High-risk Colorectal Cancer Patients Research Articles

The Predictive Value of Neutrophil Extracellular Trap-Related Risk Score in Prognosis and Immune Microenvironment of Colorectal Cancer Patients.

Colorectal cancer (CRC) has brought great healthy burden for patients. Neutrophil extracellular traps (NETs) have been explored in several tumors, while it remains largely unclear in CRC. CRC-related data were downloaded from Cancer Genome Atlas and Gene Expression Omnibus databases. Then, a NET risk score was built after univariate Cox and LASSO Cox regression analysis. Prognostic value was evaluated via survival analysis, stratification analysis, and ROC analysis. The functional enrichment analysis was conducted basing on bulk and scRNA-seq data. The immune landscape difference was analyzed using CIBERSORT, XCell, and MCPcounter portals. NET risk score was built for CRC patients, basing on G0S2, HIST1H2BC, CRISPLD2, and IL17A. In TCGA-CRC and validation datasets, regardless of age or gender, high-risk CRC patients had significantly worse prognosis, besides higher NET risk score was mainly found in samples with MSI-H and advanced T, N, and M stages. Employing multiple databases, we noticed that M0 and M2 Macrophages infiltrated the most in high-risk CRC patients, besides M2 Macrophages and neutrophils showed positive correlation with NET risk score. A novel reliable prognostic NET risk score was developed for CRC patients, and high-risk patients had unfavorable prognosis with advanced disease status.

Comprehensive analysis of basement membrane-related gene based on single-cell and bulk RNA sequencing data to predict prognosis and evaluate immune characteristics in colorectal cancer.

Basement membrane-related genes (BMs) participate in regulating cell polarity, invasion, metastasis, and survival across different tumor types. Nevertheless, the specific functions of BMs in colorectal cancer (CRC) remain uncertain. To investigate the clinical relevance of BMs in CRC, we retrieved both gene expression and clinical data from The Cancer Genome Atlas (TCGA) datasets for subsequent analysis. The Kaplan-Meier (K-M) survival curve was employed to evaluate prognosis in high- and low-risk groups. Furthermore, additional analyses, including nomogram construction, functional enrichment, examination of the tumor immune microenvironment, prediction of small-molecule drugs, and more, were conducted to delve into the significance of BM-related signatures in CRC. Single-cell data from seven CRC patients were obtained from the TISCH2 database, and expression validation and cell source exploration of BM-related signatures were performed. Lastly, the expression and function of TIMP1, a key gene in BMs that may play a role in the progression of CRC, was validated in vitro through a series of basic experiments. We constructed a seven BMs-based model to categorize CRC patients into high-risk and low-risk groups. K-M survival analysis indicated a poorer prognosis for high-risk CRC patients. Cox regression analysis further identified the risk score as an independent prognostic factor for CRC patients. The nomogram model exhibited superior discrimination and calibration abilities of CRC patients. Based on the results from GO/KEGG and GSEA, genes in the high-risk subgroup were implicated in immune-related pathways and exhibited a positive correlation with immune checkpoints. In single-cell data, we found that TIMP1 is highly expressed in many cells, especially in malignant tumor cells. We also observed up-regulation of TIMP1 in CRC cell lines, promoting cancer invasion and migration in vitro. Our study has discovered a novel prognostic index derived from BM-related genes in CRC patients. Specifically, the new model enables patient stratification, improving the selection of individuals likely to benefit from immunotherapy.

Long-term outcomes of local resection versus surgical resection for high-risk T1 colorectal cancer: A systematic review and meta-analysis.

Patients with T1 colorectal cancer (CRC) are at high risk for lymph node metastasis and recurrence after local resection (LR) and need surgical resection (SR) for additional lymph node dissection to improve prognosis. However, the net benefits of SR and LR are still unquantified. A systematic search for studies in which survival analysis among high-risk T1 CRC patients undergoing LR and SR was performed was conducted. Overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS) data were extracted. Hazard ratios (HRs) and fitted survival curves for OS, RFS and DSS were used to estimate the long-term clinical outcomes of patients in the two groups. This meta-analysis included 12 studies. Compared to those in the SR group, patients in the LR group had higher risks of death (HR 2.06, 95% CI 1.59-2.65), recurrence (HR 3.51, 95% CI 2.51-4.93) and cancer-related mortality (HR 2.31, 95% CI 1.17-4.54) in the long term. Fitted survival curves for the LR and SR groups revealed the 5-year, 10-year, and 20-year rates for OS (86.3%/94.5%, 72.9%/84.4%, and 61.8%/71.1%), RFS (89.9%/96.9%, 83.3%/93.9% and 29.6%/90.8%) and DSS (96.7%/98.3%, 86.9%/97.1% and 86.9%/96.4%, respectively). Log-rank tests showed significant differences among all the outcomes except for 5-year DSS. For high-risk T1 CRC patients, the net benefit of DSS appears to be significant when the observation period exceeds 10 years. A long-term net benefit may exist but may not be applicable to all patients, especially high-risk patients with comorbidities. Therefore, LR may be a reasonable alternative for individualized treatment for some high-risk T1 CRC patients.

