Population Of Colorectal Cancer Patients Research Articles

Family history as a major prerequisite for microsatellite instability screening in colorectal cancer is a poor selection tool.

Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable. We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria. The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively. A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

Reliability and validity of the Turkish version of the New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire.

This study aims to adapt and validate the Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire (CCF-CaQL) in Turkish, addressing the significant need for reliable, language-specific QoL measures for colorectal cancer (CRC) in Turkiye. This effort fills a critical gap in CRC patient care, enhancing both patient-provider communication and disease-specific QoL assessment. The CCF-CaQL was translated into Turkish, verified for accuracy, and reviewed for clarity and relevance. Eligible patients who underwent colorectal surgery for cancer between July 2021 and July 2022 from six hospitals completed the CCF-CaQL and SF-36 questionnaires. For analysis, confirmatory factor analysis using Smart PLS 4 and descriptive statistics were employed. The questionnaire's reliability and validity were assessed using Cronbach alpha, composite reliability, and the heterotrait-monotrait (HTMT) ratio, along with multicollinearity checks and factor loadings. Nonparametric resampling was used for precise error and confidence interval calculations, and the Spearman coefficient and split-half method were applied for reliability testing. In the study involving 244 colorectal cancer patients, confirmatory factor analysis of the CCF-CaQL indicated effective item performance, with one item removed due to lower factor loading. The questionnaire exhibited high internal consistency, evidenced by a Cronbach alpha value of 0.909. Convergent validity was strong, with all average variance extracted (AVE) values exceeding 0.4. Discriminant validity was confirmed with HTMT coefficients below 0.9, and no significant multicollinearity issues were observed (VIF values < 10). Parallel testing with the SF-36 scale demonstrated moderate to very strong correlations, affirming the CCF-CaQL's comparability in measuring quality of life. The Turkish version of the CCF-CaQL was validated for assessing quality of life in colorectal cancer patients. This validation confirms its reliability and cultural appropriateness for use in Turkiye. The disease-specific nature of the CCF-CaQL makes it a useful tool in clinical and research settings, enhancing patient care by accurately monitoring treatment effects and interventions in the Turkish colorectal cancer patient population.

Abstract B019: “It's probably just hemorrhoids”: A qualitative exploration of psychosocial and lifestyle changes and challenges accompanying an early-onset colorectal cancer diagnosis

Abstract Background: Colorectal cancer (CRC) among adults aged &amp;lt; 50 years (early-onset CRC [EOCRC]) is projected to be the leading cause of cancer-related death by 2030. Unanswered questions remain regarding the effects of EOCRC on quality-of-life and psychosocial outcomes affected by an EOCRC. This qualitative study explored the lived experiences and perceptions of a sample of adult EOCRC survivors in the United States through one-on-one interviews. Methods: An early-onset CRC advocate survivor team (AST) member led 27 structured interviews virtually with adults diagnosed with early-onset CRC (mean age at diagnosis = 33.93±5.90). The interview guide consisted of 10 questions, which was co-developed by the lead author, third author, and two AST members. Data was analyzed using a 9-step inductive approach, where a hybrid coding approach was employed that involved both a priori codes as well as any concepts, actions, relationships, and meanings that differed from the pre-set codes. Results: Study participants were from across the country, with over half living in the Southern (44.4%) or Midwestern (22.2%) regions. Most participants were women (66.6%) and self-identified as Non-Hispanic White (85.2%). The age of study participants at the time of interview ranged from 28 to 53 years (mean age = 40.19 ± 5.99) and their age at diagnosis ranged from 26 to 44 years (mean age at diagnosis = 33.93 ± 5.90). Six overarching themes were identified from the interviews with two to three subthemes: 1) Signs and Symptoms (Self-Misdiagnosis, Provider Misdiagnosis), 2) Risk Factors (Family History, Lifestyle, Blame/Defensiveness), 3) System-Level Factors (Provider Recommendations, Navigating Care/Pace of Treatment, Perceptions of Medical Workers), 4) Quality of Life (Fertility and/or Sexual Health, Mental Health/Therapy, Self-Advocacy), 5) Social Support (Support Groups and Family, Friends, and Others), and 6) Reflection (Prevention, Personal, Advocacy). Conclusions: The overall lived-experiences gathered from interviewees highlights specific needs of early-onset CRC identify patients that can be used to inform educational material and comprehensive care. Although the causes of the increase in young-onset CRC remain unknown, psychosocial as well as lifestyle changes and challenges should be considered during treatment and future intervention as well as throughout survivorship in this younger population of CRC patients. Impact: The lived experiences and perceptions of EOCRC survivors highlight specific needs of this population that can inform both educational materials and comprehensive care. Citation Format: Charles R. Rogers, Kevin M. Korous, Mary A. De Vera, Aasma Shaukat, Ellen Brooks, Candace Henley, Wenora Johnson, Tiana N. Rogers. “It's probably just hemorrhoids”: A qualitative exploration of psychosocial and lifestyle changes and challenges accompanying an early-onset colorectal cancer diagnosis [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B019.

