Five-Year Survival Prognosis of Early-Onset and Later-Onset Colorectal Cancer by Clinical and Lifestyle Characteristics.

282 Background: Approximately 50% of patients with colorectal cancer develop liver metastases (CRLM). The incidence of early onset colorectal cancer (EOCRC), defined as <50 years of age at time of diagnosis, is increasing. In this study, we aim to explore the prognosis of early vs late onset colorectal cancer patients with CRLM who receive curative-intent treatment. Methods: A retrospective study was conducted to assess clinical outcomes in patients with CRLM presenting with EOCRC compared to those with late onset colorectal cancer (LOCRC). All patients underwent surgical resection and/or ablation between 2009 and 2024 at a tertiary care center. Groups were defined by patient age at the time of diagnosis of the primary tumor < 50 years versus ≥ 50 years. Demographics, tumor characteristics, and treatment modalities were compared between groups using Chi-square, independent samples t-test, and median test. Survival outcomes were assessed using Kaplan-Meier. Results: 342 patients met inclusion criteria. There were 85 (24.9%) EOCRC patients, with a median age at diagnosis of 44 years versus 63 years in the LOCRC group. EOCRC patients had fewer major medical comorbidities. EOCRC patients had a smaller proportion of right-sided (15.9% vs 29.6%, P=0.049) tumors. Rates of synchronous metastases (74.1% in EOCRC vs 72.4%, P=0.781), median size (28cm in EOCRC vs 25cm, P=0.421) median number of metastases (2 in EOCRC vs 2, P=0.385), and initial CEA levels (339.18 + 1276.48 ng/ml vs 328.87 + 2520.59 ng/ml, P=0.482) were similar between groups. However, EOCRC patients had higher rates of node-positive disease (75.6% vs 58.8%, P=0.010) and Fong Clinical Risk Scores 3-5 (57.0% vs 39.7%, P=0.009). Both groups underwent similar operative management with no differences in morbidity, but more EOCRC patients received neoadjuvant therapy (82.4% vs 66.1%, P=0.017). There were no significant differences in RAS/RAF (37.6% in EOCRC vs 34.2%, P=0.669) or TP53 (25.9% vs 34.6%, P=0.98) mutational status or microsatellite instability (stable in 74.1% in EOCRC vs 69.3%, P=0.523). Both intra- (46.5% in EOCRC vs 50.6%, P=0.535) and extra-hepatic (47.7% in EOCRC vs 38.1%, P=0.129) recurrences occurred at similar rates, with no significant differences in post-recurrence treatments received. Patients with CRLM and EOCRC had significantly worse overall survival, with a median time of 80 months versus 116 months (P=0.042). Conclusions: Despite similar clinical, pathologic, and genetic features, fewer medical comorbidities, and receiving similar medical and surgical treatments, EOCRC patients had worse median overall survival than LOCRC patients. High risk Fong Clinical Risk Scores were more common in the EOCRC group, who also received neoadjuvant therapy at higher rates. Additional research is needed to understand the differences in survival.

Purpose: Despite declines in the overall incidence and mortality of colorectal cancer (CRC), there have been increases in the incidence and mortality of CRC among those < 50 years old (early-onset CRC). Although the reasons for the increases in early-onset CRC are unknown, one hypothesis is that temporal changes in dietary patterns has led to changes in the consumption of foods that are associated with increased CRC risk, in particular red and processed meats. Thus, the purpose of our analyses was to evaluate differences in dietary factors between early-onset and late-onset CRC patients. Methods: We used the Puget Sound SEER cancer registry to identify a population-based sample of patients diagnosed with CRC from 4/1/2016 through 12/31/2018. CRC patients were recruited to the study via mail and telephone, and consented patients completed a questionnaire assessing patient demographics, medical history, and CRC risk factors, including diet. For dietary factors, we ascertained information on the average number of servings per week of fruits, vegetables, red meat, processed meat, and “spicy” foods two years prior to CRC diagnosis. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing dietary intake in early-onset vs. late-onset CRC. ORs were adjusted for sex, race/ethnicity, cigarette smoking history, diabetes, hyperlipidemia, and alcohol consumption. Results: There were 304 early-onset and 1,150 late-onset CRC patients in our analyses. Compared to late-onset patients, those with early-onset CRC were less likely to be current smokers or to have a history of diabetes or hyperlipidemia. After adjustment for these differences, compared to late-onset CRC, early-onset CRC patients had higher intake of red meat (OR for quartile 4 vs. quartile 1 = 1.49 CI: 1.02 - 2.17), processed meat (OR for quartile 4 vs. quartile 1 = 1.63 CI: 1.16 -2 .29), and spicy food (OR for quartile 4 vs. quartile 1 = 1.80 CI: 1.25 - 2.58). However, there was not a statistically significant difference between early- and late-onset CRC patients with regard to fruit (OR for quartile 4 vs. quartile 1 = 1.07 CI: 0.73 - 1.57) or vegetable (OR for quartile 4 vs. quartile 1 = 0.87 CI: 0.62 - 1.22) consumption. Conclusion: Our results suggest that dietary patterns differ between early- and late-onset CRC patients; in particular, early-onset CRC patients had higher intake of red meat, processed meat, and spicy food. This may reflect differences is dietary patterns by age; additional research with population-based controls is needed to determine the association between diet and early-onset colorectal cancer. Citation Format: Andrea N. Burnett-Hartman, Mimi (Trucmai) Ton, Chad (Qianchuan) He, Rachel C. Malen, Amanda I. Phipps, Julia D. Labadie, Heather Spencer Feigelson, Polly A. Newcomb. A comparison of dietary factors between early-onset and late-onset colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-161.

