Colon Cancer Recurrence Research Articles

Abstract 5604: Circulating tumor DNA for predicting peritoneal only disease recurrence in colon cancer

Abstract Background: Peritoneal Carcinomatosis in Colon Cancer (PCCC) is a major cause of morbidity. Early detection of PCCC is important for early intervention like systemic chemotherapy and cytoreductive surgery (CRS) +/- hyperthermic intraperitoneal chemotherapy (HIPEC). Circulating tumor DNA (ctDNA) testing is a promising method to assess recurrence not detectable yet on imaging, identifying 87.5% of recurrences in Stage I-III CRC with a mean lead-time of 8.7 months. It is unclear if ctDNA testing is sensitive in detection of recurrent PCCC ahead of clinical/radiological presentation. We report data from 6 CRC patients with PCCC who underwent complete CRS and were followed with serial ctDNA testing. Methods: In this single institution study, patients with PCCC were included from our prospectively enrolled GI cancer patient cohort (GIMER: IRB #201202743). Peritoneal carcinomatosis at CRS was determined using the Peritoneal Cancer Index. ctDNA concentration in mean tumor molecules/mL of plasma was assessed using a commercially available tumor-informed, personalized ctDNA assay (Signatera™, Natera, Inc.) that uses patient-specific somatic single-nucleotide variants. Plasma samples for ctDNA analysis were collected before surgery, 1, 2, 4, 6 months post-surgery, then every 3 months until a positive ctDNA test triggered CT imaging. Patients also had routine CT imaging every 6 months after surgery. Results: 5 of 6 patients met endpoint with median time of 35 days from positive ctDNA to recurrence on imaging. In 4 patients, positive ctDNA prompted CT imaging which was negative, but follow-up PET scan was positive. Patient 6 was ctDNA negative and recurrence-free at last follow-up. Conclusions: This analysis demonstrated the potential of longitudinal ctDNA monitoring for early detection of PCCC recurrence by prompting early imaging. PET was more sensitive in detecting recurrence than CT, and should be considered when determining PCCC recurrence. Enrollment and further analysis of ctDNA continues. Table 1. Patient Pre-op Chemo Post-chemo, pre-op ctDNA Peritoneal Cancer Index Post-op (1m) ctDNA 2m ctDNA 4m ctDNA 6m ctDNA 9m ctDNA 12m ctDNA 15m ctDNA Recurrence Days between ctDNA positivity and positive imaging Imaging Findings 1 Yes 0 5 0 0 0 0 0.48 - - Yes 6 CT CAP Positive 2 Yes 0 4 0 0 0 0.04 - - - Yes 54 CT CAP Negative; PET Positive 3 Yes 0.28 18 0 0 0 0 0.09 - - Yes 25 CT CAP Negative; PET Positive 4 Yes 0 0 0 0 0 0 0 0 0.18 Yes 35 CT CAP Negative; PET Positive 5 Yes 0.61 5 0 0 0.17 0 0.32 0.12 - Yes 274 CT CAP Negative; PET Positive 6 Yes 0 5 0 - 0 0 - - - No NA CT CAP Negative to date Citation Format: Kevin C. Chang, Daniel Berg, Chandrika Chandrasekharan, Kelsey Steckly, Saima Sharif, Carlos H. Chan. Circulating tumor DNA for predicting peritoneal only disease recurrence in colon cancer. [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 5604.

Our Experiences of Tertiary Referral Centers in the Management of Recurrent Colonic Cancer after an Initial Curative Right-sided Colonic Resection