Abstract 2306: Potential clinical utility of circulating tumor DNA detected by digital PCR in a nationwide Danish cohort of high-risk colorectal cancer patients

Abstract Introduction: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment, with the potential to guide postoperative treatment decisions. Low ctDNA levels immediately after surgery necessitate extremely sensitive detection methods. Additionally, for potential clinical implementation, detection methods should ideally feature short turnaround times (TATs) and low analysis costs. Compared to sequencing-based detection methods, digital PCR is low-cost, and features TATs of less than a day. Consequently, digital PCR is a good candidate for clinical implementation. Here, we present ctDNA detection results from a highly optimized, tumor-informed digital PCR strategy in a large cohort of stage II-III colorectal cancer (CRC) patients. Methods: Stage II-III CRC patients (n=864) treated with curative intent were recruited from Danish surgical centers from 2014 to 2021. Whole exome sequencing was conducted on matched tumor and buffy coat from all patients. After thorough clonality assessment, a mutational target was chosen for digital PCR analysis. Plasma samples (8mL) collected before and within 60 days after surgery, were investigated for ctDNA using digital PCR. Additionally, a subset of patients (n=229) had serial samples collected every three months analyzed for ctDNA. Results: Before surgery, ctDNA was detected in 569/828 (69%) analyzed blood samples. A minimum of 12 months of radiological follow-up was available for 598/864 patients at time of writing, enabling prognostic evaluation of ctDNA detection in these patients. Postoperative ctDNA detection was highly correlated to future recurrence (HR=9.6, 95%CI 6.3-15, P<0.001). The median time to recurrence was significantly shorter for postoperatively ctDNA positive patients (10 months, interquartile range (IQR) 3.8-12 months) compared to ctDNA negative patients (18 months, IQR 12-26 months, P<0.001), indicating a higher disease burden postoperatively in ctDNA positive patients. In a subset of patients with samples collected immediately after adjuvant treatment (n=95) and serially (n=186), ctDNA was also prognostic of recurrence (HR=6.4, CI95% 2.9-14, P<0.001; HR=27, 95%CI 14-52, P<0.001). A minimum of 12 months of follow-up is expected to be available for 700 patients before the AACR meeting 2023. Conclusion: These results from one of the largest ctDNA detection cohorts of stage II-III CRC patients demonstrate that our personalized digital PCR approach effectively detects MRD immediately after surgery. Additionally, our approach shows promise for serial ctDNA detection for recurrence surveillance applications. With digital PCR being a widespread and cost-effective method with low TATs, clinical implementation of ctDNA analysis may be more forthright using this method over cost-intensive sequencing-based methods. Citation Format: Tenna V. Henriksen, Christina Demuth, Amanda Frydendahl, Marijana Nesic, Mads H. Rasmussen, Thomas Reinert, Ole H. Larsen, Anders H. Madsen, Uffe S. Løve, Per V. Andersen, Ole Thorlacius-Ussing, Ismail Gögenur, Jakob Lykke, Allan G. Pedersen, Peter Bondeven, Nis H. Schlesinger, Lene H. Iversen, Kåre A. Gotschalck, Claus L. Andersen. Potential clinical utility of circulating tumor DNA detected by digital PCR in a nationwide Danish cohort of high-risk colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2306.

Emerging glyco-risk prediction model to forecast response to immune checkpoint inhibitors in colorectal cancer.

