Non-metastatic Colorectal Cancer Research Articles

The Usefulness of Vitamin K-Dependent Proteins in the Diagnosis of Colorectal Carcinoma

Colorectal cancer (CRC) is one of the most common neoplasms in developed countries, with increasing incidence and mortality, even in young people. A variety of serum markers have been associated with CRC (CEA, CA 19-9), but neither should be used as a screening tool for the diagnosis or evolution staging of CRC. The sensitivity and specificity of these markers are not as good as is required, so new ones need to be found. Matrix Gla protein and PIVKA II are involved in carcinogenesis, but few studies have evaluated their usefulness in predicting the presence and severity of CRC. Materials and Methods: Two hundred patients were divided into three groups: 80 patients were included in the control group; 80 with CRC and without hepatic metastasis were included in Group 1; 40 patients with CRC and hepatic metastasis were included in Group 2. Vitamin K-dependent proteins (VKDPs) levels in plasma were determined. Results: Patients with CRC without methastasis (Group 1) and CRC patients with methastasis (Group 2) presented significantly higher values of CEA, CA 19-9, PIVKA II (310.05 ± 38.22 vs. 430.13 ± 122.13 vs. 20.23 ± 10.90), and ucMGP (14,300.00 ± 2387.02 vs. 13,410.52 ± 2243.16 vs. 1780.31 ± 864.70) compared to control group (Group 0). Interestingly, Group 1 presented the greatest PIVKA II values. Out of all the markers, significant differences between the histological subgroups were found only for ucMGP , but only in non-metastatic CRC. Studying the discrimination capacity between the patients with CRC vs. those without, no significant differences were found between the classical tumor markers and the VKDP AUROC curves (PIVKA II and ucMGP AUROCs = 1). For the metastatic stage, the sensitivity and specificity of the VKDPs were lower in comparison with those of CA 19-9 and CEA, respectively (PIVKA II AUROC = 0.789, ucMGP AUROC = 0.608). Conclusion: The serum levels of these VKDPs are significantly altered in patients with colorectal carcinoma; it is possible to find additional value of these in the early stages of the disease.

Abstract PO4-10-02: Implementing Just ASK™ to achieve diverse participation and representation in a RCT of chemotherapy-induced peripheral neuropathy

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting complication of cancer treatment which disproportionally affects Black patients, and can negatively impact survival and quality of life. Strategies to improve diverse participation and representation in clinical trials are necessary to reduce this health disparity. Methods: To ensure diverse representation in our RCT of CBD vs placebo in patients with grade 2-3 CIPN after treatment with taxane or platinum-based chemotherapy, key evidence-based strategies outlined in the ASCO-ACCC Just ASK™ Training Program were implemented. Eligibility criteria were as inclusive as possible, including CIPN duration up to 2 years and a range of diagnoses: nonmetastatic breast, colorectal, endometrial; and ovarian cancer. Few comorbidities were excluded. The diverse research team engaged every potentially eligible patient with the opportunity to make an informed decision to participate in the study. Using an assets-based approach, the team assessed and addressed social drivers of health (SDoH) and built trust by providing transparency, timely access to all team members, flexible study visits (including telemedicine), and study materials which were comprehensive, understandable, and accessible, within a culture of respect for patient autonomy and privacy. Results: Between 6/1/2020 and 8/8/2022, 230 patients were prescreened, 124 met eligibility, 54 consented and joined, and 46 completed ≥8 of the 12-week treatment phase and were included in the analysis. The study successfully enrolled a participant population that was 30% Black and 67% White (Table), reflecting community demographics of the enrolling facility. Attrition was lower than expected (15% vs 30% assumed in statistical plan) and only 5 of 425 planned study visits for the 46-patient cohort were missed. The most effective strategy to achieve diverse participation was prescreening the electronic medical record (EMR) with daily Epic® and OncoEMR® queries (DQ) by a research assistant. DQ allowed all potentially eligible patients to be approached to participate and yielded about half of enrollees. Also key to success were engaged study champions among medical oncology fellows, oncology nurses, nurse navigators, clinical research coordinators, and research-oriented attending physicians. Some physician referrals were facilitated by the ease of secured texts and EMR messages, and peer recognition; however, few referrals came from non-research-oriented physicians. Eleven of the 54 consented patients were identified to have essential needs and received facilitated social work assistance, including psychosocial support, financial assistance (for monetary grants for direct expenses or access to medical insurance and other benefits); and support for transportation, nutrition; child and eldercare. Of the 11 patients with essential needs, 4 were unable to complete the study due to either personal (3) or medical issues (1). Conclusions: The ASCO-ACCC Just ASK™ approach was successful for diverse clinical trial enrollment with strong protocol adherence and low attrition. Key steps included: study team diversity, a culture of respect and transparency, EMR prescreening, SDoH assessment and solutions, and engagement of research-oriented study champions. As achieving diverse participation in clinical trials is essential to reducing health disparities, the Just ASK™ approach should be considered an essential aspect of clinical trial design and implementation. Table. Baseline Characteristics Total n = 46 Age (Mean/SD) 59.6 (8.8) Gender Male 5 (10.9%) Female 41 (89.1%) Race White 31 (67.4%) Black 14 (30.4%) Other 1 (2.2%) Ethnicity Hispanic 2 (4.4%) Not Hispanic 44 (95.6%) Cancer Type Breast 29 (63.0%) Colo-rectal 9 (19.6%) Ovarian 7 (15.2%) Uterine 1 (2.2%) Citation Format: Marisa Weiss, Muath Giaddui, Stephanie Kjelstrom, Arezoo Ghaneie, Jennifer Hong, Jessica Burrell, Sarah Windawi, Ebuwa Erebor, Barry Mann, Shonalie Roberts, Gabrielle Bidas, Sam Meske, Lisa Saeed, Katherine Aliano Ruiz, Juliana Hibbs, John Marks, David Holtz, Zonera Ali, Aarthi Shevade, Robin Ciocca, Paul Gilman, Sharon Larson, Shoichi Shimamoto, Diana Martinez, Fumiko Chino, Nadine Barrett. Implementing Just ASK™ to achieve diverse participation and representation in a RCT of chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-02.

