Young-onset Colorectal Cancer Research Articles

Abstract 719: Advocacy organizations as critical players in the research ecosystem: A case study in the value and use of real world evidence

Abstract Background: Patient-reported outcomes (PROs) are defined as critical data points in the overall assessment of healthcare quality. Coupled with advances in treatment and the evolution of patient-provider relationships, there is an increased emphasis on evaluating patient satisfaction and wellness, often most accurately captured using PROs to describe aspects of a patient’s health status, as directly reported by patients. The importance of direct patient reporting has been highlighted by both FDA and the European Medicines Agency (EMA). The Colorectal Cancer Alliance’s Never Too Young (N2Y) Survey provides accurate, accessible, and reusable data to show trends in young-onset colorectal cancer (YO-CRC) incidence rates, patient care, quality of life outcomes and research. Methods: To support the YO-CRC community and understand unmet needs, the Colorectal Cancer Alliance (Alliance) launched an annual N2Y survey in 2015. Survivors and caregivers played an indispensable role in the development of this survey. In 2022, the Alliance engaged in a comprehensive literature review to analyze how N2Y survey data and publications have been cited and utilized in research, showcasing survey data's value and global impact. Results: Data from our surveys produced 22 abstracts cited by more than 150 publications. The data provides healthcare providers and researchers with valuable information and metrics that did not previously exist from a YO-CRC patient and caregiver perspective. These reports are particularly important to patients with CRC due to the adverse effects of colorectal cancer treatments. Many citations reference the reports to emphasize the need to focus on YO-CRC for a national screening program and the importance of provider vigilance towards symptoms regardless of age., Additionally, our reports were used to elucidate the need for YO centers that comprehensively address the unique needs of patients with specific services selected based on PRO data from the Colorectal Cancer Alliance. Conclusion: Innovative advocacy efforts like PRO collection from organizations like the Colorectal Cancer Alliance using validated and systematic methodology can facilitate efficient, life-saving decision-making globally. With careful consideration and acknowledgment of PROs, positive care experiences can develop to better clinical outcomes overall. PROs indicate the importance of teams who actively communicate well with each other and with the patient to achieve positive outcomes through personalized, precision medicine and better position future research with implications for education and practice. As we advance, the patient and patient advocacy community should work collaboratively with researchers, industry, clinicians and investigators. Citation Format: Kimberly Lynn Newcomer, Andrea Goodman. Advocacy organizations as critical players in the research ecosystem: A case study in the value and use of real world evidence [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 719.

“The Reynolds–McElhenney effect?”: effect of celebrity endorsement on colonoscopy-related videos on TikTok

Background and AimsCases of young-onset colorectal cancer (CRC) have risen substantially over the last 20 years, and physicians are increasingly harnessing the influence of celebrities to raise awareness for CRC screening. Celebrity actors Ryan Reynolds and Rob McElhenney filmed their experiences undergoing colonoscopy as part of an initiative to raise awareness for CRC screening. Herein, we assess the quality of information on TikTok regarding colonoscopies and evaluate the effect of this celebrity endorsement.MethodsHashtags encompassing colonoscopy were searched using TikTok’s algorithm, and 75 videos were considered. The DISCERN questionnaire and analytics were used to quantify the quality and popularity of each video.ResultsColonoscopy-related videos were higher in quality (P < .01) and popularity (P < .05) after the celebrity Reynolds–McElhenney endorsement compared with those released before. After the endorsement, the difference between the quality of the content created by physicians and nonphysicians was eliminated.ConclusionsUsing TikTok, celebrities can aid in disseminating high-quality information regarding colonoscopy and other preventative medicine practices to young adults within the new social media landscape. Cases of young-onset colorectal cancer (CRC) have risen substantially over the last 20 years, and physicians are increasingly harnessing the influence of celebrities to raise awareness for CRC screening. Celebrity actors Ryan Reynolds and Rob McElhenney filmed their experiences undergoing colonoscopy as part of an initiative to raise awareness for CRC screening. Herein, we assess the quality of information on TikTok regarding colonoscopies and evaluate the effect of this celebrity endorsement. Hashtags encompassing colonoscopy were searched using TikTok’s algorithm, and 75 videos were considered. The DISCERN questionnaire and analytics were used to quantify the quality and popularity of each video. Colonoscopy-related videos were higher in quality (P < .01) and popularity (P < .05) after the celebrity Reynolds–McElhenney endorsement compared with those released before. After the endorsement, the difference between the quality of the content created by physicians and nonphysicians was eliminated. Using TikTok, celebrities can aid in disseminating high-quality information regarding colonoscopy and other preventative medicine practices to young adults within the new social media landscape.