"It's Probably Just Hemorrhoids": A Qualitative Exploration of the Lived Experiences and Perceptions of Long-term Survivors of Early-Onset Colorectal Cancer.

Colorectal cancer among adults aged <50 years [early-onset colorectal cancer (EOCRC)] is projected to be the leading cause of cancer-related death by 2030. Although evidence-based guidelines for colorectal cancer screening now recommend beginning screening at age 45, the needs of many at-risk young adults are potentially being overlooked. Unanswered questions also remain regarding the effects of EOCRC on quality-of-life and psychosocial outcomes. This qualitative study explored the lived experiences and perceptions of a sample of adult EOCRC survivors in the United States through one-on-one interviews. An EOCRC advocate survivor team member led 27 structured virtual interviews using a 10-question interview guide. Data were analyzed using a 9-step inductive approach. Participants were geographically diverse. Most were women (66.6%) who self-identified as non-Hispanic White (85.2%). The mean age at interview was 40.19 ± 5.99; at diagnosis, 33.93 ± 5.90. Six overarching themes emerged: signs and symptoms, risk factors, system-level factors, quality of life, social support, and reflection. The specific needs of individuals in this younger population of patients with colorectal cancer should be considered during treatment and future interventions and throughout survivorship. While the reasons for the increasing incidence of EOCRC are currently unknown, the lived experiences and perceptions of EOCRC survivors noted in this study highlight specific needs of this population that can inform educational materials, comprehensive care, future research, and policy change.

The clinicopathological spectrum and treatment outcomes in metastatic colorectal cancer in the KwaZulu-Natal province of South Africa.

In high-income countries (HICs) 17-20% of colorectal cancer (CRC) patients have metastatic CRC (mCRC) at the time of diagnosis, of which 10-25% are or become resectable, and a further 4-11% of patients will develop metachronous metastases. The study aimed to establish the prevalence and pattern of metastatic CRC to document treatment outcomes in KwaZulu-Natal (KZN), and to compare results to international norms. The study population comprised patients with mCRC presenting between 2000 and 2019. Demographics, primary tumour site, spectrum of metastatic disease and resection rate were assessed. MCRC occurred in 33% of the CRC patient population. Eight hundred and thirty-six patients had metastatic disease, comprising Africans (325, 38.8%), Indians (312, 37.3%), Coloureds (37, 4.4%) and Whites (161, 19.2%). Six hundred and fifty-four patients (79%) had synchronous metastases and 182 patients had metachronous metastases (21%). Single organ metastases occurred in 596 patients (71.2%) (M1A) and multiple organ metastasis occurred in 240 patients (28.7%) (M1B). Metastases occurred in the liver (613), lung (240) and peritoneum (85). Fifty-two patients (6.2%) underwent resection of their metastases. The prevalence of stage IV CRC in our setting is at the upper limit of international norms. mCRC occurred in 33%, with similar proportions in all races. Resection rate for metastases is low.