Changes in clinical guidelines for the treatment of colorectal cancer in 2024

Aim. The ensuring that changes to clinical guidelines can be discussed more widely before they are formally introduced into clinical practice.Materials and methods. A brief review of the literature and rationale for each proposed major change in the treatment section is presented. The refusal to carry out preoperative radiation therapy for cancer of the upper ampullary rectum, the narrowing of indications for preoperative radiation therapy for cancer of the mid-ampullary rectum, as well as the expansion of indications for total non-adjuvant chemotherapy for rectal cancer with damage to the circular resection margin are discussed. Changes to the drug treatment section are discussed.Results. This article presents planned changes to clinical guidelines for the treatment of non-metastatic colorectal cancer in 2024. The most significant alterations concerned neoadjuvant treatment of rectal cancer and adjuvant treatment of colon cancer. A new algorithm was proposed for choosing rectal cancer neoadjuvant therapy, considering individual treatment decisions.Conclusion. A consensus was achieved concerning the necessity to expand indications for neoadjuvant rectal cancer chemotherapy, but only in patients with good functional status. The most benefit can be achieved in patients, for whom complete clinical response is the aim of the treatment and in patients with positive circumferential resection margin.

The Expression Patterns of Immune Checkpoint Molecules in Colorectal Cancer: An Analysis Based on Microsatellite Status.

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibited concomitantly. Our objective was to investigate the patterns of ICM expression in patients with CRC and the differences in ICM expression based on microsatellite instability status. The immunohistochemical expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) in the tumor center and periphery was assessed in patients with non-metastatic colorectal cancer. We enrolled 83 patients with CRC: a total of 40 microsatellite-stable (MSS) and 43 microsatellite-instability-high (MSI-H) cancer patients. PD-L1 was more frequently expressed in the tumor center in the MSI-H patients with than that in the MSS patients (18 [41.9%] vs. 3 [7.5%], respectively; p < 0.001), and the same trend was observed for TIM-3 expression (30 [69.8%] vs. 19 [47.5%], respectively; p = 0.047). The concomitant expression of two or more ICMs was more frequently observed than no expression or the expression of a single molecule in both the MSS and MSI-H groups; a total of 34 (79.7%) patients with MSI-H cancer and 23 (57.5%) with MSS cancer showed ICM expression at the tumor center, whereas 34 (79.7%) patients with MSI-H cancer and 22 (55%) with MSS cancer showed expression at the tumor periphery. Patients with the genetic characteristics of MSI-H cancer showed higher expression levels of ICMs than those in patients with MSS cancer, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC.

Abstract 5533: The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high colorectal cancer