Abstract Background: Colon cancer is one of the most common types of cancer. Oncological surgical resection is the most effective method to achieve a successful outcome, but the prognosis of recurrence is poor. Objectives: The objective of our study was to provide an insight into our management of patients who have experienced recurrences by first assessing the 5-year survival rate of patients who underwent curative surgery for right-sided colon cancer and then reporting on the rate and management of recurrences. Study Design: We conducted a retrospective study using a prospective database of patients with recurrent colon cancer following an initial curative right-sided resection. Setting: In the study, patients diagnosed and treated at King’s College Hospital for colorectal cancer between 2011 and 2015 were included. Patients and Methods: The study included patients with right-sided colonic adenocarcinoma (including the cecum, ascending colon, hepatic flexure, and proximal two-thirds of the transverse colon) who had undergone curative surgical resection and had completed follow-up. Main Outcome Measures: Our main outcome measures were survival after curative resection of right-sided colon cancers, recurrence, and survival after recurrence. Sample Size: Our study included 195 patients. Results: In this study, 195 patients with stages I–III right-sided colonic tumors were treated with primary curative surgical resection (R0), of which 173 (86.7%) were treated electively and 22 (11.3%) were treated as an emergency. A total of 104 men (53.3%) and 91 women (46.7%) participated in our study, and the mean age at diagnosis was 69.2 (12.8) years. After a 5-year follow-up period, 145 patients (74.4%) successfully completed the follow-up with no loss of patients. We noted that 88.7% of the patients had no recurrence, but 22 (11.3%) of 195 patients experienced recurrences and 28 (14.4%) died. Following further analysis of the patients with recurrences, we found that 13 (6.6%) had distant metastases, seven (3.5%) had local recurrences, and two (1.2%) had multiple recurrences. The mean time to recurrence was 15.1 (10.8) months. Recurrence was associated with a mean survival rate of 39.64 (19.2) months compared to 53.9 ± 15.1 for patients without recurrence (Log Rank P = 0.000). Among patients with recurrences, the 5-year survival rate was 31.8%; however, it was 80.9% (Log Rank P = 0.000) for those without recurrences. Patients with recurrent cancer who received curative treatment had a 5-year survival rate of 40.0% compared to 14.3% for those who received palliative treatments (Log Rank P = 0.068). Conclusion: In our study, right-sided colorectal cancer after oncological surgical resection was associated with a recurrence rate of 11.3%. The survival rate was inversely proportional to the stage of the disease at the time of diagnosis. Detection of recurrence and surgical intervention in a timely manner are associated with improved survival rates. Limitations: This study has limitations, including its retrospective nature. We collected data for this study from electronic records and databases of patients after completion of follow-up. Conflict of Interest: The authors have no conflict of interest to declare.

Identification of immunotherapy and chemotherapy-related molecular subtypes in colon cancer by integrated multi-omics data analysis.

Colon cancer is a highly heterogeneous disease, and identifying molecular subtypes can provide insights into deregulated pathways within tumor subsets, which may lead to personalized treatment options. However, most prognostic models are based on single-pathway genes. In this study, we aimed to identify three clinically relevant subtypes of colon cancer based on multiple signaling pathways-related genes. Integrative multi-omics analysis was used to explain the biological processes contributing to colon cancer aggressiveness, recurrence, and progression. Machine learning methods were employed to identify the subtypes and provide medication guidance for distinct subtypes using the L1000 platform. We developed a robust prognostic model (MKPC score) based on gene pairs and validated it in one internal test set and three external test sets. Risk-related genes were extracted and verified by qPCR. Three clinically relevant subtypes of colon cancer were identified based on multiple signaling pathways-related genes, which had significantly different survival state (Log-Rank test, p<0.05). Integrative multi-omics analysis revealed biological processes contributing to colon cancer aggressiveness, recurrence, and progression. The developed MKPC score, based on gene pairs, was robust in predicting prognosis state (Log-Rank test, p<0.05), and risk-related genes were successfully verified by qPCR (t test, p<0.05). An easy-to-use web tool was created for risk scoring and therapy stratification in colon cancer patients, and the practical nomogram can be extended to other cancer types. In conclusion, our study identified three clinically relevant subtypes of colon cancer and developed a robust prognostic model based on gene pairs. The developed web tool is a valuable resource for researchers and clinicians in risk scoring and therapy stratification in colon cancer patients, and the practical nomogram can be extended to other cancer types.