Disparities in screening, diagnosis, treatment, and survivorship care among urban and rural patients with colorectal cancer in the United States: A systematic review and meta-analysis.

e18558 Background: Older rural patients suffer from disproportionately higher rates of colorectal cancer (CRC) and mortality due to CRC compared to older urban patients. These disparities may be multifactorial including geographic barriers to care, lack of health insurance coverage, or lack of preventive health behaviors, among others. To further understand this burden of rural-urban CRC disparities along the cancer care continuum, we sought to evaluate and synthesize literature on screening, diagnosis, treatment, and survivorship care differences between urban and rural CRC patients. Methods: We performed a systematic literature review using PubMed and EMBASE in August 2022 using keywords related to screening, diagnosis, treatment, and survivorship care for CRC urban-rural patients for studies published in 2000 to 2022. A meta-analysis was performed for results related to screening using a random-effects model. Results: Of 836 studies collected, 46 met criteria for review, and 12 for a meta-analysis evaluating the effect of rurality on any reported CRC screening. The majority of studies evaluated disparities in screening (46%), followed by diagnosis (30%), treatment (20%), and survivorship care (4%). In general, studies indicated urban CRC patients as more likely to report age-appropriate screening, to receive early-stage diagnosis, and to receive timely and appropriate treatment compared to rural CRC patients. Only one study was found evaluating a difference in receipt of surveillance colonoscopy in urban/rural CRC survivors, with rural survivors as 2.28 times more likely to report nonadherence to surveillance screening (OR = 2.28, 95%CI:1.07-4.85). Meta-analysis results indicate that rural patients had 22% lower odds of reporting screening compared to urban patients prior to any diagnosis (pooled OR = 0.78, 95%CI:0.66-0.92, I2= 42.9%). Conclusions: Despite widespread support and effort to implement policy aimed toward reducing disparities of care, screening, diagnosis, and treatment gaps are still present between urban and rural CRC patients. Further research must be performed to evaluate the effects of these disparities on clinical outcomes in the rural CRC patient population.

The Effect of Proton Pump Inhibitor Use on Survival of Patients With Colorectal Cancer: A Study of a Racially Diverse Population.

Introduction Proton pump inhibitor (PPI) use is increasing in the general population. Chronic PPI use can lead to hypergastrinemia, which has been purported to increase the risk of developing colorectal cancer (CRC). Several studies have failed to report any association between PPI use and the risk of CRC. However, little is known about the effect of PPI use on CRC survival. In this retrospective analysis, we studied the effect of PPI use on CRC survival in a racially diverse population. Methods Data were abstracted for 1050 consecutive patients diagnosed with CRC from January 2007 to December 2020. The Kaplan-Meier curve was created to study the effect of PPI exposure compared to no exposure on overall survival (OS). Univariate and multivariate analyses were performed to investigate predictors of survival. Results Complete data were available for 750 patients with CRC, 52.5% were males, 22.7% were Whites, 60.1% were Asians, and 17.2% were Pacific Islanders. A total of 25.6% of patients had a history of PPI use. Moreover, 79.2% had hypertension, 68.8% had hyperlipidemia, 38.0% had diabetes mellitus, and 30.2% had kidney disease. There was no difference in median OS among PPI users compared to non-users, p value=0.4. Age, grade, and stage were predictors of inferior OS. No significant association was noticed with gender, race, comorbidities, or treatment with chemotherapy. Conclusion In this retrospective analysis of a racially diverse population of CRC patients, we found that PPI use was not associated with worse OS. Until high-quality prospective data are available, physicians should not stop PPIs that are clinically indicated.