Abstract Introduction: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) consists of 15% of all CRC but only 2-4% of metastatic CRC. The favorable prognosis of non-metastatic (early-stage) MSI-H CRC may be related to vigorous immune reaction in tumor microenvironment. However, the mechanisms of immune evasion in metastatic (late stage) MSI-H CRC are largely unknown. Materials and Methods: We retrospectively collected patients with MSI-H CRC from National Taiwan University Hospital and Kaohsiung Chang Gung Memorial Hospital. The archival tumor specimens were used for immune cells analysis by Nanostring PanCancer Immune Panel, and spatial immune characterization by multiplex immunofluorescence stains. Only surgical resected primary tumors and metastatic tumors were included. Gene expression and immune cells composition were compared between non-metastatic and de novo metastatic tumors. Results: We enrolled 59 and 27 patients with early-stage and late-stage MSI-H CRC, respectively. Twelve metastatic site tumors were also collected. The clinicopathologic characteristics between patients who have early- and late-stage MSI-H CRC were not significantly different. There are heterogeneous immune cell compositions in these 98 MSI-H tumors. Compared to early-stage MSI-H tumors, there are significantly fewer cytotoxic (difference -0.497, p = 0.001) and dendritic cells (difference -0.528, p = 0.021) in late-stage MSI-H tumors. Gene set enrichment analysis disclosed significantly decrease in the expression of JAK-STAT-IFN-γ- and antigen processing-related pathways in late-stage MSI-H tumors. The top 5 genes with significantly differential expression between late-stage and early-stage tumors are C7, TNFRSF12A, MFGE8(up-regulated) and CXCL5, IFNL1, GZMH, HMGB1 and CXCR1 (down-regulated). Conclusions: There are significantly fewer cytotoxic and dendritic cells in late-stage MSI-H CRC, compared to early-stage MSI-H CRC, which is associated with decrease expression in JAK-STAT-IFN-γ- and antigen processing-related pathways. Citation Format: Kuo-Hsing Chen, Chia-Lang u Hs, Yu-Li Su, Chang-Tsu Yuan, Jia-Huei Tsai, Yi-Hsin Liang, Ann-Lii Cheng, Kun-Huei Yeh. The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5533.

Abstract 2200: Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance)

Abstract Background: Plant-based diet is recommended by multiple cancer survivorship guidelines and was reported to be associated with better survival among patients with non-metastatic colorectal cancer. However, the association between plant-based diet and survival in metastatic colorectal cancer is unknown. Methods: Using an NCI-sponsored systemic therapy trial conducted from 2005 to 2015 (CALGB/SWOG 80405), we included 1,279 patients who completed validated food frequency questionnaires at the initiation of treatment for metastatic colorectal cancer. To emphasize different impact of healthful plant foods, less healthful plant foods, and animal foods, we used 18 food groups to calculate three plant-based indexes (ranges: 18-90 points): overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). The primary outcome was overall survival, and the secondary outcome was progression-free survival. We estimated the associations of three indexes (quintiles) with survival using multivariable Cox proportional hazards regression. Results: Of 1,279 patients (median follow-up: 6.1 years), mean (SD) age at diagnosis was 58.8 (11.7) years, 57.4% were men, 85.6% were White, and 1,096 deaths and 1,201 events of progression occurred. The mean (SD) points of three indexes were 51.2 (6.3) for PDI, 51.1 (6.7) for hPDI, and 51.2 (8.1) for uPDI. Compared to the lowest quintile (Q1), the highest quintile (Q5) of PDI was significantly associated with better overall survival (HR: 0.80 [0.65-0.99]) and progression-free survival (HR: 0.80 [0.65-0.98]). Similar findings were observed for hPDI, but uPDI was not significantly associated with worse survival. Conclusions: Our findings suggest that plant-based diet is associated with better survival among patients with metastatic colorectal cancer, and plant-based dietary interventions should be considered for future trials in metastatic colorectal cancer. Table. Adjusted Associations of Plant-Based Diet with Survival in Metastatic Colorectal Cancer Q1 Q2 Q3 Q4 Q5 P for trend Overall Survival PDI 1.00 0.96 (0.80-1.16) 0.93 (0.77-1.14) 0.82 (0.67-0.99) 0.80 (0.65-0.99) 0.01 hPDI 1.00 0.95 (0.78-1.14) 0.94 (0.77-1.15) 0.86 (0.70-1.04) 0.84 (0.68-1.03) 0.07 uPDI 1.00 1.14 (0.95-1.39) 1.07 (0.87-1.31) 1.18 (0.97-1.45) 1.17 (0.95-1.45) 0.15 Progression-free Survival PDI 1.00 0.84 (0.70-1.01) 0.94 (0.78-1.14) 0.93 (0.77-1.12) 0.80 (0.65-0.98) 0.10 hPDI 1.00 0.86 (0.72-1.03) 0.83 (0.69-1.01) 0.80 (0.67-0.97) 0.80 (0.66-0.97) 0.03 uPDI 1.00 1.12 (0.94-1.34) 1.11 (0.91-1.34) 1.10 (0.91-1.34) 1.15 (0.94-1.41) 0.23 Citation Format: En Cheng, Fang-Shu Ou, Chao Ma, Alan P. Venook, Heinz-Josef Lenz, Eileen M. O’Reilly, Peter T. Campbell, Chaoyuan Kuang, Bette J. Caan, Kimmie Ng, Jeffrey A. Meyerhardt. Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2200.