A Case of Simultaneous Resection of Recurrent Colorectal Liver Metastases as part of Colorectal Cancer Treatment Journey

Combining systemic treatments with liver resection in patients with colorectal liver metastases has been proven to be successful in delivering favorable survival outcomes. We describe a 68-year-old man who underwent six cycles of chemotherapy before developing recurrent colon cancer with liver metastases. Prior to this, he underwent a Hartmann’s procedure for obstructive malignant rectal cancer. Shortly after the initial procedure, he underwent a Hartmann’s reversal. Imaging revealed locoregional recurrence with increased CEA as well as metastatic lesions in segments 4b and 8 of the liver at the time of recurrence. After a complete multidisciplinary evaluation, the simultaneous resection of the liver metastasis and the bowel recurrence was carried out without incident, and adjuvant therapy was then administered. This case report detailed the patient’s experience with many chemotherapy treatments and an early recurrence of CRLM, followed with surgical resection of recurrent primary and liver metastatasis. As part of multidisciplinary therapy, we propose that simultaneous excision of the recurring bowel location and the liver metastases offers the potential for superior care.

Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer

The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited. To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer. This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022. Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization. The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression. Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival. This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes. ClinicalTrials.gov Identifier: NCT01150045.

Working Toward a Vaccine to Help Patients Avoid Colon Cancer Recurrence

Working Toward a Vaccine to Help Patients Avoid Colon Cancer Recurrence

Integrative Clinical and DNA Methylation Analyses in a Population-Based Cohort Identifies CDH17 and LRP2 as Risk Recurrence Factors in Stage II Colon Cancer.

Stage II colon cancer (CC), although diagnosed early, accounts for 16% of CC deaths. Predictors of recurrence risk could mitigate this but are currently lacking. By using a DNA methylation-based clinical screening in real-world (n = 383) and in TCGA-derived cohorts of stage II CC (n = 134), we have devised a novel 40 CpG site-based classifier that can segregate stage II CC into four previously undescribed disease sub-classes that are characterised by distinct molecular features, including activation of MYC/E2F-dependant proliferation signatures. By multivariate analyses, hypermethylation of 2 CpG sites at genes CDH17 and LRP2, respectively, was found to independently confer either significantly increased (CDH17; p-value, 0.0203) or reduced (LRP2; p-value, 0.0047) risk of CC recurrence. Functional enrichment and immune cell infiltration analyses, on RNAseq data from the TCGA cohort, revealed cases with hypermethylation at CDH17 to be enriched for KRAS, epithelial-mesenchymal transition and inflammatory functions (via IL2/STAT5), associated with infiltration by 'exhausted' T cells. By contrast, LRP2 hypermethylated cases showed enrichment for mTORC1, DNA repair pathways and activated B cell signatures. These findings will be of value for improving personalised care paths and treatment in stage II CC patients.

Prognostic Factors of Disease Recurrence and Overall Survival Following Curative Resection of Colon Cancer: A 10-year Cohort from a Referral Center.

Background: The growing incidence of colorectal cancer around the world highlights the significance of tumor recurrence and patient survival as 2 key elements of patient therapy. We aimed to study the factors linked with disease recurrence and survival in colon cancer. Methods: Patients with colon cancer who underwent tumor excision as their primary treatment were enrolled in this prospective cohort and monitored for 10 years. Various demographic and clinicopathologic factors of these patients were studied in association with the 2 primary outcomes of this study, including tumor recurrence and patient survival. Statistical tests and survival analysis were utilized to explore the study aims. Results: An overall number of 113 patients were included in this survey with a mean age of 54.7 (±SD, 14.1), and most of the patients were men (56.6%). The mean follow-up period was 28.3 (±25.5) months. Tumor recurrence occurred in 32 (28.3%) patients in the study period. The estimated mean survival of patients was 54.9 (95% CI, 45.3-64.4) months. N staging ( p = 0.036), T staging ( p = 0.009), and pathologic staging (P = .004) were the significant pathological factors to higher tumor recurrence and lower survival rates. Conclusion: Advanced tumor staging led to increased disease recurrence and lower survival of colon cancer patients in this survey. Further public health screening and education programs are needed to improve the early detection and prognosis of these patients in Iran.