Aberrant glycosylation is one of the most common post-translational modifications leading to heterogeneity in colorectal cancer (CRC). This study aims to construct a risk prediction model based on glycosyltransferase to forecast the response to immune checkpoint inhibitors in CRC patients. Based on the TCGA dataset and glycosyltransferase genes, the NMF algorithm and WGCNA were used to identify molecular subtypes and co-expressed genes, respectively. Lasso and multivariate COX regression were used to identify prognostic glycosyltransferase genes and construct a glyco-risk prediction model in CRC patients. Univariate and multivariate Cox regression, Kaplan-Meier, and ROC curves were applied to further verify the prognostic performance of the model in CRC patients in the training and validation sets. We compared the responsiveness of immunotherapy and chemotherapy between the two groups. In vitro experiments and clinical specimens verified the specific function of the key glycosyltransferase genes in CRC. The CRC cohort was divided into two subtypes with prominent differences in survival based on the well-robust seven-gene glyco-risk prediction model (composed of ALG1L2, HAS1, PYGL, COLGALT2, B3GNT4, POFUT2, and GALNT7). The nomograms based on the risk model could predict the prognosis of CRC patients independently of other clinicopathologic characteristics. Our prediction model showed a better overall prediction performance than other models. Compared with the low-risk group, the high-risk CRC patients showed a lower immune infiltration state, but a higher TMB and a lower response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapy. Clinical specimen validation showed an obvious difference in the expression of seven glycosyltransferase genes between the low- and high-risk groups. Significant reduction in POFUT2 expression in high-risk groups was associated with reduced N-glycans production. Our study constructed a robust glyco-risk prediction model that could provide direction for immunotherapy and chemotherapy in CRC patients, which could help clinicians make personalized treatment decisions.

DNA Methylation and Gene Expression of the Cysteinyl Leukotriene Receptors as a Prognostic and Metastatic Factor for Colorectal Cancer Patients.

Colorectal cancer (CRC), one of the leading causes of cancer-related deaths in the western world, is the third most common cancer for both men and women. As a heterogeneous disease, colon cancer (CC) is caused by both genetic and epigenetic changes. The prognosis for CRC is affected by a variety of features, including late diagnosis, lymph node and distant metastasis. The cysteinyl leukotrienes (CysLT), as leukotriene D4 and C4 (LTD4 and LTC4), are synthesized from arachidonic acid via the 5-lipoxygenase pathway, and play an important role in several types of diseases such as inflammation and cancer. Their effects are mediated via the two main G-protein-coupled receptors, CysLT1R and CysLT2R. Multiple studies from our group observed a significant increase in CysLT1R expression in the poor prognosis group, whereas CysLT2R expression was higher in the good prognosis group of CRC patients. Here, we systematically explored and established the role of the CysLTRs, cysteinyl leukotriene receptor 1(CYSLTR1) and cysteinyl leukotriene receptor 2 (CYSLTR2) gene expression and methylation in the progression and metastasis of CRC using three unique in silico cohorts and one clinical CRC cohort. Primary tumor tissues showed significant CYSLTR1 upregulation compared with matched normal tissues, whereas it was the opposite for the CYSLTR2. Univariate Cox proportional-hazards (CoxPH) analysis yielded a high expression of CYSLTR1 and accurately predicted high-risk patients in terms of overall survival (OS; hazard ratio (HR) = 1.87, p = 0.03) and disease-free survival [DFS] Hazard ratio [HR] = 1.54, p = 0.05). Hypomethylation of the CYSLTR1 gene and hypermethylation of the CYSLTR2 gene were found in CRC patients. The M values of the CpG probes for CYSLTR1 are significantly lower in primary tumor and metastasis samples than in matched normal samples, but those for CYSLTR2 are significantly higher. The differentially upregulated genes between tumor and metastatic samples were uniformly expressed in the high-CYSLTR1 group. Two epithelial-mesenchymal transition (EMT) markers, E-cadherin (CDH1) and vimentin (VIM) were significantly downregulated and upregulated in the high-CYSLTR1 group, respectively, but the result was opposite to that of CYSLTR2 expression in CRC. CDH1 expression was high in patients with less methylated CYSLTR1 but low in those with more methylated CYSLTR2. The EMT-associated observations were also validated in CC SW620 cell-derived colonospheres, which showed decreased E-cadherin expression in the LTD4 stimulated cells, but not in the CysLT1R knockdown SW620 cells. The methylation profiles of the CpG probes for CysLTRs significantly predicted lymph node (area under the curve [AUC] = 0.76, p < 0.0001) and distant (AUC = 0.83, p < 0.0001) metastasis. Intriguingly, the CpG probes cg26848126 (HR = 1.51, p = 0.03) for CYSLTR1, and cg16299590 (HR = 2.14, p = 0.03) for CYSLTR2 significantly predicted poor prognosis in terms of OS, whereas the CpG probe cg16886259 for CYSLTR2 significantly predicts a poor prognosis group in terms of DFS (HR = 2.88, p = 0.03). The CYSLTR1 and CYSLTR2 gene expression and methylation results were successfully validated in a CC patient cohort. In this study, we have demonstrated that CysLTRs' methylation and gene expression profile are associated with the progression, prognosis, and metastasis of CRC, which might be used for the assessment of high-risk CRC patients after validating the result in a larger CRC cohort.