Abstract 4834: Racial disparities in pain and psychiatric medication use in patients with metastatic colorectal cancer

Abstract Background: In the United States, colorectal cancer (CRC) is a public health concern, as it is the second leading cause of cancer-related death, accounting for over 50,000 deaths annually. In addition to its high mortality, CRC is associated with significant comorbidities including pain and psychiatric symptoms, particularly in late-stage disease. Supportive care medications (SCM) are frequently used for symptom management and improving health-related Quality of Life (HRQoL). Racial disparities in clinical outcomes including HRQoL have been reported in CRC. While racial disparities have been described in the use of SCM for some cancer types, no investigation of SCM use in late-stage CRC have been performed. The purpose of our study was to explore the relationship between SCM use and race/ethnicity in patients with metastatic CRC. Methods: We used the National Cancer Institute Surveillance Epidemiology and End Results (NCI SEER)- Medicare-linked database to analyze all patients with a CRC diagnosis and a newly initiated outpatient prescription claim for an SCM of interest from 2009-2018. Patients on SCM before cancer diagnosis or who had non-metastatic CRC at diagnosis were excluded. We assessed six SCM classes: opioids, non-opioid analgesics, skeletal muscle relaxants, antidepressants, anxiolytics, and antipsychotics. Results: After application of inclusion/exclusion criteria, 28, 212 patients were included in the final analysis (White: 72.8%, Black: 12.7%, Hispanic: 9.5%, Asian: 4.6%, Native American: 0.4%). After controlling for socioeconomic factors and compared to non-Hispanic White patients, there were significant differences across multiple SCM drug classes. When considering pain medications, these differences were bi-directional. Black patients were less likely to receive opioids (adjusted Odds Ratio [aOR] 0.86, 95% CI: 0.80-0.93), while Hispanic patients were more likely to receive opioids (aOR: 1.12, 95% CI: 1.03-1.22) and non-opioid analgesics (aOR 1.22, 95% CI: 1.06-1.40). Asian patients were more likely to receive non-opioid analgesics (aOR 1.71, 95% CI: 1.45-2.03), but less likely to receive skeletal muscle relaxants (aOR 0.60, 95% CI: 0.43-0.82). When considering psychiatric medications, decreased use among all racial groups was noted for antidepressants (Black: aOR 0.53, 95% CI: 0.50-0.60; Hispanic: aOR 0.82, 95% CI: 0.75-0.90; Asian: aOR 0.48, 95% CI: 0.42-0.56), and anxiolytics (Black: aOR 0.43, 95% CI: 0.38-0.49; Hispanic: aOR 0.76, 95% CI: 0.67-0.85; Asian: aOR 0.45, 95% CI: 0.37-0.55). Among antipsychotics, only Asian patients had less use compared to non-Hispanic White patients. Conclusion: Racial disparities in the use of pain and psychiatric medications among patients with late-stage CRC were present, even after controlling for multiple confounders. Further investigation is needed to understand drivers and their impact on HRQoL outcomes. Citation Format: John M. Allen, Olga M. Trejos Kweyete, Yi Guo, Sherise C. Rogers, Lisa Scarton, David L. DeRemer, Chardae Whitner, Diana J. Wilkie. Racial disparities in pain and psychiatric medication use in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4834.

Abstract 3418: Preoperative nutritional status and overall survival among non-metastatic colorectal cancer patients: The ColoCare Study

Abstract Introduction: Preoperative malnutrition in colorectal cancer (CRC) patients undergoing major abdominal surgery is a common and serious issue that affects postoperative recovery and clinical outcomes. The aim of this study was to evaluate the associations between preoperative nutritional status and overall survival (OS) of prospectively followed, non-metastatic CRC patients. Methods: The target cohort consisted of 415 patients with newly-diagnosed stage I-III CRC who underwent curative surgery at the Heidelberg University Hospital in Germany. Nutritional status was evaluated using predefined accessible laboratory parameters (haemoglobin, albumin, total protein, and thrombocytes), and the Geriatric Nutritional Risk Index (GNRI), a screening tool to identify patients with malnutrition: (GNRI) = 14.89 × serum albumin concentration (g/dl) + 41.7 × present weight/ideal weight. Ideal weight was calculated as follows: height(cm)-100-[(height(cm)-150)/4] for men and height(cm)-100-[(height(cm)-150)/2.5] for women. Patients were categorized into normal vs. out of normal range for laboratory parameters and into four grades of nutrition-related risk: major risk (GNRI: &amp;lt;82), moderate risk (GNRI: 82 to &amp;lt;92), low risk (GNRI: 92 to ≤98), and no risk (GNRI: &amp;gt;98). Vital status has been obtained through study-specific follow-ups or the tumor registry. OS was calculated as the interval between the date of surgery and the date of death from any cause or the last follow-up examination. Using Cox proportional hazards regression, we examined associations of the nutritional status with OS. Models were adjusted for potential confounders. Results: After a median follow-up of 2.24 years for OS, 13% (54) of the 415 patients died. Of all patients, 35.1%, 3.4%, 12.5%, and 10,8% had values out of the normal range for haemoglobin, albumin, total protein, and thrombocytes, respectively. Further, 6.4%, 33.8%, 29.7%, and 30.2% of the patients had major, moderate, low, and no nutrition-related risk, respectively. Patients with out of normal range haemoglobin and thrombocyte values had a significantly increased risk of death (HRHb: 2.8; 95% CI, 1.6-4.9, p&amp;lt;0.001 and HRThr: 3.0; 95% CI, 1.5-6.1, p=0.003). The major nutrition-related risk group had a significantly increased risk of death compared to the no nutrition-related risk group (HRGNRI: 7.2; 95% CI, 2.7-19.3, p&amp;lt;0.001). We did not observe significant associations between preoperative albumin and total protein values and OS among CRC patients. Conclusion: Patients with out of normal range levels of preoperative haemoglobin and thrombocytes had a significantly worse OS. Further, the GNRI may have a close relationship with the prognosis in non-metastatic CRC patients. Findings from this study yield important clinical information that could help to strategically combat malnutrition prior to surgery in order to improve clinical outcomes. Citation Format: Biljana Gigic, Victoria Damerell, Tengda Lin, Jennifer Ose, Christoph Kahlert, Jane C. Figueiredo, Christopher I. Li, Martin Schneider, David Shibata, Erin M. Siegel, Adetunji T. Toriola, Cornelia M. Ulrich. Preoperative nutritional status and overall survival among non-metastatic colorectal cancer patients: The ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3418.