A Systematic Review of Complementary Therapies in Colorectal cancer patients: Summarizing the Current Global Options

Colorectal cancer patients have been experiencing various side effects related to the therapies, both physically and physiologically. Complementary medicine was used to help patients alleviate complaints and increase their quality of life. This systematic review aimed to sort out complementary medicines that could be advised to be used for colorectal cancer patients. Search limitations include the population of colorectal cancer patients, published between 2015 and 2021 and written in English. We found that traditional Chinese medicine, aromatherapy massage, acupuncture, and mindfulness-based stress reduction tests were beneficial in improving patients’ physical and physiological complaints. However, dosing and herb-herb interactions in Chinese traditional medicine and the beneficial persistency effect of other modalities needed further investigation, especially in colorectal cancer patient therapy. Complementary modalities are generally safe; however, some therapies still warrant further investigation to confirm safety and beneficial consistency.

A signature of Prevotella copri and Faecalibacterium prausnitzii depletion, and a link with bacterial glutamate degradation in the Kenyan colorectal cancer patients.

Colorectal cancer (CRC) is the fifth most diagnosed cancer in Sub-Saharan Africa. In Kenya, CRC incidence rates tripled from 1997 to 2017. In the Moi Teaching and Referral Hospital, Moi University, there has been an increase in CRC cases, notably for younger patients. A suggested pathobiology for this increase is gut microbiome dysbiosis. Since, for the Kenyan CRC patient population, microbiome studies are rare, there is a need for a better understanding of how microbiome dysbiosis influences CRC epidemiology in Kenya. In this single-center study, the focus was on profiling the gut microbiome of Kenyan CRC patients and healthy volunteers and evaluating associations between microbiome profiles and the age of CRC patients. The gut mucosa-associated microbiome of 18 CRC patients and 18 healthy controls were determined by 16S rRNA sequencing and analyzed for alpha and beta diversity, differential abundance, and microbial metabolic profiling. Alpha diversity metrics showed no significant differences, but beta diversity metrics showed dissimilarities in the microbial communities between CRC patients and healthy controls. The most underrepresented species in the CRC group were Prevotella copri (P. copri) and Faecalibacterium prausnitzii (F. prausnitzii), although Bacteroides fragilis (B. fragilis) and Prevotella nigrescens were overrepresented (linear discriminant analysis, LDA score >2, P<0.05). Also, for CRC patients, significant metagenomic functional alterations were evident in microbial glutamate metabolic pathways (L-glutamate degradation VIII was enriched, and L-glutamate and L-glutamine biosynthesis were diminished) (P<0.05, log2 Fold Change >1). Moreover, the microbiome composition was different for patients under 40 years of age compared to older patients (LDA score >2, P<0.05). Microbiome and microbial metabolic profiles of CRC patients are different from those of healthy individuals. CRC microbiome dysbiosis, particularly P. copri and F. prausnitzii depletion and glutamate metabolic alterations, are evident in Kenyan CRC patients.

Significant position of C-myc in colorectal cancer: a promising therapeutic target.

Colorectal cancer (CRC) is a malignant tumor initiating from the mucosa of the colorectum. According to the 2020 statistics from the World Health Organization, there are 10.0% CRC cases among all 19.3 million new cancers, followed by lung and breast cancer, and 9.4% CRC cases among all 9.9 million cancer deaths, ranking second. The population of CRC patients in China is large, and its incidence and mortality continue to increase each year. Despite the continuous development of surgical methods, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the overall survival of CRC patients remains low. Past research has suggested that c-myc plays a pivotal role in the development of CRC. A higher expression level of c-Myc is a negative prognostic marker in CRC. However, there are few drugs targeting c-myc directly. Therefore, we focused on discovering the mechanism of c-myc in CRC to provide a reference for a better therapy choice for patients.

EP-334 The Impact of Combined DNA Repair and Oncogene Mutations in Colorectal Cancer Survival