A novel model based on protein post-translational modifications comprising the immune landscape and prediction of colorectal cancer prognosis.

Phosphorylation is a critical post-translational modification (PTM) type contributing to colorectal cancer (CRC). The study aimed to construct a nomogram model to predict colon adenocarcinoma (COAD) prognosis based on PTM signatures. The Cancer Genome Atlas (TCGA) database has been indexed for COAD patients' RNA sequencing, proteomic data, and clinical details. To find potential PTM prognostic signatures, the least absolute shrinkage and selection operator (LASSO) was deployed. Model validation procedures included the use of the Kaplan-Meier (K-M) method, the receiver operating characteristic (ROC) curve, the area under the curve (AUC), and the decision curve analysis (DCA). Additionally, biological enrichment, tumor immune microenvironment, and chemotherapy were also assessed. To validate the model, CRC cells were used in in vitro experiments using western blotting, proliferation assay, colony formation assay, and flow cytometry. The LASSO regression analysis identified 8 PTM sites. Based on the median PTM score, patients were classified into low- and high-risk groups. K-M results showed that high-risk patients had worse prognoses (P<0.001). Our model demonstrated powerful effectiveness and predictive value (TCGA whole group: 1-year AUC =0.611, 2-year AUC =0.574, 3-year AUC =0.627). Additionally, high-risk CRC patients were enriched in KRAS signaling pathways (P=0.01), possessed more robust immune escape capacity (P=0.001, and induced cell-cycle arrest of CRC cells (P<0.01). We established and validated a novel nomogram model related to PTM that can predict prognosis and guide the treatment of COAD.

Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular Features

Brain metastases (BMs) from colorectal cancer (CRC) are associated with significant morbidity and mortality, with chemoresistance and short overall survival. Migrating cancer stem cells with the ability to initiate BM have been described in breast and lung cancers. In this study, we describe the identification and characterization of cancer stem cells in BM from CRC. Four brain metastasis stem cell lines from patients with colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) were obtained by mechanical dissociation of patient's tumors and selection of cancer stem cells by appropriate culture conditions. BM-SC-CRCs were characterized invitro by clonogenic and limiting-dilution assays, as well as immunofluorescence and Western blot analyses. In ovo, a chicken chorioallantoic membrane (CAM) model and invivo, xenograft experiments using BALB/c-nude mice were realized. Finally, a whole exome and RNA sequencing analyses were performed. BM-SC-CRC formed metaspheres and contained tumor-initiating cells with self-renewal properties. They expressed stem cell surface markers (CD44v6, CD44, and EpCAM) in serum-free medium and CRC markers (CK19, CK20 and CDX-2) in fetal bovine serum-enriched medium. The CAM model demonstrated their invasive and migratory capabilities. Moreover, mice intracranial xenotransplantation of BM-SC-CRCs adequately recapitulated the original patient BM phenotype. Finally, transcriptomic and genomic approaches showed a significant enrichment of invasiveness and specific stemness signatures and highlighted KMT2C as a potential candidate gene to potentially identify high-risk CRC patients. This original study represents the first step in CRC BM initiation and progression comprehension, and further investigation could open the way to new therapeutics avenues to improve patient prognosis.

The Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer.

The gut microbiome has long been known to play a role in various aspects of health modulation, including the pathogenesis of colorectal cancer (CRC). With immunotherapy recently emerging as a successful treatment in microsatellite instability high (MSI-high) CRC, and with a newly demonstrated involvement of the gut microbiome in the modulation of therapeutic responses, there has been an explosion of research into the mechanisms of microbial effects on CRC. Harnessing and reprogramming the microbiome may allow for the expansion of these successes to broader categories of CRC, the prevention of CRC in high-risk patients, and the enhancement of standard treatments. In this review, we pull together both well-documented phenomena and recent discoveries that pertain to the microbiome and CRC. We explore the microbial mechanisms associated with CRC pathogenesis and progression, recent advancements in CRC systemic therapy, potential options for diagnosis and prevention, as well as directions for future research.