Abstract 3421: Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer

Abstract Introduction: Dysregulation of the kynurenine pathway of tryptophan metabolism has been linked to the development of inflammation-related chronic diseases, such as colorectal cancer (CRC). Circulating concentrations of certain kynurenine metabolites, the kynurenine/tryptophan ratio (KTR), and the pro-inflammatory marker neopterin increase during inflammation, particularly in response to interferon-gamma. However, comprehensive data on the associations between inflammation markers and kynurenine metabolites and clinical outcomes in CRC patients are lacking. To address this gap in knowledge, we investigated associations of circulating kynurenine metabolites and neopterin with overall survival (OS) in prospectively followed non-metastatic CRC patients. Methods: Pre-surgery blood samples from 2,101 stage I-III CRC patients participating in the international FOCUS consortium were used to measure circulating levels of nine tryptophan-kynurenine pathway metabolites and neopterin using liquid chromatography-tandem mass spectrometry. Multivariable linear regression models and Spearman partial correlation analyses were conducted to quantify associations between kynurenine metabolites and neopterin. Based on the results from correlation analyses, a subset of patients (n=984) was categorized into different groups (‘kynurenine metabolite/neopterin‘: i.e. ‘low/high‘, ‘high/high‘) using the median biomarker concentration as cut-off. Associations of biomarkers with OS were assessed using Cox proportional hazards regression models. All models were adjusted for age at diagnosis, sex, tumor stage, tumor site, circulating creatine levels and cohort. Results: Tryptophan was inversely correlated with neopterin (r=−0.21, β=−0.48, Plinear&amp;lt;0.001). Neopterin was positively correlated with kynurenine (kyn) (r=0.25, β=0.57, Plinear&amp;lt;0.001), the KTR (r=0.42, β=0.87, Plinear&amp;lt;0.001), 3-hydroxykynurenine (r=0.26, β=0.32, Plinear&amp;lt;0.001), anthranilic acid (r=0.29, β=0.36, Plinear&amp;lt;0.001), and quinolinic acid (QA) (r=0.41, β=0.56, Plinear&amp;lt;0.001). After a median follow-up of 3.2 years for OS, 14% (141) patients deceased. While patients with ‘high neopterin’ levels had a 43% increased risk of death (HR, 1.43, 95%CI 0.95-2.16), the ‘high kyn/high neopterin‘ patient group had a 52% increased risk of death (HR, 1.52, 95%CI 1.04-2.22). Similarly, the ‘high QA/high neopterin‘ and ‘high KTR/high neopterin‘ patient groups had a 85% and 89% increased risk of death, respectively (HRQA/Neopt, 1.85, 95%CI 1.24-2.75, HRKTR/Neopt, 1.89, 95%CI 1.27-2.80). Conclusion: Tryptophan-kynurenine pathway activation correlates with inflammation marker neopterin in CRC. Combined associations of kynurenine metabolites and neopterin may be a promising predictor for OS among stage I-III CRC patients. Citation Format: Victoria Damerell, Eline H. van Roekel, Stefanie Brezina, Dieuwertje E. Kok, Tengda Lin, Daniëlle D. Holthuijsen, Jennifer Ose, Caroline Himbert, Simone J. P. Eussen, Arve Ulvik, Fränzel J. van Duijnhoven, Jane C. Figueiredo, Christopher I. Li, Erin M. Siegel, Martin Schneider, David Shibata, Adetunji A. Toriola, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Ellen Kampman, Cornelia M. Ulrich, Biljana Gigic. Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3421.