ASO Visual Abstract: Locoregionally Recurrent Colon Cancer: How Far Have We Come? A Population-Based, Retrospective Cohort Study.

ASO Visual Abstract: Locoregionally Recurrent Colon Cancer: How Far Have We Come? A Population-Based, Retrospective Cohort Study.

Low Expression of SNAI1 in Lymph Node Metastasis Indicates Delayed Recurrence of Colonic Cancer.

Even though epithelial-mesenchymal transition markers in primary tumors are identified as a helpful indicator of cancer metastasis and prognosis, their expression in lymph node metastases (LNMs) remains poorly described. We aimed to investigate the difference between snail family transcriptional repressor 1 (SNAI1) and E-cadherin expression in primary tumors and LNMs, and how it affects prognosis. From 2010 to 2014, 127 patients who underwent radical surgery for stage III colonic adenocarcinoma without preoperative treatment were retrospectively reviewed for SNAI1 and E-cadherin expression in primary tumors and LNMs. High SNAI1 expression was found in 76% and 70% of primary tumors and LNMs, respectively, and low E-cadherin expression was found in 73% and 84%, respectively. High expression of SNAI1 in LNMs significantly correlated with poor overall and relapse-free survival rates. Even though the rate of liver metastasis at 5 years was similar for the groups with high and low SNAI1 expression in LNMs, the incidence in the group with low SNAI1 expression in the second year was higher than that in the first year (33% vs. 17%), whilst in the group with high SNAI1 expression, the incidence in the first year was higher than in the second year (71% vs. 29%). The rate of recurrence of lung metastasis was significantly lower when SNAI1 expression in LNMs was low (p=0.031). Low expression of SNAI1 in LNMs of colonic adenocarcinoma may indicate delayed recurrence in the liver and lung.

ASO Author Reflections: Assessing the Diagnostic Accuracy of Circulating Tumor DNA, Imaging, and Carcinoembryonic Antigen to Detect Recurrent Colon Cancer.

ASO Author Reflections: Assessing the Diagnostic Accuracy of Circulating Tumor DNA, Imaging, and Carcinoembryonic Antigen to Detect Recurrent Colon Cancer.

Locoregionally Recurrent Colon Cancer: How Far Have We Come? A Population-Based, Retrospective Cohort Study

BackgroundThe reported outcomes of locoregionally recurrent colon cancer (LRCC) are poor, but the literature about LRCC is scarce and aged. Recent population-based studies to provide current insight into LRCC are warranted. This study aimed to provide an overview of the incidence, risk factors, treatment, and overall survival (OS) of patients with LRCC after curative resection of stage I–III primary colon cancer.MethodsData on disease recurrence were collected for all patients with a diagnosis of non-metastasized primary colon cancer in the Netherlands during the first 6 months of 2015. Patients who underwent surgical resection (N = 3544) were included in this study. The 3-year cumulative incidence, risk factors, treatment, and OS for patients with LRCC were determined.ResultsThe 3-year cumulative incidence of LRCC was 3.8%. Synchronous distant metastases (LRCC-M1) were diagnosed in 62.7% of the patients. The risk factors for LRCC were age of 70 years or older, pT4, pN1-2, and R1-2. Adjuvant chemotherapy was associated with a decreased risk of LRCC for high-risk stage II and stage III patients [hazard ratio (HR), 0.47; 95% confidence interval (CI) 0.31–0.93]. The median OS for the patients with LRCC was 13.1 months (95% CI 9.1–18.3 months). Curative-intent treatment was given to 22.4% of the LRCC patients, and the subsequent 3 years OS was 71% (95% CI 58–87%). The patients treated with palliative treatment and best supportive care showed 3-year OS rates of 15% (95% CI 7.0–31%) and 3.7% (95% CI 1.0–14%), respectively.ConclusionsThe cumulative incidence of LRCC was low, and adjuvant chemotherapy was associated with a decreased risk for LRCC among targeted patients. Curative-intent treatment was given to nearly 1 in 4 LRCC patients, and the OS for this group was high.