Differences in tumor-associated T cell receptor repertoires between young-onset and average-onset colorectal cancer.

207 Background: The incidence of colorectal cancer (CRC) among individuals younger than age 50 (young-onset CRC; YOCRC) has increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. Some studies suggest that YOCRCs have more aggressive biology. Here, we compare tumor-associated T cell repertoires between patients with YOCRC and average-onset CRC (AOCRC). A robust, focused T cell response is a positive prognostic indicator; therefore, we hypothesized that YOCRCs demonstrate lower T cell abundance and greater T cell diversity than AOCRCs. Methods: The discovery cohort included 242 patients with histologically confirmed Stage I-IV CRC who underwent surgical resection at Cleveland Clinic from 2000 to 2020 and consented to a biorepository. YOCRC was defined as &lt; 50 years at diagnosis (N = 126), and AOCRC as &gt; 60 years (N = 116). DNA was extracted from frozen tumors, and T Cell Receptor (TCR) abundance and clonality were measured using immunoSEQ (Adaptive Biotechnologies). Following quality control, logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 YOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study with adjustment for sex, Jewish ethnicity, tumor location, and stage. Results: YOCRC patients were more likely to have left-sided tumors and be diagnosed at advanced stages in both cohorts. In the discovery cohort, YOCRC tumors had significantly lower TCR clonality (higher T cell diversity) compared to AOCRC tumors in a multivariable model adjusting for sex, race, tumor location and stage (OR: 0.38, 95% Confidence Interval (CI): 0.25-0.56, p &lt; 0.0001). This association was also observed in the replication cohort (OR: 0.74, 95% CI: 0.62-0.89, p = 0.0013). In the replication cohort, further adjustment for microsatellite instability status did not substantially change the association (OR: 0.73, 95% CI: 0.61-0.88 p = 0.0012). When restricting to microsatellite stable tumors, clonality remained statistically significant in both the discovery and replication cohorts. No significant difference in TCR abundance was observed between YOCRC and AOCRC in either cohort. Conclusions: Higher T cell repertoire diversity, indicating a less focused intratumoral T cell response, is more frequently observed in YOCRC. Further studies are warranted to investigate the role of T cell diversity in the etiology and outcomes of YOCRC.

Exploring demographic differences and outcomes in young-onset colorectal cancer.

35 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States (1). The incidence of young-onset CRC is on the rise based on recent data (2). Previous research on other cancers has shown that patients living in rural areas have worse outcomes (3). This study aimed to investigate the geographic and socio-demographic disparities in young-onset CRC patients. Methods: We conducted a retrospective study on colorectal cancer patients between 1975 and 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariable analyses were performed to evaluate overall survival (OS) and disease-specific survival (DSS). Socio-demographic factors, including the location of residence [metro area (MA) or rural area (RA)], gender, race, insurance status, and marital status, were analyzed. Young-onset colorectal cancer (CRC) was defined as the age of diagnosis less than 50 years. The program used for analysis was SAS software 9.4 (SAS Institute Inc., Cary, NC, USA.) Univariate and multivariable models were analyzed using Cox proportional models. Demographic differences between urban and rural population were assessed using Wilcoxon Rank Sum test (continuous variable) and Chi-square test (categorical variables). Results: A total of 73,378 [RA, N = 7,636(10.6%); MA, N = 64,605(89.4%)] young-onset CRC patients were included. RA had more Caucasian patients compared to MA (80.5% vs 60%, p &lt; 0.001). Patients living in RA were more likely to be uninsured (4.8% vs 3%, p &lt; 0.001) than MA. During the study period, the incidence and mortality rates were consistently higher in RA vs. MA. Univariate and multivariable analysis showed that RA had worse OS (multivariate HR = 1.14; p &lt; 0.01) and DSS (multivariate HR = 1.15; p &lt; 0.001) compared to MA. Similarly, males, single and uninsured patients had worse OS and DSS compared to females, married, and insured patients, respectively. Conclusions: Our study identified social and demographic disparities in young-onset CRC incidence and outcomes. Potential causes may include access to healthcare, diet, health behavior, and environmental factors. Future research is needed to understand and attenuate such disparities.

Racial disparities in tumor microbiome in young-onset and average-onset colorectal cancer.