Analysis of NLR, PLR, and Carcinoembryonic Antigen in Colorectal Cancer Patients

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. The development and prognosis of CRC are affected by the tumor's appearance and the host's inflammatory response. A combination of several parameters, including the Neutrophil-Lymphocyte Ratio (NLR) and Platelet-Lymphocyte Ratio (PLR), has been used as a cancer prognostic marker. Research needs to be performed to analyze its role in CRC. This study aimed to determine the differences in the NLR, PLR, and CEA values with the severity and site of CRC. Medical record data were collected from 246 CRC patients from January 2021 to June 2022 at Dr. Wahidin Sudirohusodo Hospital were used and grouped by severity (metastatic and non-metastatic) and site (left colon, right colon, rectum). This study collected the data on NLR, PLR, and CEA levels. The Mann-Whitney, Spearman Rho, and Kruskal-Wallis tests were used for statistical analysis by the research objectives (significant if p&lt;0.05). There were differences in median PLR (194.47 vs. 201.18; p=0.045) and CEA (3.3 ng/mL vs. 11.95 ng/mL; p&lt;0.001) between the metastatic and non-metastatic groups, whereas there was no significant difference of median NLR between the two groups (2.77 vs. 2.79; p=0.438). No correlation was found between the NLR, PLR, and CEA level values with the location of CRC (p-values 0.978, 0.511,  0.419, respectively). PLR and CEA values were higher in metastatic CRC than in non-metastatic CRC, while NLR value was not significantly different. There was no correlation between the NLR, PLR, and CEA level values with the CRC site.  

Incidence of late recurrence and second primary cancers 5-10 years after non-metastatic colorectal cancer.

The fraction of patients who are cancer-free survivors 5 years after curative-intended surgery for colorectal cancer (CRC) is increasing, suggesting that extending surveillance beyond 5 years may be indicated. Here we estimate the incidence of late recurrence, metachronous CRC, and second primary cancers 5-10 years postoperative. All patients resected for UICC stage I-III CRC in Denmark through 2004-2013 were identified. Through individual-level linkage of nationwide health registry data, recurrence status was determined using a validated algorithm. Cancer-free survivors 5 years after surgery, were included. Cumulative incidence functions (CIF) of late recurrence, metachronous CRC, and second primary cancer 5-10 years postoperative were constructed. Subdistribution hazards ratios (sHR) were computed using Fine-Gray regression. Among 8883 patients, 370 developed late recurrence (5-10-year CIF = 4.1%, 95%CI: 3.7%-4.6%), 270 metachronous CRC (5-10-year CIF = 3.0%, 95%CI: 2.7%-3.4%), and 635 a second primary cancer (5-10-year CIF = 7.2%, 95%CI: 6.7%-7.7%). The risk of late recurrence was reduced for patients operated in 2009-2013 compared to 2004-2008 (2.9% vs. 5.6%, sHR = 0.52, 95% CI: 0.42-0.65). The risk of metachronous CRC was likewise reduced from 4.1% to 2.1% (sHR = 0.50, 95%CI: 0.39-0.65). While the risk of second primary cancer did not change between 2009-2013 and 2004-2008 (7.1% vs. 7.1%, sHR = 0.98, 95% CI: 0.84-1.15). Using nation-wide 10-year follow-up data, we document that the incidences of late recurrence and metachronous CRC are low and decreasing from 2004 to 2013. Thus, despite increasing numbers of long-term cancer survivors, the data do not advocate for extending CRC-specific surveillance beyond 5 years.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. During a median follow-up of 11years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-uses, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p=.005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p=.04; HR, 0.79; 95% CI, 0.70-0.88), p<.001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity =.004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p=.005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Predicting 5-year recurrence risk in colorectal cancer: development and validation of a histology-based deep learning approach.

Accurate estimation of the long-term risk of recurrence in patients with non-metastatic colorectal cancer (CRC) is crucial for clinical management. Histology-based deep learning is expected to provide more abundant information for risk stratification. We developed and validated a weakly supervised deep-learning model for predicting 5-year relapse-free survival (RFS) to stratify patients with different risks based on histological images from three hospitals of 614 cases with non-metastatic CRC. A deep prognostic factor (DL-RRS) was established to stratify patients into high and low-risk group. The areas under the curve (AUCs) were calculated to evaluate the performances of models. Our proposed model achieves the AUCs of 0.833 (95% CI: 0.736-0.905) and 0.715 (95% CI: 0.647-0.776) on validation cohort and external test cohort, respectively. The 5-year RFS rate was 45.7% for high DL-RRS patients, and 82.5% for low DL-RRS patients respectively in the external test cohort (HR: 3.89, 95% CI: 2.51-6.03, P < 0.001). Adjuvant chemotherapy was associated with improved RFS in Stage II patients with high DL-RRS (HR: 0.15, 95% CI: 0.06-0.38, P < 0.001). DL-RRS has a good predictive performance of 5-year recurrence risk in CRC, and will better serve the clinical decision-making.