Mesenteric Recurrence of Colon Cancer: Evidence for the Use of Oncologic Complete Mesocolic Excision

INTRODUCTION: The principles surrounding complete mesocolic excision (CME) of colon cancer are 1) careful dissection between the mesenteric plane and parietal fascia, 2) removal of the complete mesentery with encasement of the mesenteric fascia and visceral peritoneum and 3) high/central vascular ligation. All mesenteric lymph nodes draining the tumor centrally should be excised. CME has been associated with a decreased rate of colon cancer recurrence but is somewhat controversial. We present a consecutive series of patients referred to our institution with recurrent colon cancer and evidence of a previous, non-CME colon cancer resection. METHODS: Patients were prospectively identified from Tumor Board discussions between 11/2018 and 02/2022. All had mesenteric/nodal recurrence and evidence of residual mesentery and/or vascular supply of after previous operation. RESULTS: Eleven patients (8/73% male, mean age 64.8 ± 16.9 years) were included. The primary tumor was located in the ascending colon (n=5), sigmoid/descending colon (n=4), transverse colon (n=1) and caecum (n=1). Nine recurrences (82%) were in the mesentery only and 2 were in the colon/anastomosis and mesentery. Time from primary operation to identification of mesenteric cancer recurrence was 2 months-4.9 years. Eight (73%) underwent chemotherapy after primary resection (7 with 5 FU based). Seven (64%) patients underwent a subsequent resection based on CME principles. CONCLUSION: We describe a cohort of patients with a mesenteric colon cancer recurrence after a radiologically confirmed, non-CME resection. The majority had chemotherapy after their index resection. A total of 37% were not amenable to a subsequent salvage CME-based resection.

340P Prediction of relapse in colon cancer patients by machine learning models combining radiomics and deep features extracted from baseline computed tomography

Up to 40% of localized colon cancer (CC) patients relapse despite optimal initial treatment. Circulating tumor DNA has emerged as a new prognostic biomarker in this setting. However, liquid biopsy tests provide a limited accuracy in the early prediction of relapse. On this basis, radiomics and artificial intelligence (AI) are posed to provide relevant insights in the prediction of relapse and patient outcome. Here we propose a predictive model of CC recurrence using clinical data in combination with radiomics and deep features extracted from baseline computed tomography (CT) images. A single-center retrospective observational study was designed. Real-world clinical data and CT examinations were collected from 2015 to 2017. Manual segmentation of the tumor was performed slice by slice by a radiologist with 10+ years of experience in CC using ITK-SNAP. Feature extraction techniques were applied to the tumor voxels through an analysis pipeline in Python adapted from Quibim Precision® software (Quibim, Valencia, ES). Feature reduction techniques were applied to select the characteristics providing independent information. The types of features extracted were: Radiomics, Deep features and fractal dimension. Several classifiers were trained with the clinical and image features as the input, to predict relapse from CC. Relapse and non-relapse classes were balanced to the number of slices containing tumor. Train-validation data ratio was 70:30. Baseline CT exams from 60 localized CC patients were included. 48% and 20% of them had stage III and high-risk stage II, respectively. The remaining patients were diagnosed with low-risk CC. 36.7% of patients relapsed. Merging the clinical data with the radiomics, fractal and deep features provided a high and increased accuracy 95% (CI 95%: 85 – 100) when compared to clinical variables alone (55%, CI 95%: 32 – 78). Random Forest and cross validation model provided the best performance. The extraction of radiomics and deep features from CT exams in CC patients and their combination in an AI model provide promising insights towards the early prediction of relapse, leading to identify new and accurate prognostic imaging panels.

Serial Circulating Tumor DNA in Monitoring the Effect of Neoadjuvant and Adjuvant Immunotherapy in Patients With Colon Cancer: Case Series and Review of the Literature.