Long-term outcomes after endoscopic versus surgical resection of T1 colorectal carcinoma.

The long-term outcomes of patients with T1 colorectal cancer (CRC) who undergo endoscopic and/or surgical treatment are not well understood. Invasive CRC confined to the colonic submucosa (T1 CRC) is challenging in terms of clinical decision-making. We compared the long-term outcomes of T1 CRC by treatment method. We examined 370 patients with pathological T1 CRC treated between 2000 and 2015 at Seoul St. Mary's Hospital. In total, 93 patients underwent endoscopic resection (ER) only, 82 underwent additional surgery after ER, and 175 underwent surgical resection only. Patients who did not meet the curative criteria were defined as "high-risk." High-risk patients were classified into three groups according to the treatment modalities: ER only (Group A: 35 patients), additional surgery after ER (Group B: 72 patients), and surgical resection only (Group C: 133 patients). The recurrence-free and overall survival (OS) rates, and factors associated with recurrence and mortality, were analyzed. Factors associated with lymph node metastasis (LNM) were subjected to multivariate analysis. Of the 370 patients, 7 experienced recurrence and 7 died. All recurrences occurred in the high-risk group and two deaths were in the low-risk group. In high-risk groups, there was no significant group difference in recurrence-free survival (P = 0.511) or OS (P =0.657). Poor histology (P =0.042) was associated with recurrence, and vascular invasion (P =0.044) with mortality. LNMs were observed in 30 of 277 patients who underwent surgery either initially or secondarily. Lymphatic invasion was significantly associated with the incidence of LNM (P < 0.001). ER prior to surgery did not affect the prognosis of high-risk T1 CRC patients, and did not worsen the clinical outcomes of patients who required additional surgery. Lymphatic invasion was the most important predictor of LNM.

Cuproptosis patterns and tumor immune infiltration characterization in colorectal cancer.

Faced with the high heterogeneity and poor prognosis of colorectal cancer (CRC), this study sought to find new predictive prognostic strategies to improve the situation. Cuproptosis is a novel cell death mechanism that relies on copper regulation. However, the role of cuproptosis-related gene (CRG) in CRC remains to be elucidated. In this study, we comprehensively assessed the CRG landscape in CRC based on The Cancer Genome Atlas (TCGA). We identified differential expression and genetic alterations of CRG in CRC. CRG is highly correlated with initiation, progression, prognosis, and immune infiltration of CRC. We construct a risk score signature containing 3 CRGs based on LASSO. We explored the correlation of CRG-Score with clinicopathological features of CRC. Age, stage, and CRG-Score were integrated to construct a nomogram. The nomogram has robust predictive performance. We also understand the correlation of CRG-Score with CRC immune landscape. CRG-Score can effectively predict the immune landscape of CRC patients. Low-risk CRC patients have greater immunogenicity and higher immune checkpoint expression. Low-risk CRC patients may be better candidates for immunotherapy. At the same time, we also predicted more sensitive drugs in the high-risk CRC patients. In conclusion, the CRG risk score signature is a strong prognostic marker and may help provide new insights into the treatment of individuals with CRC.

The Impact of Virtual Cancer Care on Chemotherapy Delivery and Clinical Outcomes in Colorectal Cancer Patients Receiving Systemic Therapy: A Pre- and Intra-Pandemic Analysis.

(1) Background: The coronavirus 2019 pandemic has resulted in an abrupt transition to virtual oncology care worldwide. This study’s objective is to evaluate chemotherapy delivery and clinical outcomes in patients on systemic treatment for colorectal cancer before and during the pandemic. (2) Methods: Clinical data was collected on patients with colorectal cancer receiving intravenous chemotherapy at The Ottawa Hospital from June 2019 to March 2021. Patients were stratified by whether they were started on chemotherapy pre-pandemic (June 2019–January 2020) or intra-pandemic (February 2020–March 2021). Multiple regression analysis was used to compare outcomes between pandemic periods; (3) Results: There were 220 patients included in this study. The proportion of virtual consultations (1.2% to 64.4%) and follow-up visits (5.2% to 83.3%) increased during the pandemic. There was no difference in the incidence of treatment delays (OR = 1.01, p = 0.78), chemotherapy dose reductions (OR = 0.99, p = 0.69), emergency department visits (OR = 1.23, p = 0.37) or hospitalizations (OR = 0.73, p = 0.43) between pandemic periods. A subgroup analysis revealed no difference in outcomes independent of the presence of metastases; (4) Conclusion: These findings serve as an important quality-care indicator and demonstrate that virtual oncology care appears safe in a cohort of high-risk colorectal cancer patients.