13 Background: The occurrence of young-onset colorectal cancer (yoCRC) is rising alarmingly, with a disproportionate incidence in Black patients as compared to White. We and others have previously shown differences in tumor microbiomes between yoCRC and average-onset colorectal cancer (aoCRC), but it is unknown if these differences contribute to racial disparities. We therefore analyzed racial differences in the intra-tumoral microbiome of CRC in young adults (&lt;50 years). Methods: We analyzed 277 samples of histologically confirmed cases of stage I-IV CRC patients identified as either non-Hispanic Black or non-Hispanic White, who underwent surgical resection at Cleveland Clinic from year 2000-2020, who consented to a prospective biorepository. Fresh frozen specimens from the primary tumor with paired adjacent nonmalignant tissue were analyzed. The 16s rRNA gene was amplified and sequenced using V4 region primers and Illumina’s MiSeq system. Using DADA2, the quality filtered 16S rRNA amplicon reads were clustered and annotated as amplicon sequence variants (ASVs). The abundance count matrix was analyzed for alpha and beta diversity and differential abundance analysis (DAA) using Phyloseq package. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression and Wilcoxon test. DAA and correlation analysis were controlled for false discovery rate using Benjamini Hochberg correction. Results: Differential abundance analysis highlighted key differences in the microbiome composition of Black and White patients with yoCRC. Amongst Black patients, the most prevalent taxa were Limosilactobacillus, Bacillus, Staphylococcus, Listeria and Akkermansia, whereas amongst White patients the most prevalent taxa were Enterococcus and Escherichia-Shigella (Table). Microbial profiles were also significantly different between Black patients with yoCRC and aoCRC and between White patients with yoCRC and aoCRC. At ASV level, the microbiome of Black yoCRC is more similar (R2 =0.87) to Black aoCRC, in comparison to white yoCRC (R2=0.57). Conclusions: We found significant differences between the intra-tumoral microbiome of yoCRC in the United States by race. Future epidemiologic studies and public health interventions need to account for these differences to reduce risk of yoCRC across various US populations. [Table: see text]

Internet-based assessment tools for predicting colorectal cancer risk: How do they communicate individualized risk to the young adult?

72 Background: Online prediction tools for cancer risk can inform individuals about their risk and potentially encourage adoption of risk-modifying health behavior. The Colorectal Cancer Risk Assessment Tool (CCRAT) is an interactive tool developed by the National Cancer Institute for estimating colorectal cancer (CRC) risk for individuals between the ages of 45 and 85 without high risk predisposing conditions. Given the rising incidence of CRC among young adults under age 50, we aimed to investigate the performance of CCRAT in estimating their CRC risk. Methods: An institutional protocol prospectively enrolled 563 patients newly diagnosed with non-hereditary CRC and administered a health behavior questionnaire at baseline. Self-reported demographics, diet and physical activity, medication use, and family history were extracted and entered into the CCRAT ( https://ccrisktool.cancer.gov/calculator.html ) to calculate their predicted 5-year and lifetime CRC risks. Health behaviors and the predicted CRC risks in reference to the population average were compared among three groups: youngest- (aged 18-44, N = 276, 49%), young- (aged 45-50, N = 178, 32%), and older-onset (aged &gt; 50, N = 109; 19%). Results: The patient groups did not significantly differ in gender or in family history of CRC, but the youngest group had significantly more non-White patients (27, 22, vs. 19%; p = 0.008) and distal tumors (80, 76 and 65%; p = 0.05). The youngest and young groups had a higher prevalence of morbid obesity (18 and 15% vs. 12%; p = 0.002) and active smokers (6 and 8% vs. 3%; p = 0.005). There were no significant differences in vegetable intake, moderate exercise, NSAID use, or female hormone use. The 5-year CRC risk was correctly predicted as “higher than average population” for a significantly smaller proportion of the youngest (42%) and young (45%) patients, when compared to their older counterpart (71%; p &lt; 0.001). Similarly, the tool communicated “higher than average” lifetime risk for CRC in only 56 and 60% of the youngest and young patients, but 72% of the older ones (p = 0.021). Conclusions: The existing risk prediction tool inadequately communicated CRC risk for adults younger than 50 years of age. Risk factors underlying young-onset CRC likely differ from and extend beyond those as currently assessed. New tools capturing age-specific risk factors are needed to accurately communicate individualized risk and potentially motivate risk-modifying lifestyles.

Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.