Abstract Aims To examine the coexistent effect of either KRAS or BRAF gene status with MMR gene status on patient outcomes in a rural population of colorectal cancer patients. Methods Using a colorectal cancer database, results for patient mutation status for mismatch repair genes and other oncogenes, obtained by DNA sequencing and immunohistochemical analysis, were assessed to see if there were significant differences in survival probability in patients with and without single and combined risk factors. Kaplan-Meier survival analyses were performed to examine overall survival probability in the different groups of patients. Results Comparison of survival outcomes in patients with and without KRAS and MLH1 mutations showed a significant difference (p=0.018). Pairwise analysis reveals that this difference is mostly between the group with wild-type status for both genes and a patient with mutant KRAS and EGFR status with wildtype MLH1 status (p=0.062 with bonferroni correction). Combined KRAS and PMS2 status results in a borderline insignificant (p=0.056) survival difference as well. The effects of mutations in other combinations of oncogenes, as well as sex or tumour sidedness and mutation statuses, were not significant on survival probability. Conclusions These preliminary results should be interpreted with caution owing to the relatively small sample size. This study supports previous findings that mutant oncogenes, combined with altered MMR genes can be predictive of colorectal cancer survival outcome.

Abstract 1371: Rho-GEF hampers CD8+T cells-mediated immunosurveillance by reducing antigen presentation

Abstract Immune response is a critical anti-tumor response to overcome tumorigenesis. In line with this, immune checkpoint blockade shows tremendous anti-tumor efficacy by enhancing cytotoxicity of CD8+ cytotoxic T lymphocytes (CTLs). However, cancer cells develop different mechanisms of immune evasion, among which suppression of immune recognition of somatic mutations via tumor antigen is prevalent. In fact, 65% to 90% of the cancers show reduced MHC-I antigen presentation. There is, nonetheless, little achievement toward the therapeutic approaches to restore antigen presentation on tumor cells. Colorectal cancer (CRC), the second deadliest cancer in U.S., shows increasing incidence and mortality rates over the past years. Standard conventional CRC treatments, surgery, chemotherapy and radiotherapy, often lead to many side effects due to their non-specificity and cytotoxicity. While immunotherapy is very promising, only a small population of CRC patients respond to the current immune checkpoint inhibitors. In this study, our objective was to harness a novel immunological approach to target CRC tumors. We developed a bioinformatics tool to create a pool of genes whose expression negatively correlates with cytotoxicity of CD8+ CTLs in the tumor microenvironment of CRC patients. Given the central role of antigen presentation in activating CD8+ CTLs, we further screened these genes based on the scope of their effects on antigen presentation. To this end, we developed stable clones of OVA expressing MC38 cells (MC38OVA) where OVA-derived peptide, SIINFEKL, will be bound to MHC-I complex for cell surface presentation. 4 genes with highest capacity to alter MHC-I cell surface levels were identified. Our consequent in vivo experiments and in vitro cytotoxicity assays identified that “Rho-GEF” gene was the top actionable target with striking suppressive effects on tumor growth. TCGA database analysis showed Rho-GEF is upregulated in 22% of CRC patients accompanied by a poor prognosis. Rho-GEF knockdown (KD) significantly inhibited tumor growth in immunocompetent mice whereas it only showed minor effects on immunocompromised mice, suggesting that the Rho-GEF may modulate tumor growth by regulating the interaction of tumor cells with non-tumor cells such as immune cells. Consistent with the major contribution of antigen presentation in promoting CD8+ CTLs activity, TNFα, IFNγ, and GZMB levels in CD8+ T cells isolated from Rho-GEF KD MC38-derived tumors showed a significant increase compared to the wild type tumors. Taken together, we introduced Rho-GEF as a potential clinical target involved in CRC immune evasion by modulating antigen presentation and CD8+ CTLs anti-tumor responses. Citation Format: Haniyeh Eyvani, Xinna Zhang. Rho-GEF hampers CD8+T cells-mediated immunosurveillance by reducing antigen presentation [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 1371.

A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.

e15579 Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.

Pre-Diagnosis Aspirin Use Has No Effect on Overall Survival in Patients With Colorectal Cancer: A Study of a Multi-Racial Population.