Comprehensive exploration of tumor immune microenvironment feature and therapeutic response in colorectal cancer based on a novel immune-related long non-coding RNA prognostic signature.

Colorectal cancer (CRC) is one of the most common malignant tumors with a high incidence rate and mortality. LncRNA is an important regulator of the immune system. It is of great significance to study immune-related lncRNAs (IR-lncRNAs) for CRC. In this study, we screened IR-lncRNAs differentially expressed in normal and CRC tissues, and Univariate Cox regression and the Least Absolute Shrinkage and Selection Operator were applied to construct IR-lncRNA prognostic signature in TCGA training dataset, and its predictive capability for the prognosis of CRC patients was verified in GSE39582 validation dataset. The novel signature was identified as an independent predictor of prognosis in CRC patients. In addition, the signature could accurately predict the feature of the immune microenvironment and therapeutic response in CRC patients. The CMap database was adopted to screen for small molecule candidate drugs that can reverse and treat high-risk CRC patients. Finally, the expression of six IR-lncRNAs were verified by qRT-PCR in clinical specimens from our patient cohort. In conclusion, we construct an IR-lncRNA prognostic signature, which is a powerful biomarker of CRC and can accurately predict the prognosis, immune microenvironment feature, and therapeutic response of CRC patients.

Identification of an EMT-related Gene Signature Predicting Recurrence in Stage II/III Colorectal Cancer

To identify a prognostic significant gene signature for predicting colorectal cancer (CRC) recurrence. Traditional prognostic risk assessment in stage II/III CRC patients remains controversial. Epithelial-mesenchymal transition is thought to be closely related to the malignant progression of tumors. Thus, it is promising to establish a prognostic model based on epithelial-mesenchymal transition-related gene (ERG) signature. We retrospectively analyzed transcriptome profiles and clinical information of 1780 stage II/III CRC patients from 15 public datasets. Coefficient variant analysis was used to select reference genes for normalizing gene expression levels. Univariate, LASSO, and multivariate Cox regression analyses were combined to develop the ERG signature predicting disease-free survival (DFS). The patients were divided into high-risk and low-risk based on the ERG signature recurrence risk score. The survival analysis was performed in different CRC cohorts. The proposed ERG signature contained 7 cancer-related ERGs and 3 reference genes. The ERG signature recurrence risk score was prognostically relevant in all cohorts ( P <0.05) and proved as an independent prognostic factor in the training cohort. In the pooled cohort, high-risk CRC patients exhibited worse DFS ( P <0.0001) and overall survival ( P =0.0058) than low-risk patients. The predictive performance of the ERG signature was superior to Oncotype DX colon cancer. An integrated decision tree and nomogram were developed to improve prognosis evaluation. The identified ERG signature is a promising and powerful biomarker predicting recurrence in CRC patients. Moreover, the presented ERG signature might help to stratify patients according to their tumor biology and contribute to personalized treatment.

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2

In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.

Abstract LB164: Combination of naproxen and a novel longer acting eicosapentaenoic acid analogue provide synergistic tumor protection in polyposis in rat colon (PIRC) model