174 Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age&lt;50 years (yoCRC or young controls) or age&gt;60 years (aoCRC or older controls). Serum metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p&lt;0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p=0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p=0.11), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p=0.03), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p=0.04, arginine biosynthesis, FDR p=0.04, and amino-acid t-RNA biosynthesis, FDR p=0.04). There were no significant metabolomic differences between young and older controls. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism and associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. The study provides future directions for more precise analyses with a larger sample size for healthy controls and adjusting for confounders. [Table: see text]

Updated epidemiology of gastrointestinal cancers in East Asia.

Globally, gastrointestinal cancers represent more than one-fourth of all cancer incidence and one-third of cancer-related mortality. Although there has been much progress in screening colorectal cancer, the prognosis of other gastrointestinal cancers tends to be poor. The highest burden of gastrointestinal cancers, including stomach, liver, oesophageal and gallbladder cancers, was observed in regions in East Asia. The increasing burden of gastrointestinal cancers in East Asian regions is related to population growth, ageing and the westernization of lifestyle habits in this region. Furthermore, the rising incidence of young-onset colorectal cancer is an emerging trend in East Asia. This Review provides a comprehensive and updated summary of the epidemiology of gastrointestinal cancers in East Asia, with emphasis on comparing their epidemiology in East Asia with that in Western regions, and highlights the major risk factors and implications for prevention. Overall, to optimally reduce the disease burden incurred by gastrointestinal cancers in East Asian regions, a concerted effort will be needed to modify unhealthy lifestyles, promote vaccination against the hepatitis virus, control Helicobacter pylori, liver fluke and hepatitis virus infections, increase the uptake rate of colorectal cancer screening, enhance detection of early cancers and their precursors, and improve cancer survivorship through an organized rehabilitation programme.

Single-Cell RNA Sequencing Reveals Heterogeneity in the Tumor Microenvironment between Young-Onset and Old-Onset Colorectal Cancer.

The incidence of sporadic young-onset colorectal cancer (yCRC) is increasing. Compared with old-onset colorectal cancer (oCRC), yCRC has different clinical and molecular characteristics. However, the difference in the tumor microenvironment (TME) between yCRC and oCRC remains unclear. Fourteen untreated CRC tumor samples were subjected to single-cell RNA sequencing analysis. B cells and naïve T cells are enriched in yCRC, while effector T cells and plasma cells are enriched in oCRC. Effector T cells of yCRC show decreased interferon-gamma response and proliferative activity; meanwhile, Treg cells in yCRC show stronger oxidative phosphorylation and TGF-β signaling than that in oCRC. The down-regulated immune response of T cells in yCRC may be regulated by immune and malignant cells, as we observed a downregulation of antigen presentation and immune activations in B cells, dendritic cells, and macrophages. Finally, we identified malignant cells in yCRC and oCRC with high heterogeneity and revealed their interactions with immune cells in the TME. Our data reveal significant differences of TME between yCRC and oCRC, of which the TME of yCRC is more immunosuppressive than oCRC. Malignant cells play an essential role in the formation of the suppressive tumor immune microenvironment.

Abstract IA006: The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes

Abstract Blacks have a higher incidence of colorectal cancer (CRC) and worse survival rates when compared to Whites. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer MSI-H tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations specifically KRAS G12D and KRAS G13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, RET). In patients with young onset CRC (&amp;lt;50 years), AFR and EUR had similar frequency of MSI-H and TMB-H tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of our diverse US population. Further studies are needed to investigate the role of colon polyps and the effect of genomics, ancestry and social determinants of health on CRC incidence and outcomes. Citation Format: Parvathi A. Myer. The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA006.

Clinical features of young onset colorectal cancer patients from a large cohort at a single cancer center.

The aim of this study is to describe the demographics and clinical features of patients with young onset (YO) CRC. A retrospective review of patients with CRC diagnosed between ages 20 and 49years was evaluated at the Memorial Sloan Kettering Cancer Center from 1/2004 to 6/2019. We excluded those with a hereditary CRC syndrome, inflammatory bowel disease, or prior CRC diagnosis. Patient demographics; presenting symptoms; medical, surgical, and smoking history; family history of cancer; tumor characteristics; and pathology were obtained from the electronic medical record. We identified 3856 YO CRC patients (median age CRC diagnosis 43; 52.5% male). A total of 59.1% were overweight or obese (32.2% and 26.9%, respectively). Most (90.1%) had no family history of CRC in a first-degree relative; 56.3% of patients reported being never smokers; 5.2% had diabetes. The most common presenting symptoms were rectal bleeding (47.7%), abdominal pain/bloating (33.1%), and change in bowel habits (24.7%). The majority presented with left-sided cancers (77.3%), at late-stage disease (68.4% at stages 3 or 4). Most YO CRC patients presented with rectal bleeding or abdominal pain, left-sided cancers, and later-stage disease and had no family history of CRC in a first-degree relative. Over half were overweight and obese and were more likely to have never smoked. More data are needed to better understand YO CRC risk factors and to help identify high-risk populations who may benefit from earlier screening.