Although programmed death 1 blockade has significantly improved the survival of advanced colorectal cancer patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), clinical data in neoadjuvant and adjuvant setting are limited. The role of circulating tumor DNA (ctDNA) in precision oncology is promising, but its clinical significance in immunotherapy needs to be validated. We report a case series of 3 colon patients who received neoadjuvant and adjuvant immunotherapy and serial ctDNA analysis. This report summarizes clinical and molecular details for 3 patients with locally advanced or recurrent dMMR/MSI-H/polymerase epsilon ( POLE ) mutation-positive tumors treated with neoadjuvant/adjuvant immunotherapy. One stage IV recurrent colon cancer patient diagnosed with Lynch syndrome received adjuvant sintilimab monotherapy and had a progression-free survival (PFS) over 16 months, one stage Ⅲc colon cancer patient with MSI-H/high tumor mutation burden received neoadjuvant toripalimab monotherapy, was assessed as clinical complete response before surgery, continued with adjuvant sintilimab monotherapy and had a PFS over 17 months, one stage Ⅱ colon cancer patient with POLE P286R also received adjuvant sintilimab monotherapy and had a PFS over 17 months. All patients had detectable ctDNA after radical surgery and clearance of ctDNA during adjuvant immunotherapy. All 3 patients are free of tumor disease at the time of this report. Further studies are warranted to evaluate the long-term efficacy of neoadjuvant and adjuvant programmed death 1 blockade in locally advanced and metastasis in dMMR/MSI-H/ POLE mutated colorectal cancer and the role of ctDNA monitoring.

Inhibition of Colon Cancer Recurrence via Exogenous TRAIL Delivery Using Gel-like Coacervate Microdroplets.

Colon cancer (CC) belongs to the three major malignancies with a high recurrence rate. Therefore, a novel drug delivery system that can prevent CC recurrence while minimizing side effects is needed. Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) has recently been spotlighted as a protein drug that can induce apoptosis of cancer cells specifically. However, its short in vivo half-life is still a challenge to overcome. Hence, in this study, a gel-like mPEGylated coacervate (mPEG-Coa) delivery platform was developed through electrostatic interaction of mPEG-poly(ethylene arginylaspartate diglyceride) (mPEG-PEAD) and heparin for effective protection of cargo TRAIL, subsequently preserving its bioactivity. mPEG-Coa could protect cargo TRAIL against protease. Sustained release was observed for a long-term (14 days). In addition, recurrence of HCT-116 cells was suppressed when cells were treated with TRAIL-loaded mPEG-Coa for 7 days through long-term continuous supply of active TRAIL, whereas re-proliferation occurred in the bolus TRAIL-treated group. Taken together, these results suggest that our gel-like mPEG-Coa could be utilized as a functional delivery platform to suppress CC recurrence by exogenously supplying TRAIL for a long time with a single administration.

Early-stage colon cancer with high MALAT1 expression is associated with the 5-Fluorouracil resistance and future metastasis.

This study aimed to investigate the role of long noncoding RNA (LncRNA) expression profiles to predict relapse and 5-FU response in patients with stage I/II colon cancer (CC). The expression level of 15 LncRNA was analyzed in stage I/II colon tumors of 126 CC patients. To confirm the findings in-vitro, 5FU-resistant HT29 cells were generated by subjecting HT-29 cells to the increasing concentrations of 5FU for 6months. The 5FU resistance was observed in WST-1 and Annexin V analyses. The colony formation and wound healing assays were assessed to determine the metastatic properties of the cells. Expression levels of LncRNAs and mRNA of EMT-related genes were determined by RT-PCR. The role of LncRNA on metastasis and 5FU sensitivity were confirmed in pcDNA3.0-PTENP1 and si-MALAT1 expressed 5FU-resistant HT29 cell lineages. High MALAT1 (p = 0.0002) and low PTENP1 (p = 0.0044) expressions were significantly associated with 5-FU resistance and tumor relapse in stage I/II CC. The invasiveness and colony-forming characteristics of 5-FU-resistant cell lineages were higher as compared to the parent HT-29. Moreover, the expression of MALAT1 (p = 0.0009) was increased while the expression of PTENP1 (p = 0.0158) decreased in 5FU-resistant-HT-29 cells. Si-MALAT1 treatment increased cell sensitivity to 5FU, whereas it decreased invasive behaviors of 5 FU-resistant-HT-29 cells. MALAT1 may be a biomarker in predicting recurrence in early-stage CC. Our findings suggest that a cell-based therapy to target MALAT1 could be established for these patients to prevent metastasis and 5-FU resistance.