Kaempferol inhibits colorectal cancer metastasis through circ_0000345 mediated JMJD2C/β-catenin signalling pathway

BackgroundRecurrence and metastasis are the main causes of disease deterioration in colorectal cancer (CRC) patients, yet efficient therapeutic strategies are lacking. Natural compounds for efficient antitumour therapeutics are becoming increasingly prominent. Kaempferol, one of the main components of flavonoids in plants, displays a variety of pharmacological activities. Our preliminary experiments suggested that kaempferol could inhibit CRC metastasis and is significantly associated with the β-catenin signalling pathway. Moreover, we also defined the regulatory roles of JMJD2C in β-catenin signalling in our previous work. PurposeThis study aims to reveal the mechanism by which kaempferol inhibits CRC progression and regulates the JMJD2C/β-catenin signalling pathway. MethodsThe migratory capabilities of CRC cells after kaempferol intervention were measured by scratch wound healing and transwell assays. Circ_0000345 knockdown CRC stable cell lines were generated by lentivirus infection. The possible mechanism of kaempferol on circ_0000345 was verified by molecular-protein docking and verification program cellular thermal shift assay (CETSA). A dual luciferase reporter gene assay was carried out for the targeting relationship among circ_0000345, miR-205-5p and JMJD2C. Fluorescence in situ hybridization (FISH) was performed to determine the expression of circ_0000345 in tumour tissues. A pulmonary metastatic model of CRC in vitro was built to assess the antimetastatic effect and mechanism of kaempferol in vivo. ResultsIn vitro, kaempferol inhibits the ability to migrate of CRC cells by reducing the activation of the JMJD2C/β-catenin signalling pathway. MiR-205-5p is a key bridge for kaempferol to inhibit the expression of JMJD2C. The function of miR-205-5p is impeded by circ_0000345, which shows higher expression levels in human metastatic CRC tissues than nonmetastatic CRC tissues, and its formation is regulated by the RNA-binding proteins HNRNPK and HNRNPL. Mechanistically, kaempferol physically interacts with HNRNPK and HNRNPL to suppress JMJD2C by downregulating the expression of circ_0000345. In vivo, kaempferol suppresses CRC lung metastasis. Kaempferol inhibits the activation of JMJD2C/β-catenin signalling through reducing the expression of circ_0000345 in the CRC lung metastasis model. ConclusionCirc_0000345 enhances activation of the JMJD2C/β-catenin signalling pathway through miR-205-5p to promote CRC metastasis. Kaempferol inhibits CRC metastasis through the circ_0000345-mediated JMJD2C/β-catenin signalling pathway, and this effect is influenced as a direct consequence of the binding of kaempferol with HNRNPK and HNRNPL. This provides promising therapeutic and/or adjuvant agents for advanced CRC and sheds light on the multifaceted role of phytomedicine in cancer.

Type 2 Diabetes Mellitus and Non-Metastatic Colorectal Cancer: A Retrospective Study on Survival and Toxicity Profiles.

Being one of the most common cancers accounting for approximately 185 million cases globally, colorectal cancer (CRC) is one of the leading derivers of cancer-related mortalities. A high prevalence of Type 2 diabetes mellitus and CRC was noted, together with a causal link between diabetes and CRC development. Thereby, the goal of this study was to properly evaluate type 2 Diabetes mellitus in non-metastatic colorectal cancer patients, and to highlight its impacts on patient's outcome. Patients with non-metastatic colorectal cancer diagnosed between January 2016 and December 2020 were studied retrospectively. Patients were divided into two groups based on whether or not they had type II diabetes. The clinico-pathological, laboratory, treatment and survival data were gathered. A total of 318 patients were included in this study. The toxicity of the drugs used in CRC patients receiving the treatment protocols (169 in non-T2DM group and 39 in T2DM group), both groups reported close percentage of side effects and a similar frequency of drug toxicity occurrence as well as grade of toxicity, with the exception of neuropathy, which was more common in the T2DM group (33.3% vs 11.2%). As for prognosis, non-T2DM and T2DM patients had a mean progression free survival of (71.4 and 60.83 months, respectively) (p = 0.019). Overall survival was 73.1% for T2DM and 85.3% for non T2DM cases. The median overall survival was not reached for both groups in terms of overall survival. T2DM is considered a risk factor for poor survival among CRC patients. Treatment related toxicity is not affected by the presence or absence of diabetes, yet neuropathy needs further studies for diabetic patients receiving oxaliplatin.

Intensive follow-up vs conventional follow-up for patients with non-metastatic colorectal cancer treated with curative intent: A meta-analysis.

