nine-lncRNA signature closely related to OS in colon cancer patients in the training dataset. A risk score formula involving nine immune-related lncRNAs was developed to evaluate the prognostic value of the lncRNA signature in the training dataset. Colon cancer patients with a high risk score had poorer OS than those with a low risk score. A multivariate Cox regression analysis confirmed that the immune-related nine-lncRNA signature could be an independent prognostic factor in colon cancer patients. The results were further confirmed in the testing cohort and the entire TCGA cohort. Furthermore, a gene set enrichment analysis revealed several pathways with significant enrichment in the high- and low-risk groups that may be helpful in formulating clinical strategies and understanding the underlying mechanisms. Finally, a quantitative real-time polymerase chain reaction assay found that the nine lncRNAs were significantly differentially expressed in colon cancer cell lines. The results of this study indicate that this signature has important clinical implications for improving predictive outcomes and guiding individualized treatment in colon cancer patients. These lncRNAs could be potential biomarkers affecting the prognosis of colon cancer.

Calponin 3 promotes invasion and drug resistance of colon cancer cells.

BACKGROUNDCalponin 3 (CNN3) is an actin-binding protein expressed in smooth muscle and non-smooth muscle cells. It is required for cytoskeletal rearrangement and wound healing.AIMTo dissect the role of CNN3 in carcinogenesis with a focus on colon cancer.METHODSA total of 20 cancer cell lines (8 breast, 11 colon, and HeLa cervical cancer cell as a positive control for mesenchymal phenotype) and 57 formalin-fixed, paraffin-embedded sections from archived sporadic colorectal carcinomas were included in this study. CNN3 expression analysis by western blot or immunohistochemistry was followed by functional analyses. The CNN3 gene was silenced by specific small interfering RNA (commonly known as siRNA), followed by confirmation of the silencing efficiency by western blotting. Then, the silenced cells and control siRNA-transfected cells were analyzed for changes in epithelial and mesenchymal markers, invasion, and response to 5-fluoruracil treatment. We also performed proteomics analysis using a phospho-kinase array-based panel of 45 proteins.RESULTSCNN3 showed positive expression in 6/8 breast and 9/11 colon cancer lines and in HeLa cells. Interestingly, the colorectal adenocarcinoma line SW480 was negative, while the cell line developed from its matching lymph node metastasis (SW620) was positive for CNN3. CNN3 expression was fairly consistent with the metastatic phenotype in colon cancer because it was absent in one other colon cell line from a primary site and expressed in all others. We selected SW620 for subsequent functional analyses. CNN3-silenced SW620 cells showed a reduction in collagen invasion and loss of mesenchymal markers. CNN3 silencing caused an increase in the SW620 colon cancer cell sensitivity to 5-fluorouracil. Phospho-kinase array-based proteomics analysis showed that CNN3 silencing in SW620 reduced extracellular signal-regulated kinase, β-Catenin, mutant p53, c-Jun, and heat shock protein 60 activities but increased that of checkpoint kinase 2. CNN3 was expressed in 20/57 (35%) colon cancer cases as shown by immunohistochemistry. CNN3 was associated with a decrease in overall survival in colon cancer in silico.CONCLUSIONThese results show the involvement of CNN3 in lymph node metastasis and resistance to chemotherapy in colon cancer and suggest that significant oncogenic pathways are involved in these CNN3-related actions.

Diagnostic and prognostic values of C‑X‑C motif chemokine ligand 3 in patients with colon cancer.