Metabolic pathway-based molecular subtyping of colon cancer reveals clinical immunotherapy potential and prognosis.

Colon cancer presents challenges to clinical diagnosis and management due to its high heterogeneity. For more efficient and convenient diagnosis and treatment of colon cancer, we are committed to characterizing the molecular features of colon cancer by pioneering a classification system based on metabolic pathways. Based on the 113 metabolic pathways and genes collected in the previous stage, we scored and filtered the metabolic pathways of each sample in the training set by ssGSEA, and obtained 16 metabolic pathways related to colon cancer recurrence. In consistent clustering of training set samples with recurrence-related metabolic pathway scores, we identified two robust molecular subtypes of colon cancer (MC1 and MC2). Furthermore, we performed multi-angle analysis on the survival differences of subtypes, metabolic characteristics, clinical characteristics, functional enrichment, immune infiltration, differences with other subtypes, stemness indices, TIDE prediction, and drug sensitivity, and finally constructed colon cancer prognostic model. The results showed that the MC1 subtype had a poor prognosis based on higher immune activity and immune checkpoint gene expression. The MC2 subtype is associated with high metabolic activity and low expression of immune checkpoint genes and a better prognosis. The MC2 subtype was more responsive to PD-L1 immunotherapy than the MC1 subclass. However, we did not observe significant differences in tumor mutational burden between the two. Two molecular subtypes of colon cancer based on metabolic pathways have distinct immune signatures. Constructing prognostic models based on subtype differential genes provides valuable reference for personalized therapy targeting unique tumor metabolic signatures.

Cost-effectiveness of adjuvant chemotherapy for patients with high-risk stage II and stage III colon cancer in South Africa.

6599 Background: Colon cancer (CC) incidence is rising globally, and case fatality rates are greatest in low-income settings, such as South Africa (SA). Adjuvant chemotherapy is standard of care for high-risk stage II and stage III CC in the US. We evaluated the cost-effectiveness of adjuvant chemotherapy for CC in SA public hospitals. Methods: We developed a decision-analytic Markov model comparing lifetime costs and outcomes for 60-year-old high-risk stage II and stage III CC patients treated in a SA public hospital with no adjuvant chemotherapy, versus: capecitabine and oxaliplatin (CAPOX) for 3 or 6 months or capecitabine for 6 months. High-risk stage II was defined as ≥1 of: T4 disease; poorly differentiated tumor; lymphovascular/perineural invasion; &lt;12 lymph nodes dissected, bowel obstruction/perforation. Transition probabilities were derived from clinical trials estimating toxicity, disease recurrence, and survival. Costs from a SA societal perspective and utility estimates were obtained from literature and local expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) in international dollars (I$) per disability-adjusted life year (DALY) averted, with a willingness-to-pay (WTP) threshold equal to 2021 GDP/capita of SA (I$13,764). Results: CAPOX for 3 months was the cost-effective strategy for stage III CC at a lifetime cost of I$5,284 and 5.55 DALYs averted, compared to no adjuvant treatment. All other strategies were absolutely dominated. For high-risk stage II CC, CAPOX for 3 months was the cost-effective strategy (ICER = I$711/DALY averted). No adjuvant chemotherapy was on the efficiency frontier, with a lower lifetime cost, but no DALYs averted. The results of one-way deterministic sensitivity analyses showed that the model is most sensitive to CC recurrence rate. In a probabilistic sensitivity analysis, CAPOX for 3 months was optimal in 88% of iterations for high-risk stage II CC and 79% of iterations for stage III CC. Conclusions: CAPOX for 3 months is the cost-effective adjuvant treatment for high-risk stage II and stage III CC in SA public hospitals. This strategy offers the highest quality of life benefit for the lowest cost and is well within the WTP threshold for SA. The optimal strategy in other settings will vary according to local WTP thresholds. Base case estimates of cost-effectiveness, in order of cost. [Table: see text]