The frequency and content of follow-up strategies remain controversial for colorectal cancer (CRC), and scheduled follow-ups have limited value. To compare intensive and conventional follow-up strategies for the prognosis of non-metastatic CRC treated with curative intent using a meta-analysis. PubMed, Embase, and the Cochrane Library databases were systematically searched for potentially eligible randomized controlled trials (RCTs) from inception until April 2023. The Cochrane risk of bias was used to assess the methodological quality of the included studies. The hazard ratio, relative risk, and 95% confidence interval were used to calculate survival and categorical data, and pooled analyses were performed using the random-effects model. Additional exploratory analyses were performed for sensitivity, subgroups, and publication bias. Eighteen RCTs involving 8533 patients with CRC were selected for the final analysis. Intensive follow-up may be superior to conventional follow-up in improving overall survival, but this difference was not statistically significant. Moreover, intensive follow-up was associated with an increased incidence of salvage surgery compared to conventional follow-up. In addition, there was no significant difference in the risk of recurrence between intensive and conventional follow-up strategies, whereas intensive follow-up was associated with a reduced risk of interval recurrence compared to conventional follow-up. Finally, the effects of intensive and conventional follow-up strategies differed when stratified by tumor location and follow-up duration. Intensive follow-up may have a beneficial effect on the overall survival of patients with non-metastatic CRC treated with curative intent.

Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer.

The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC. We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry. High-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8+ T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8+ T cells in non-metastatic tumors. CD8+ T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort. We conclude that localization of phenotypically distinct CD8+ T cells within stroma may predict metastasis formation in MSI-H CRC.

A commentary on 'Minimally invasive surgery versus laparotomy of non-metastatic pT4a colorectal cancer: a propensity score analysis'.

A commentary on 'Minimally invasive surgery versus laparotomy of non-metastatic pT4a colorectal cancer: a propensity score analysis'.

OP21 Patient Values Project (PVP): Patient Preferences For Cancer Treatments To Inform A Framework Incorporating Patient Values Into Health Technology Assessment

IntroductionThe methodology for explicitly incorporating patient preferences by expert committees engaged in deliberative health technology assessment (HTA) processes for drug reimbursement recommendations is a relatively unexplored area despite the growing emphasis on patient-reported outcomes and patient engagement. The Patient Values Project (PVP) aims to improve patient input to expert review committees and promote a better understanding of the patient perspective using quantitative data to support the rationale in assessing new cancer drugs. Using colorectal cancer as a starting point, the PVP aims to develop a framework to objectively incorporate quantitative patient values and preferences into Canada’s cancer drug HTA decision-making process. We report on results from the first phase.MethodsIn the first phase, we developed a bilingual survey informed by qualitative focus groups, literature review and feedback from clinicians, patients and experts. The survey includes background questions, general and cancer specific quality-of-life tools, two discrete choice experiments (DCE) and a best worst scaling (BWS) experiment. After pre-testing and pilot testing, the survey was administered across Canada to metastatic and non-metastatic colorectal cancer patients and caregivers, in addition to adults from the general population. In the next phases, we will use vignettes to explore how patient preferences could be incorporated explicitly into decision-making, and what approach to use in HTA submissions.ResultsDCE1 survey results (˜n=1,000) reflect trade-offs between health-related quality-of-life and survival; DCE2 results reflect trade-offs between treatment regimens, side effects and survival/risk of recurrence; BWS results ranked and weighted the tolerability of 25 possible side effects of treatment. We observed differences in preferences amongst the general population, patients with metastatic cancer, non-metastatic cancer and caregivers.ConclusionsPatients have unique perspectives and preferences about what is important and of value to them, which may impact patient adherence to treatment. In the next phases, we will explore how this evidence from patient preferences can be translated into values that could potentially be incorporated as an explicit element of the deliberative process for HTA decision-making.

Combined impact of myosteatosis and liver steatosis on prognosis in stage I-III colorectal cancer patients.

Myosteatosis and liver steatosis (LS) have been recognized as patient-derived image biomarkers that correlate with prognosis in colorectal cancer (CRC) patients. However, the significance of considering fat deposition in multiple body areas simultaneously has been underestimated. This study aimed to investigate the combined effect of myosteatosis and LS in stage I-III CRC patients. A total of 616 stage I-III CRC patients were included in the study. Myosteatosis was assessed using skeletal muscle radiodensity (SMD), and LS was estimated by calculating the Hounsfield unit of the liver and spleen ratio (LSR). Cox proportional hazard models were utilized to evaluate disease-free survival (DFS). A combination of myosteatosis and LS was proposed, and its discriminatory performance was compared using the C-index. Among the 616 participants, the median (interquartile) age was 64 (55-72) years, and 240 (38.9%) were female. The median and interquartile range of LSR were determined as 1.106 (0.967-1.225). The optimal cutoff value for LSR was identified as 1.181, leading to the classification of patients into low (410, 66.5%) and high LSR (206, 33.4%) groups. Among the patients, 200 were categorized into the low SMD group, while 416 were allocated to the high SMD group. Both myosteatosis and LS were identified as independent prognostic factors in the multivariable analysis. The combination of these two variables resulted in a three-group classification: high SMD with low LSR group, high SMD with high LSR group, and low SMD group. When comparing the C-index values, the three-group classification exhibited superior discriminatory performance compared with considering myosteatosis and LS separately. Myosteatosis was associated with poorer survival, while the presence of LS was linked to a better prognosis in non-metastatic CRC patients. Simultaneously considering fat infiltration can serve as a more effective prognosticator in non-metastatic CRC patients.