The diagnostic and prognostic mechanisms of C-X-C motif chemokine ligand 3 (CXCL3) in colon cancer (CC) have not yet been reported. Therefore, the objective of the present study was to use cohorts of patients from Guangxi Medical University and the Gene Expression Omnibus (GEO) database to investigate and validate CXCL3 for the diagnosis and prognosis of CC, and to explore its prospective molecular mechanism. Reverse transcription-quantitative PCR (RT-qPCR) analysis of 38 paired tumor and non-tumor tissues, and immunohistochemistry (IHC) of 212 tumor and 46 non-tumor tissues was conducted to explore the expression of CXCL3 and its diagnostic and prognostic significance in the Guangxi Medical University CC cohort. A GEO dataset, GSE40967, was used to validate the prognostic significance of CXCL3. Gene set enrichment analysis (GSEA) was also conducted to explore the potential molecular mechanisms underlying the effects of CXCL3 in CC. The RT-qPCR results indicated that CXCL3 expression was significantly higher in cancer tissues compared with adjacent normal tissues, suggesting that it may have high diagnostic value for CC. Multivariate Cox analysis based on the IHC results suggested that there was no appreciable association between CXCL3 positivity and the overall survival (OS) time of CC. However, a stratified analysis revealed that high expression of CXCL3 was associated with considerably increased mortality in the subgroup of CC patients with tumor size <5 cm (adjusted P=0.042, adjusted HR=2.298, 95% CI=1.030–5.126) and with tumor thrombus (adjusted P=0.019, adjusted HR=5.096, 95% CI=1.306–19.886). In the GSE40967 dataset, high expression of CXCL3 was closely associated with poor OS in CC (adjusted P=0.049, adjusted HR=1.416, 95% CI=1.002–2.003). Furthermore, GSEA indicated that the high expression of CXCL3 was closely associated with DNA repair, cell cycle process, cell apoptosis process and the P53 regulation pathway. In summary, these result suggest that CXCL3 might serve as a novel biomarker in the diagnosis and prognosis of CC.

An immune infiltration signature to predict the overall survival of patients with colon cancer.

Immune infiltration of tumors has been increasingly accepted as a prognostic factor in colon cancer. Here, we aim to develop a novel immune signature, based on estimated immune landscape from tumor transcriptomes, to predict the overall survival of patients with colon cancer. The compositions of 22 immune cell subtypes from three microarray datasets were characterized with the CIBERSORT deconvolution algorithm. A prognostic immunoscore (PIS) model for overall survival prediction was established by using least absolute shrinkage and selection operator (LASSO) penalized regression analysis. A total of 17 immune cell markers were screened out in the LASSO model and were then aggregated to generate the PIS. In the training cohort (n = 490), patients with high PIS exhibited a remarkably poorer overall survival than those with low PIS. Similar results were obtained in patients with different TNM stages and in patients receiving adjunctive chemotherapy or not. Multivariate Cox regression indicated that the PIS was an independent predictor for overall survival in colon cancer (hazard ratio: 2.734, 95% confidence interval: 2.052-3.643, p < .001). The prognostic capability of PIS was also confirmed in the testing cohort (n = 245) and the entire cohort (n = 735). As for biological implications, the PIS was significantly associated with some immune checkpoints, inflammatory factors, epithelial-mesenchymal transformation regulators, and many known signaling pathways in cancer. The results of our study provide a novel and promising immune signature for overall survival prediction of patients with colon cancer.

ITGB4 is a novel prognostic factor in colon cancer.

Integrin β4 (ITGB4) has been reported to be involved in carcinomas. Currently, ITGB4 has been characterized in colon cancer, however, its clinical significance is not very clear. In the present study, we utilized the large public datasets from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and collected clinical samples in our center to investigate the transcriptional expressions of ITGB4 in colon cancer, and then explored the associations of ITGB4 with clinicopathological features and overall survival. The statistical analyses suggested that ITGB4 mRNA expressions were up-regulated significantly in colon cancer. High ITGB4 expression was observed to be associated with elder onset age, proximal tumor location, and high microsatellite instability (MSH) status. Further, Kaplan-Meier curves and univariate analysis demonstrated high ITGB4 expression was significantly associated with unfavorable overall survival in colon cancer (HR=1.292, 95%CI=1.084-1.540, P=0.004). And significant association was also found after adjusting the confounding factors including age, gender, and stage (adjusted HR=1.254, 95%CI=1.050-1.497, P=0.012). The annotation of ITGB4 co-expressed genes suggested the pathways including cell growth, positive regulation of cell migration, and apoptotic signaling might be involved in the potential mechanisms of ITGB4 in colon cancer development. The molecular regulation mechanism of ITGB4 ectopic expression in colon cancer was also explored and the results indicated that ITGB4 might be up-regulated by the transcription factor FOSL1 (FOS like 1, AP-1 Transcription Factor Subunit) and its promoter hypomethylation. Our results revealed that ITGB4 might be a therapeutic target and prognosis marker for individual therapy of colon cancer.