S244 An Appraisal of the Referral, Uptake and Outcomes of Genetic Counseling and Testing in Patients With Young Onset Colorectal Cancer

Introduction: The incidence of young-onset colorectal cancer (YOCRC) defined as CRC in individuals < 50 years of age is rapidly rising. Germline genetic testing is currently recommended for all patients with CRC< 50 years. Germline pathogenic variants (PV) are detected in 16-20% of patients with YOCRC and many are diagnosed with an actionable PV not typically associated with CRC, highlighting a need for genetic counseling and multi-panel gene testing (MGPT) in these patients. We aimed to determine the rate of referral to genetic counseling, and uptake and outcomes of germline testing in YOCRC patients seen at a tertiary referral center. Methods: Patients diagnosed with YOCRC from 2010-2019 were included. Patients with appendiceal cancer, known family history of a hereditary cancer syndrome and inflammatory bowel disease were excluded. Demographic data including age, sex, race and family history of CRC were extracted from the electronic medical record (EMR).Genetic counseling referral was confirmed through an order in the EMR, clinical documentation in office visits with colorectal surgery, oncology or gastroenterology, or a completed visit with the genetic counselor. Data was analyzed using STATA, Chi-square and t-test and descriptive analyses were included. Results: 793 YOCRC patients (457 male and 336 female) were included. 56% (445) were referred for genetic counseling and 88% of referred patients completed genetic testing. 20.5% had a PV detected; 83% were in CRC associated genes and 18% were in other actionable genes (Table). Referral to genetic counseling was higher in younger patients (mean age= 40 years in those referred vs. mean age= 43 years in those not referred, p < 0.05) and those with a family history of CRC (70% of patients with family history of CRC vs. 53% of patients without family history were referred, p< 0.05) There was no significant association between referral rate and sex or race. Conclusion: Even in a large academic center, the rates of referrals for genetic counseling in patients with YOCRC were documented in only about half the patients. 1 in 5 YOCRC patients had a PV detected. If the 348 patients not referred to genetic counseling underwent testing, an additional 71 patients may be detected with a germline PV. Our findings highlight the need to raise awareness of the importance of genetic counseling and testing in YOCRC patients, and suggest that health systems should consider implementing care pathways to mitigate the potential impact of under-referral. Table 1. - Demographics, Referral to and Uptake of Genetic Counseling and Testing and Outcome of Genetic Testing Number of patients with YOCRC 793 Demographics N (%) Mean (SD) Age 41.9 (6.8) Sex Male 457 (57.6) Female 336 (42.4) Race White 684 (86.3) Black 72 (9.1) Other 37 (4.7) Family History of CRC Yes 280 (40.2) No 417 (59.8) Referral for Genetic Counseling 445 (56.1) Attended Genetic Counseling 390 (87.6) Underwent Genetic Testing 376 (96.4) • Pathogenic Variant Detected 77 (20.5) • Variant of Uncertain Significance Detected 88 (23.4) • No Variant Detected 211 (56.1) Genetic Testing Outcomes Genetic Syndrome Pathogenic Variant Number of Patients Total (%) CRC and polyposis genes N=64 (83%) Lynch syndrome N=37 (48%) MLH1 11 37 (48) MSH2 13 MSH6 8 PMS2 5 FAP N= 15 (19.4%) APC 15 15 (19.4) MYH- Associated polyposis N =10 (12.9%) MUTYH (Biallelic) 6 10 (12.9) MUTYH (Monoallelic) 4 Juvenile polyposis syndrome N = 1 (1.2%) SMAD4 1 1 (1.2) MSH3 (monoallelic) 1 1 (1.2) Other genes N=13 (17%) ATM 4 13 (17) BRCA1/2 4 BLM (monoallelic) 1 CHEK2 2 FLCN 1 CDKN2A 1

Metagenomic analysis of the fecal microbiome in colorectal cancer patients compared to healthy controls as a function of age.