IntroductionAspirin has been associated with a reduction in mortality in patients diagnosed with colorectal cancer (CRC). A possible mechanism for this is related to the programmed cell death 1 (PD-1) immune checkpoint pathway. Aspirin may have a synergistic effect with PD-1 inhibitors via inhibition of prostaglandin E2 (PGE2) production, which can reverse the ability of tumor cells to evade the immune system. This appears to be strongest in cancers that express PI3 kinase (PI3K) signaling activity, which aspirin downregulates. However, the benefit of pre-diagnosis aspirin use on CRC overall survival (OS) and cancer-specific survival is still controversial, and most studies have been performed in racially homogenous populations. Our study examines the effect of pre-diagnosis aspirin therapy on OS in a racially diverse group of patients with CRC.MethodsThis is a retrospective chart review of 782 patients diagnosed with CRC from January 2007 to December 2020. Kaplan-Meier curve was created to study the association of aspirin exposure compared to no exposure on OS. In addition, univariate and multivariate binary logistic regression analyses were done to investigate potential predictors of survival.ResultsOf the 782 patients with CRC, 55.1% were males, 22.2% whites, 58.5% Asians, and 17.7% Pacific-Islanders. Moreover, 38.4% of the patients had a history of aspirin use, 79% of them used it for more than one year. There were more patients with hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and chronic kidney disease (CKD) among those with a history of aspirin use. There was no difference in one, three, and five-year OS among aspirin users compared to non-users, p-value = 0.63. Age, grade, and stage were potential predictors of worsened OS. However, treatment with chemotherapy and CKD were potential predictors of worsened OS on univariate analysis only. No significant association was noticed with gender, tumor location, or other associated comorbidities.ConclusionThe effect of pre-diagnosis aspirin use on CRC survival is not clear. In this retrospective analysis of a racially diverse population of CRC patients, we found that aspirin use was not associated with improved OS. Therefore, physicians should be careful about using aspirin as adjuvant therapy in CRC patients until high-quality prospective data are available, given the potential associated complications.

Predicting Colorectal Cancer Recurrence and Patient Survival Using Supervised Machine Learning Approach: A South African Population-Based Study

Background: South Africa (SA) has the highest incidence of colorectal cancer (CRC) in Sub-Saharan Africa (SSA). However, there is limited research on CRC recurrence and survival in SA. CRC recurrence and overall survival are highly variable across studies. Accurate prediction of patients at risk can enhance clinical expectations and decisions within the South African CRC patients population. We explored the feasibility of integrating statistical and machine learning (ML) algorithms to achieve higher predictive performance and interpretability in findings.Methods: We selected and compared six algorithms:- logistic regression (LR), naïve Bayes (NB), C5.0, random forest (RF), support vector machine (SVM) and artificial neural network (ANN). Commonly selected features based on OneR and information gain, within 10-fold cross-validation, were used for model development. The validity and stability of the predictive models were further assessed using simulated datasets.Results: The six algorithms achieved high discriminative accuracies (AUC-ROC). ANN achieved the highest AUC-ROC for recurrence (87.0%) and survival (82.0%), and other models showed comparable performance with ANN. We observed no statistical difference in the performance of the models. Features including radiological stage and patient's age, histology, and race are risk factors of CRC recurrence and patient survival, respectively.Conclusions: Based on other studies and what is known in the field, we have affirmed important predictive factors for recurrence and survival using rigorous procedures. Outcomes of this study can be generalised to CRC patient population elsewhere in SA and other SSA countries with similar patient profiles.

Adherence to clinical practice guidelines for adjuvant chemotherapy for colorectal cancer in Uruguay: A population-based study.