Abstract 5911: A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer

Abstract Background: Combination of cytotoxic treatments with immunotherapeutic agents seem more efficacious than using either strategy alone. Oncolytic viral vectors carrying immunostimulatory genes like GM-CSF have emerged as treatment options in various tumors. Previously, we have shown that combination of suicide gene therapy either with GM-CSF or vector-induced dendritic cells has significant anti-tumor efficacy. In the current study, we aimed to combine the cytotoxic effect of the suicide gene cytosine deaminase and the immunostimulatory effect of granulocyte macrophage colony stimulating factor in a single vector construct. Methods: We have constructed a bicistronic adenoviral vector carrying cytosine deaminase (CD) and granulocyte macrophage-colony stimulating factor (GM-CSF) genes combined with an IRES element and driven by CMV promoter (Ad-CMV-CDiresGMCSF). We tested the in vitro efficacy of the vector in various tumor cell lines and in a mouse model of colon cancer. Results: Our bicistronic vector Ad-CMV-CDiresGMCSF showed significant in-vitro cytotoxic effects on tumor cell lines similar to the vector carrying CD gene alone when 5-FC added. Likewise, the GM-CSF producing efficacy of the bicistronic vector was comparable to the vector carrying GM-CSF gene alone. In the syngeneic colon cancer model, the bicistronic vector carrying CD and GM-CSF genes yielded significant tumor shrinkage and overall survival when compared to the control suicide vector carrying CD gene alone. Accordingly, anti-tumor immune response parameters including CTL assay and immune cell infiltration of tumor tissue were significantly improved in the Ad-CMV-CDiresGMCSF vector treated group (p&amp;lt;0.01). Conclusions: The Ad-CMV-CDiresGMCSF vector construct suggests a potential for the treatment of established tumors by inducing significant tumor killing and tumor-specific immune response. Citation Format: Hakan Akbulut, Arzu Coleri, Gunce Sahin, Yucheng Tang, Albert Deisseroth, Fikri Icli. A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5911.

Time to surgery in colon cancer: Predictors and association with survival—An analysis of the National Cancer Database (NCDB).

599 Background: Time-to-surgery (TTS) refers to the wait time from the diagnosis of cancer to surgical resection of the primary tumor. In breast and bladder cancers, longer TTS has been shown to be associated with lower long-term survival. Prior evidence in colon cancer, has shown that older age, urban residence, and comorbidity are independent predictors of TTS. However, evaluation of TTS with survival in colon cancer has been limited to mostly single-center studies. Using the NCDB, this study aimed to both evaluate patient and clinical factors associated with TTS, and determine if TTS was associated with overall survival in colon cancer. Methods: Patients with colon cancer who underwent partial or subtotal colectomy/hemicolectomy were included, excluding those receiving neoadjuvant therapy. With prior colon cancer studies showing a median TTS of 15-20 days, we dichotomized the number of days from diagnosis to definitive surgery (TTS) as ≤ 21 days or &gt; 21 days. A modified Poisson regression model was utilized to evaluate relative risk of TTS &gt; 21 days. Overall survival in association with TTS was estimated using both the Kaplan-Meier method and multivariable Cox regression model, adjusting for patient-, disease- and facility-level characteristics. All analyses were conducted with SAS version 9.4, p-values &lt; 0.05 were considered significant. Results: We identified 26,999 colon cancer patients from 2006-2012 from the NCDB. Approximately 25.7% of patients had a TTS &gt; 21 days. Patients with comorbidities, who were older, were African American, with lower disease stage, and treated in academic facilities located in the Northeast, had a significantly increased relative risk of a TTS &gt; 21 days. Considering survival, a TTS &gt; 21 days was associated with a 24.5% decreased adjusted risk of death (95% CI: 21.6% to 27.2%). Conclusions: A longer TTS with colon cancer is understandably associated with older age, greater comorbidity, and lower stage, but questionably so in African American patients. However, given that TTS &gt; 21 days was associated with a lower adjusted risk of death, it may indicate that a reasonable delay could be pursued for more accurate preoperative evaluation and staging in colon cancer.

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance).

Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

CCR2 Expression Is an Independent Predictor of Overall Survival in Colon Cancer by Stimulation of Direct and Indirect Inflammatory Pathways

Chemokines are group of proteins that are involved in regulation of cancer microenvironment directly by crosstalk between cancer cells and stromal cells. The receptors are widely expressed on cancer cells. In this study, we analyzed the prognostic significance of CCR2 expression in …