Colorectal cancer (CRC) incidence is increasing in young patients without a clear etiology. Emerging data have implicated the fecal microbiome in CRC carcinogenesis. However, its impact on young onset CRC is poorly defined. We performed a meta-analysis of fecal metagenomics sequencing data from n= 692 patients with CRC and n= 602 healthy controls from eleven studies to evaluate features of the fecal metagenome associated with CRC. We hypothesized that known carcinogenic virulence factors (colibactin, fadA) and species abundance may be differentially enriched in young CRC patients relative to older CRC patients and controls. Summary odds ratios (OR) for CRC were increased with the presence of colibactin (OR 1.92 95% CI 1.08-3.38), fadA (OR 4.57 95% CI 1.63-12.85), and F. nucleatum (OR 6.93 95% CI 3.01-15.96) in meta-analysis models adjusted for age, gender, and body mass index. The OR for CRC for the presence of E.coli was 2.02 (0.92-4.45). An increase in the prevalence of Fusobacterium nucleatum (OR=1.40 [1.18; 1.65]) and Escherichia coli (OR=1.14 [1.02; 1.28]) per 10-year increase in age was observed in models including samples from both CRC and healthy controls. Species relative abundance was differentially enriched in young CRC patients for five species-Intestinimonas butyriciproducens, Holdemania filiformis, Firimicutues bacterium CAG 83, Bilophilia wadsworthia, and Alistipes putredinis. In this study, we observed strong associations with CRC status for colibactin, fadA, and Fusobacterium nucleatum with CRC relative to controls. In addition, we identified several microbial species differentially enriched in young colorectal cancer patients. Studies targeting the young CRC patients are warranted to elucidate underlying preclinical mechanisms.

Dysbiosis of human tumor microbiome and aberrant residence of Actinomyces in tumor-associated fibroblasts in young-onset colorectal cancer.

Colorectal cancer (CRC) is the third most common form of cancer, and the incidence of sporadic young-onset colorectal cancer (yCRC) has been increasing. Microbiota residing in the tumor microenvironment are emerging tumor components. The colonic microbiome differs between patients with CRC and healthy controls; however, few studies have investigated the role of the tumor microbiota in disease diagnosis and tumorigenesis of yCRC. We performed 16S rRNA sequencing analysis to identify the microbiome in CRC and found that tumor microbial diversity decreased in yCRC. Proteobacteria and Firmicutes were the most abundant phyla in all CRC samples, and Actinomyces and Schaalia cardiffensis were the key microbiota in the yCRC group. Correlation analysis revealed that Actinomyces co-occurred with various pro-tumor microbial taxa, including Bacteroidia, Gammaproteobacteria, and Pseudomonas. An independent cohort was used to validate the results. The Actinomyces in CRC was co-localized with cancer-associated fibroblasts and activated the TLR2/NF-κB pathway and reduces CD8+ T lymphocyte infiltration in CRC microenvironment. This study suggests that tumoral microbiota plays an important role in promoting tumorigenesis and therefore has potential as a promising non-invasive tool and intervention target for anti-tumor therapy.

Patterns of Healthcare Utilization Leading to Diagnosis of Young-Onset Colorectal Cancer (yCRC): Population-Based Case-Control Study.

Simple SummaryThere is a rising incidence of colorectal cancer among young patients. We attempted to characterize how young colorectal cancer patients use the healthcare system prior to diagnosis to see if there is a potential window where we could diagnose patients earlier. We found that young colorectal cancer patients did not seem to present more frequently than healthy controls in the years leading up to their diagnosis, contrary to prior studies. Other interventions are needed to diagnose yCRC patients earlier.Background: The increasing risk of young-onset colorectal cancer (yCRC) in adults < 50 years has called for better understanding of patients’ pathways to diagnosis. This study evaluated patterns of healthcare utilization before diagnosis of yCRC. Methods: Using linked administrative health databases in British Columbia, Canada, we identified yCRC cases and cancer-free controls matched (1:10) on age, sex, and healthcare utilization. The index date was the date of diagnosis for yCRC cases and matched date for controls. Outpatient visits, emergency department visits, and hospitalizations over a 5-year prediagnosis period (e.g., year-1 to year-5) were compared using descriptive statistics and Poisson regression models. Results: The study included 2567 yCRC cases (49.6% females, 43.0 ± 5.8 years) and 25,455 controls (48.6% females, 43.0 ± 5.8 years). We observed an increasing number of outpatient visits from prediagnosis year-5 (median = 3) to year-1 (median = 8) for yCRC cases. Among controls, outpatient visits were stable and did not have a pattern of increase. Poisson regression models indicated higher adjusted count ratios for outpatient visits for yCRC cases compared to controls in the year before diagnosis (1.11; 95% CI, 1.07 to 1.15). In the year before diagnosis, 35.1% of yCRC cases had potentially related visits to CRC (e.g., nausea, vomiting) and 16.9% had potentially red flag visits (e.g., gastrointestinal hemorrhage or iron deficiency anemia). Conclusions: Using population-based data, we found that individuals with yCRC did not have higher healthcare utilization than individuals without in the prediagnosis period except for the year before diagnosis.