53 Background: Despite surgery, the 5-year risk of systemic recurrence of colorectal cancer (CRC) in the absence of any further therapy is approximately 50 % for those with lymph node involvement and 20 ─ 30 % if the lymph nodes are negative. Adjuvant chemotherapy contributes to improved disease-free and overall survival for node-positive (stage III) or high-risk node negative (stage IIB) colon cancer. Similar benefits are observed for adjuvant chemoradiotherapy in rectal cancer. Previous research shows varied rates of adherence to published adjuvant chemotherapy Clinical Practice Guidelines (CPGs) for CRC, although population-based data is scarce. Purpose: The aim of this analysis was to assess adherence rates to adjuvant chemotherapy prescription within 16 weeks of surgery according to local and international CPGs for CRC patients treated with curative intent between 2008 and 2019 at the Uruguayan National Cancer Institute. Data regarding factors associated with chemotherapy receipt beyond 16 weeks from surgery and chemotherapy non receipt was also retrieved and analysed. Methods: We retrospectively reviewed medical and pathology reports of 833 patients diagnosed with CRC at our institution. Patients with stages IIB or III CRC who underwent curative-intent surgery were identified and included in the present analysis. A 16-week benchmark timeline for treatment initiation from date of surgery was considered. Fisher’s exact test was used to determine factors independently associated with receipt of chemotherapy and meeting the 16-week benchmark (p 0.05). Results: A total of 400 patients were identified of which 72% had peritoneal colorectal tumors and 28% had sub-peritoneal rectal tumors. Approximately 70% of the latter group received neoadjuvant chemo-radiotherapy. Considering the total cohort, 61% received adjuvant chemotherapy. Factors predicting chemotherapy receipt in the peritoneal colorectal group were age ≤ 70 and stage III disease. In the sub-peritoneal rectal group no significant effect was found. The 16-week benchmark was met in 72% (175) of those receiving chemotherapy and 70.6% (167) completed 6 months of systemic adjuvant treatment. A total of 156 patients (39%) did not receive adjuvant chemotherapy. The factors predicting chemotherapy non receipt were age &gt; 70 and stage IIB in the peritoneal colorectal group. Conclusions: This analysis of adherence to CPGs identified several factors associated with chemotherapy non receipt and chemotherapy receipt outside of timeline benchmarks from date of curative-intent surgery in Montevideo, Uruguay. The two main factors significantly associated with chemotherapy non receipt were advanced age and lower disease stage. To our knowledge, our data is the first to elucidate these specific factors in the Uruguayan CRC patient population.

Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy

ABSTRACT Introduction Microsatellite instability-high (MSI-H) colorectal cancer (CRC) represents a unique subset of CRC characterized by elevated neoantigen expression and a high degree of intraepithelial T-cell infiltrate. These characteristics make MSI-H tumors particularly susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab which inhibit the negative regulation of cytotoxic T-cells and promote T-cell mediated anti-tumor activity. Areas covered We discuss the drug development of pembrolizumab including the seminal studies which enabled the drug to garner FDA approvals in the refractory and first-line settings for patients with MSI-H CRC, the pharmacokinetic & pharmacodynamic profile of the agent, and the adverse event profile of the ICI. We also discuss unmet needs in the arena of ICIs including strategies to overcome tumor resistance and to increase the applicability of the agents to a broader population of CRC patients. Expert opinion Despite the anti-tumor activity of pembrolizumab in patients with MSI-H CRC, 30–35% of patients fail to derive any benefit. Ongoing research efforts are seeking to identify ICI combinations, which can overcome CRC resistance to pembrolizumab, move ICIs into the treatment paradigm for patients with localized MSI-H CRC and enable ICIs to become meaningful treatment options for patients with microsatellite stable CRC.

Targeting the Tumor in Colorectal Cancer – Where do we Stand with Precision Medicine in 2020

Colorectal cancer (CRC) has still got a high mortality rate. A large number of patients will be diagnosed at an advanced stage with no curative option. This disease is characterized by its heterogeneity and alterations in multiple molecular pathways throughout its development. Predictive mutations such as RAS or mismatch repair gene deficiency (MMR-d) are routinely tested for treatment strategies and prognostic calculation. Nevertheless, there is a high clinical demand for reliable and powerful prognostic markers identifying a “high-risk” population of CRC patients who will benefit from adjuvant therapy. Moreover, tools like biomarker evaluation for treatment guidance have moved into the spotlight. This narrative review will highlight the current clinically relevant molecular markers of CRC as well as the relevance of tools, e.g., circulating tumor DNA (ctDNA), that could become indispensable in the coming years.