Abstract The purpose of this study was to determine whether or not Naproxen and novel TP-252 combine for synergistic tumor protection in the PIRC model. Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds of polyps that unless removed by prophylactic colectomy, will progress to CRC at an early age. In recent decades, non-steroidal anti-inflammatory drugs (NSAIDs) and ω-3 marine fish oils such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventative potential in delaying the onset of CRC in high-risk patients. In this study, we examined the tumor protective effect of Naproxen alone, or in combination with EPA in the intestinal tumorigenesis Apcam1137 PIRC rat model. Since the free fatty acid form of EPA (FFA-EPA) is readily oxidized, we included a novel longer acting chemically stabilized form of EPA (magnesium L-lysinate bis-eicosapentaenoate), TP-252. Rats were fed a modified AIN-93G diet containing 200 ppm Naproxen, alone or in combination with two dose levels of TP-252 (1.5%, or 3%) or a single concentration of FFA-EPA (2%) by weight for 20 weeks. Rats that received 200 ppm Naproxen alone showed reduced tumor number by 66% (p &amp;lt; 0.0001) and size by 83% (p &amp;lt; 0.0001), respectively, compared to rats fed AIN-93G (control diet). However, when Naproxen was combined with high-dose TP-252 (3%), tumor number and size were reduced by 95% (p &amp;lt; 0.0001) and 98% (p &amp;lt; 0.0001) respectively, when compared to control AIN-93G diet. To elucidate potential mechanisms of tumor protection, a comprehensive lipidomic analysis was performed on colon tissue and plasma to determine potential metabolic changes associated with drug treatment. Naproxen or EPA alone resulted in significantly reduced arachidonic acid (AA)-derived ω-6 eicosanoids (PGE2, LTB4, and 5-HETE), but the combination of Naproxen and EPA yielded the most significant reduction that was also correlated with tumor protection. In addition, groups receiving EPA, either as FFA or TP-252, had a dose-dependent increase in anti-inflammatory EPA-derived ω-3 eicosanoids, as well as a panel of bioactive resolvins. Our lipidomic analysis also uncovered several lipid metabolites, including PGE3, RvE2, and 5-HEPE, that were correlated with tumor protection. Further studies should be focused on dose optimization, and the role of these lipid mediators in CRC initiation and progression. (Supported by the NCI Prevent Program 75N91019D00019, Task Order 75N91019F00132). Citation Format: Ryan Beach, Daniel W. Rosenberg, Altaf Mohammed. Combination of naproxen and a novel longer acting eicosapentaenoic acid analogue provide synergistic tumor protection in polyposis in rat colon (PIRC) model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB164.

The impact of virtual oncology care on chemotherapy continuity and clinical outcomes in patients treated for colorectal cancer: A pre-post analysis of the COVID-19 pandemic.

e13649 Background: The coronavirus (COVID-19) pandemic has resulted in an abrupt transition to virtual oncology care at most cancer centres worldwide. A pillar of the American Medical Association’s proposed framework for digitally enabled care is assessing clinical quality, safety, and outcomes. This study’s objective is to evaluate chemotherapy quality and clinical outcomes in patients receiving intravenous chemotherapy for colorectal cancer before and during the COVID-19 pandemic. Methods: This is an observational study assessing patients treated with intravenous chemotherapy for colorectal cancer consecutively at the Ottawa Hospital Cancer Centre from June 2019 to September 2021. Patients with non-metastatic rectal cancer were excluded. Patient were stratified by whether they were started on chemotherapy pre-pandemic (June 2019 – Jan 2020) versus intra-pandemic (Feb 2020 – Sept 2021). Baseline characteristics and treatment data were collected from the electronic medical records. Outcomes of interest included chemotherapy delays, dose reductions, emergency department (ED) visits and hospitalizations. We used generalized linear and binary logistic regression modelling to compare outcomes between pre- and intra-pandemic periods. Results: There were 220 patients included in this study with 108 (49%) diagnosed with metastatic disease. In total, there were 66 (30%) patients treated in the pre-pandemic and 154 (70%) in the intra-pandemic period. As expected, virtual care consultations increased during the pandemic from 1.5% to 43.5% (p &lt; 0.001). Likewise, the proportion of follow-up visits also increased from 37% to 84% (p &lt; 0.001). There was no difference in the incidence of treatment delays (odds ratio [OR] = 1.01, p = 0.78), dose reductions (OR = 0.99, p = 0.69), ED visits (OR = 1.23, p = 0.37), hospitalizations (OR = 0.73, p = 0.43) or the total length of time off treatment (OR = 0.85, p = 0.17) between the pre- and intra-pandemic periods by multivariable analysis. A subgroup analysis was performed based on stage, which showed no difference in outcomes independent of the presence of metastases. Conclusions: This study demonstrates no significant difference in chemotherapy interruptions, dose intensity, or clinical outcomes in patients treated for colorectal cancer during the COVID-19 pandemic. These findings serve as an important quality-care indictor and demonstrate that virtual oncology care appears safe in a cohort of high-risk colorectal cancer patients. Future work dedicated to other tumor sites would allow for broader application of these findings.