Direct medical costs of young-onset colorectal cancer: a worldwide systematic review

BackgroundGiven the rising incidence of young-onset colorectal cancer (yCRC) among individuals younger than 50 years old, understanding the economic burden of yCRC is required to inform the delivery of healthcare services. Therefore, we conducted a systematic review of studies assessing the direct medical costs of yCRC, and where relevant average-age onset CRC (aCRC).MethodsWe searched MEDLINE, EMBASE, and Web of Science from inception to May 2022 for original, peer-reviewed studies, that reported direct medical costs (e.g., chemotherapy, radiotherapy, outpatient visits, inpatient care, prescription medications) for yCRC and aCRC. We used a modified version of the Consolidated Health Economic Evaluation Reporting Standards checklist to appraise the studies. Costs were inflation-adjusted to 2020 US dollars.ResultsWe included 14 studies from 10 countries, including the USA, England, France, Korea, Vietnam, China, Italy, Australia, Canada and Japan. Five studies focused on prevalent disease and reported annualized per-capita cost of prevalent yCRC, ranging from $2,263 to $16,801 and $1,412 to $14,997 among yCRC and aCRC cases, respectively. Nine studies estimated the cost of incident disease. Synthesis of per-capita costs incurred 12 months following colorectal cancer diagnosis ranged from $23,368 to $89,945 for yCRC and $19,929 to $67,195 for aCRC. Five studies used multivariable approaches to compare costs associated with yCRC and aCRC, four showed no differences and one suggested greater costs with yCRC.ConclusionOur synthesis of direct medical costs of yCRC across multiple jurisdictions provide relevant information for healthcare decisions, including on-going considerations for expanding CRC screening strategies to younger adults.

Clinically Significant Metachronous Colorectal Pathology Detected Among Young-Onset Colorectal Cancer Survivors: Implications for Post-Resection Surveillance Guidelines

The incidence of colorectal cancer (CRC) has been increasing worldwide among young adults aged 18–50 years, and the reason remains unknown.1,2 Patients with sporadic young-onset CRC (YOCRC; diagnosed at 50 years or younger) are postulated to have a more biologically active colorectum prone to malignant transformation earlier in life. Exposure risk factors, such as Western-style diet, obesity, physical inactivity, antibiotic use, and microbiome, overlaid with gene–environment interactions, have been implicated as plausible triggers.

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer.

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.

Favorable Survival After Screening for Young-Onset Colorectal Cancer: Benefits of Screening in Young Adults.