Differences in Colorectal Cancer (CRC) patients who did and did not undergo screening

Abstract Background The Australian National Bowel Cancer Screening Program (NBSCP) is a free population-based screening program which aims to identify precancerous lesions and early colorectal cancer (CRC) using an immunochemical faecal occult blood test in average risk Australians. Formally commencing in 2006, NBCSP participation rate in eligible 50-74-year-old people was 42% in 2018. The barriers and facilitators of participation in the NBCSP have been explored for the general, at-risk population but not in a population of CRC patients. This is the first study to assess a population of CRC patients, post diagnosis, who would have been eligible for CRC screening to determine the barriers and facilitators to screening. Methods A cross sectional study nested within a cohort study. Data from CRC patients who participated in the 45 and Up Study; the largest cohort study in Australia and southern hemisphere, were analysed to compare those who had and had not participated in CRC screening. Logistic regression analyses were conducted using RStudio (version 3.5.2, Boston, Massachusetts, USA.). Multiple Imputation (MI), was used to handle missing values assumed to be missing at random. Results A total of 339 CRC patients were included. Patients who were female, overweight (≥25kg/m2), consumed less than the recommended five servings of vegetables per day, consumed less than or equal to fourteen standard drinks per week (compared to non-drinkers) or did not meet physical activity guidelines were significantly less likely to have participated in screening. Conclusions Our study has taken a unique approach to identifying a high-risk group by exploring factors to screening participation in CRC patients. CRC patients with less healthy lifestyles were less likely to participate in screening. In contrast to previous studies, female patients were less likely to participate in screening than males were. This was an unexpected finding and should be replicated. Key messages Not surprising that those with less healthy lifestyle practices also reflected less than ideal screening practices. Surprising that female patients participated less in screening than males. Future interventions to improve CRC screening participation rates should consider specialised messaging for average-risk females who are overweight not meeting dietary or physical activity guidelines.

Results of a fifty-gene breast cancer RNA subtype classifier applied to 167 colorectal cancer (CRC) patients.

20 Background: ERBB2 (HER2) is thought to be a target in &lt;10% of CRC patients versus 20% of breast cancers, 15% of gastroesophageal cancers, and 10% of biliary cancers, based on FISH or IHC. Intrinsic molecular subtype is used to classify cancers into distinct biologic subtypes (eg. CMS 1-4 in CRC). A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. The HERACLES trial (trastuzumab plus lapatinib) resulted a 32% ORR and median TTP of 5.5 months in heavily pre-pretreated HER2+ CRC patients. We determined molecular subtypes using the 50-gene breast cancer classifier to identify an expanded CRC patient population eligible for HER2 therapy. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) data from NantHealth was performed. Breast Cancer Intrinsic Subtypes based on RNAseq was used to classify CRC into 5 BC subtypes. Results: 167 CRC patients were classified using the Nant50 Breast Cancer classifier: 15.0% as Luminal B, 13.1% as Luminal A, and 1.8% as Basal-like. Surprisingly, 117/167 (70%) classified as HER2-enriched (HER-E). 15/167 (9.0%) had over-expression of ERBB2 by RNAseq or CN gain, which is consistent with published data of HER2+ CRC. ERBB2 is very significantly differentially expressed in HER2-E subtyped CRC (p=&lt;0.001), more than ERBB2 CN gain, suggesting that HER2-E may be more HER2 driven. Across subtypes APC and TP53 were the most commonly mutated genes at 65.3% and 52.6% respectively, however both were more enriched in HER2-E CRC (APC OR=3.3, p=0.001, TP53 OR=2.6, p=0.007). Other known drivers of CRC such as PIK3CA, KRAS, and BRAF, were not differentially mutated in HER2-E CRC, however NRAS mutants were significantly more enriched in non-HER2-E CRC (OR=4.6, p=0.02). Conclusions: Even after excluding known HER2 over-expression and CN gain, PAM50-like gene classifier identifies a far higher than expected percentage of HER-E subtype CRC (99/167 = 59%) which may represent an under appreciated population for HER2 directed therapy and clinical trials.