A NOD-Like Receptor Signaling-Based Gene Signature Identified as a Novel Prognostic Biomarker for Predicting Overall Survival of Colorectal Cancer Patients

Background: Colorectal Cancer (CRC) is the most frequently diagnosed gastrointestinal tract malignant tumor worldwide, which is closely associated with distant metastasis and poor prognosis. Due to high degree of heterogeneity, reliable prognostic biomarkers are urgently needed to guide the therapeutic intervention of CRC patients. Objective: The present study aimed to develop a NOD-Like Receptors (NLRs) signaling-based gene signature that can successfully predict the overall survival of CRC patients. Methods: Firstly, differentially expressed NLR signaling-related genes were identified between primary and metastatic human CRC samples. Genes with prognostic value were then screened through univariate Cox regression analysis. Next, the NLR signaling-based prognostic signature was constructed by LASSO-penalized Cox regression analysis, and its predictive ability was further confirmed in an independent cohort. Furthermore, functional studies including GO, GSEA, ssGSEA and chemotherapeutic response analyses were performed to explore the role of the NLR signaling-based signature in CRC pathogenesis and therapy. Results: The established prognostic signature that consisted of 7 NLR signaling-related genes can effectively stratify the high-risk and low-risk CRC patients in both training and validation cohorts. Moreover, the signature proved to be an independent indicator of overall survival in CRC patients. Functional annotation and chemotherapeutic response analyses showed that the signature was closely associated with immune status and chemotherapeutic sensitivity of CRC patients. Conclusion: The novel NLR signaling-based gene signature could serve as a potential tool for survival prediction and therapeutic evaluation, thereby contributing to the personalized prognostic management of CRC patients.

The Effectiveness of the Use of Digital Media in Improving Knowledge on Cadres of Colorectal Malignancy in the Era of Pandemi COVID-19

This study increasing the role of cadres as public health providers in the initial screening of high-risk patients and colorectal cancer patients in the community, especially in the era of the COVID-19 pandemic, and as public health providers who can help increase awareness and knowledge about colorectal cancer, to help reduce the incidence of colorectal cancer and early detection. The research design was cross sectional with pre and post test conducted in October 2020. The sample was divided into 3 groups based on region. All groups received education on colorectal cancer online and were evaluated through pre / post-tests both directly and via google form. The sampling technique used was accidental sampling by distributing questionnaires to respondents in order to obtain secondary data. Repetition of the test on education that has been given previously within 2 months without the provision of active material from the counselor, to evaluate the retention of the educational understanding that has been given is attached or not. The results obtained, have a very good response by evaluating that there is a pre- / post-test, although they still have not achieved the expected results, namely more than 70% success, but achieved success as much as 100% from the attendance of invited participants which indicates that memory retention is still good. The counseling that was carried out received positive responses from cadres and many enthusiasts in the counseling that was carried out.There was an increase in participants' knowledge of colorectal cancer after counseling by the authors. All participants showed improved knowledge outcomes as measured by the posttest score indicator and showed good memory retention

Effect of Adjuvant Chemotherapy on Elderly Stage II High-Risk Colorectal Cancer Patients.

PurposeAdjuvant chemotherapy (AC) is recommended for patients with stage II colorectal cancer with adverse features. However, the effect of adjuvant treatment in elderly patients with high-risk stage II colorectal cancer remains controversial. This study aimed to investigate the oncologic outcomes in elderly high-risk stage II colorectal cancer patients who underwent curative resection with or without AC.MethodsPatients aged over 70 years having stage II colorectal adenocarcinoma with at least 1 adverse feature who underwent radical surgery between 2008 and 2017 at a single center were included. We compared recurrence-free survival (RFS) and overall survival (OS) between patients who received more than 80% of the planned AC cycle (the AC+ group) and those who did not receive it (the AC− group).ResultsThe AC+ and AC– group contained 46 patients and 50 patients, respectively. The log-rank test revealed no significant intergroup differences in RFS (P=0.083) and OS (P=0.122). In the subgroup of 27 patients with more than 2 adverse features, the AC+ group (n=16) showed better RFS (P=0.006) and OS (P=0.025) than the AC− group. In this subgroup, AC was the only significant factor affecting RFS in the multivariate analysis (P=0.023). AC was significantly associated with OS (P=0.033) in the univariate analysis, but not in the multivariate analysis (P=0.332).ConclusionAmong elderly patients with stage II high-risk colorectal cancer, the AC+ group did not show better RFS or OS than the AC− group. However, selected patients with more than 2 adverse features might benefit from AC.