The increasing incidence and mortality of young-onset colorectal cancer has drawn increasing attention. However, screening for young adults is controversial given the limited evidence regarding its effectiveness. We aimed to clarify the characteristics of young-onset colorectal cancer and to compare long-term outcomes of screening-detected colorectal cancer and non-screening-detected colorectal cancer. This was a retrospective cohort study. This study evaluated data from a colorectal cancer registry and medical records at a tertiary Japanese cancer center. All patients with colorectal cancer who were registered at a Japanese tertiary cancer center between January 2007 and December 2016 were included. The colorectal cancer cases were categorized as screening-detected colorectal cancer and non-screening-detected colorectal cancer, and patients were categorized into 3 age groups: <50 years (young-onset), 50 to 75 years, and >75 years. The baseline characteristics and survival outcomes of the groups were compared using Cox regression models. A total of 4345 patients were identified, with a median follow-up of 4.6 years. Relative to 50- to 75-year-old individuals, young-onset colorectal cancer was linked to a higher proportion of rectal cancer (50.4% vs 43.3%), a lower proportion of screening-detected colorectal cancer (29.4% vs 35.8%), a lower proportion of stage I colorectal cancer (15.2% vs 30.3%), and a higher proportion of stage III to IV colorectal cancer (64.0% vs 49.4%). Among patients who were <50 years old, screening-detected colorectal cancer was associated with a 50% lower risk of mortality relative to non-screening-detected colorectal cancer (HR, 0.50; 95% CI, 0.26-0.95). The findings were limited by the retrospective analysis from a single center. Young-onset colorectal cancer was more likely to present at an advanced stage and had a lower rate of screening-detected colorectal cancer. Nevertheless, young-onset screening-detected colorectal cancer was associated with better overall survival than non-screening-detected colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B829 . ANTECEDENTES:La creciente incidencia y mortalidad del cáncer colorrectal en paciente joven ha atraído una atención cada vez mayor. Sin embargo, el cribado para adultos jóvenes es controvertido, dado la evidencia limitada con respecto a su efectividad.OBJETIVO:Nuestro objetivo fue identificar las características del cáncer colorrectal en paciente joven y comparar los resultados a largo plazo del cáncer colorrectal detectado por cribado y el cáncer colorrectal no detectado por cribado.DISEÑO:Este fue un estudio de cohorte retrospectivo.ESCENARIO:Este estudio evaluó datos de un registro de cáncer colorrectal y registros médicos en un centro oncológico terciario japonés.PACIENTES:Se incluyeron todos los pacientes con cáncer colorrectal registrados en un centro oncológico terciario japonés entre enero de 2007 y diciembre de 2016.PRINCIPALES MEDIDAS DE RESULTADO:Los casos de cáncer colorrectal se categorizaron como cáncer colorrectal detectado mediante cribado y cáncer colorrectal no detectado mediante cribado, y los pacientes se clasificaron en tres grupos de edad: <50 años (joven), 50-75 años y >75 años. Las características basales y los resultados de supervivencia de los grupos se compararon mediante modelos de regresión de Cox.RESULTADOS:Se identificaron un total de 4345 pacientes, con una mediana de seguimiento de 4,6 años. En relación con las personas de 50 a 75 años, el cáncer colorrectal de inicio en la juventud se relacionó con una mayor proporción de cáncer de recto (50,4% frente a 43,3%), una menor proporción de cáncer colorrectal detectado mediante exámenes de cribado (29,4% frente a 35,8%), una menor proporción de cáncer colorrectal en estadio I (15,2% frente a 30,3%) y una mayor proporción de cáncer colorrectal en estadio III-IV (64,0% frente a 49,4%). Entre los pacientes menores de 50 años, el cáncer colorrectal detectado mediante cribado se asoció con un 50% menos de riesgo de mortalidad, en comparación con el cáncer colorrectal no detectado mediante cribado (HR: 0,50; IC 95%: 0,26-0,95).LIMITACIONES:Los hallazgos fueron limitados por el análisis retrospectivo de un solo centro.CONCLUSIONES:El cáncer colorrectal en paciente joven presenta más probabilidades de presentarse en una etapa avanzada y con una tasa más baja de detección mediante cribado. No obstante, el cáncer colorrectal detectado por cribado de aparición temprana se asoció con una mejor supervivencia general que el cáncer colorrectal no detectado por cribado. Consulte Video Resumen en http://links.lww.com/DCR/B829 . (Traducción-Dr. Felipe Bellolio ).

Young-Onset Colorectal Cancer in Serbia: Tertiary Cancer Center Experience.

Purpose: Early-onset colorectal cancer (CRC) is a growing problem. The aim of the study was to identify adolescent and young adult (AYA) patients with CRC in Serbia, treated in the single tertiary cancer center. Materials and Methods: This is a retrospective study that included only AYA patients (ages 18-39 years) with histologically confirmed CRC. In 11 year (2009-2019), 109 patients were identified from a single-institution database and their clinical variables and outcomes were analyzed. Results: The prevalence of a positive family history of CRC was 12.8%. Presenting symptoms were not different than traditional CRC. More than a quarter were diagnosed as an emergency. Left-sided tumors were diagnosed in 83.4% and mucinous tumors were recorded in one-third of the patients. Postoperatively patients mainly were in PS0-1 (97%). Patients presented as stages II (18.3%), III (47.7%), and IV (33.9%). The recurrence rate in local stages was 50%. Surgical treatment of localized metastatic disease was performed in almost half of the stage IV patients. Median disease-free survival for patients with the recurrent disease was 11.8 months. Median overall survival (OS) for the local and metastatic stage was 64.3 and 20.5 months, respectively. Survival analysis showed that performance status, bowel obstruction, N2 status, local invasions, disease stage, and surgery in stage IV had a statistically significant influence on OS. Conclusion: Serbian AYA CRC patients are of good general condition, with advanced left-sided tumors, common mucinous histology, and inverse histology features. Surgery in metastatic disease provided long-term survival. The outcome of the patient is influenced by a late diagnosis, inverse histological features, and treatment provided.