P-280 Can immune checkpoint inhibitors plus surgery cure advanced mismatch repair-deficient cancer?

There is a strong body of evidence supporting use of immune checkpoint inhibitors (ICI) in unresectable mismatch repair-deficient (MMRd) / microsatellite unstable (MSI) high colorectal cancer (mCRC); anti-PD-1 therapy is the standard of care for first-line treatment of mCRC (Andre, NEJM 2021). Emerging evidence also demonstrates high rates of complete pathological response (pCR) following neoadjuvant ICI in patients with stage I-III MSI colon cancer (Chalabi, Nature 2020) and in MSI gastric cancer (Andre, ASCO GI 2022). This leads to the question of whether ICI with or without surgery could lead to cures in advanced MSI cancers. Herein we describe our single institutional experience of immunotherapy followed by surgery in MSI intestinal cancers. In this retrospective series the institutional electronic health record was reviewed for patients with ICI treated MSI intestinal cancers with subsequent surgical resection. Demographics and clinicopathological characteristics were collected, with ICI therapy details and toxicity, radiological response and operative details. Post-operative histology was reviewed. Overall survival was calculated using the Kaplan-Meier method. Five patients were identified; 5 (100%) female. Mean/median age was 37/46 years (range 22-78). Four (80%) had MLH1/PMS2 deficient cancers, 1 was MSH2/MSH6 deficient. One had germline MLH1 mutation, one germline pending. Two (40%) had concurrent tumour BRAF V600E mutation, two (40%) had KRAS G12D mutation. Four (80%) had colon cancer (1 ascending colon, 1 synchronous ascending colon and hepatic flexure, 1 transverse colon, 1 rectosigmoid); 1 patient jejunal adenocarcinoma. Three colon cancer patients had lymph node metastases distant from the primary, one had local pelvic side wall recurrence, one had direct invasion of liver and pancreas. All patients received ICI with initial palliative intent (1 ascending colon 2nd line nivolumab, 1 synchronous tumours 1st line nivolumab/ipilimumab, 1 rectosigmoid 2nd line nivolumab/ipilimumab, 1 transverse 1st line pembrolizumab, jejunal 1st line nivolumab). Two patients had admissions with ICI related fevers, 1 experienced ICI G3 pneumonitis and 1 experienced G3 hepatitis. All patients had radiological response to ICI. Two patients (transverse colon / jejunal cancer) experienced stricture in responding primary tumour and required surgery. One ascending colon cancer had surgery a symptomatic PET-avid mass, 1 synchronous cancer patient had right total mesocolic excision, partial hepatectomy and Whipples. One recurrent rectosigmoid colon cancer had total pelvic exenteration following ICI and radiotherapy. All patients had R0 resection. Two patients had pCR (ypT0N0) (ascending colon, rectosigmoid colon); both complete responders had experienced ICI related toxicity. Other patients’ stage were transverse colon (ypT3N0), jejunal cancer (ypT0N1) and synchronous tumours (ypT4N0 and ypT2N0). After median follow up of 15 months, no patient has recurrent disease. Median overall survival is not reached. In this series we demonstrate that a combination of ICI and surgery can render patients with advanced MSI cancers disease free by downstaging previously unresectable cancers and eliminating distant metastases. As complete responses were demonstrated in two patients with suspicious pre-operative radiological findings on resection, improved imaging techniques or ctDNA may be helpful in guiding which patients require surgery in future.