The incidence of early-onset colorectal cancer (EOCRC) is rapidly increasing worldwide in decade when screening of colorectal cancer (CRC) is more prevalent. The clinicopathological and molecular characteristics of EOCRC have not yet been clarified. This study aims to evaluate clinicopathological and molecular features among EOCRC and late-onset colorectal cancer (LOCRC) patients according to different tumor locations. We identified CRC patients from a prospectively maintained CRC database between January 2015 and December 2018. The clinicopathological and molecular characteristics including dMMR, mutation of PIK3CA, BRAF and KRAS were compared between EOCRC and LOCRC. The relationships according to different tumor locations were assessed. Totally 4468 patients were analyzed in this study. Compared to LOCRC patients, EOCRC patients were more likely to have status of dMMR (OR, 2.52; P < 0.001), regardless of tumor location. EOCRC patients were more likely to be detected with mutation of PIK3CA (OR, 1.24; P = 0.041), which only tended to exist in the left-side colon (OR, 1.51; P = 0.06), but not in the right-side colon or rectum. No significant difference was found for BRAF or KRAS mutation, but mutation of KRAS was more frequently found in left-side colon (OR, 1.34; P = 0.04) among EOCRC patients. Status of dMMR, mutation of PIK3CA, BRAF and KRAS was different between EOCRC and LOCRC patients according to different tumor locations, which implied that EOCRC might be a unique subgroup of CRC patients. Further investigations of molecular and genetic differences should be performed to help define new diagnosing and therapeutical strategies for EOCRC patients.

Introduction: The incidence of colorectal cancer in the younger population (20-49) continues to rise at a rapid pace. EOCRC patients are potentially at risk for developing additional secondary malignancies. There is a lack of reported data in the EOCRC space. In this analysis, we seek to examine the incidence, trends, and outcomes of secondary malignancies in EOCRC patients. Methods: The surveillance, epidemiology, and end-result (SEER) database was utilized to assess and compare the incidence and factors associated with development of secondary malignancies among EOCRC patients. Patient characteristics were summarized by secondary cancer status and compared using the Pearson chi-square test. Further OS was assessed using Kaplan- -Meier methods and compared across groups using the log-rank test. Multivariable Logistic regression models using backward selection approach were used to evaluate the association between patient characteristics and risk of secondary cancers. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Of the 53,891 patients analyzed, 2578 (4.8%) patients with EOCRC developed a secondary malignancy in the SEER database from 2000-2019. The mean age for developing a secondary malignancy was 47.6 yo (median 48 yo; range 20-69). There was a higher likelihood of second cancers among men(56%), white patients (61.4%), those with stage II (25.5%). and III (32.8%) CRC. The patients who most commonly developed a secondary malignancy were in the age group 40-49(p &amp;lt;.001). Of the patients who developed a secondary malignancy, 1843 (71.5%) initially had a primary colon cancer compared to 920 (22.6%) having rectal cancer, with the remainder having a rectosigmoid cancer. Of the patients who developed secondary malignancies, a majority had received prior chemotherapy (58.5%), and a minority of patients received radiation therapy (20.6%) Patients who had a partner had a higher incidence of secondary malignancy (59.5%) and they were more likely to have resided in a metropolitan area compared to a nonmetropolitan area (86.6 versus 13.2% respectively). The most common sites of secondary malignancy were: an additional colorectal cancer (47.7%), followed by breast cancer (8.2%) urinary tract cancer (7.1%), thyroid cancer (7%) and prostate cancer (5%). Patients who developed a secondary cancer were found to have an improved disease specific survival (DSS) compared to those who did not develop a secondary malignancy (3 year mDSS 89% vs 74%; p &amp;lt;.001)The overall survival of patients who developed a secondary malignancy was worse than those who did not develop one (mOS 208 months vs 229 mos respectively). Conclusion: EOCRC patients are likely to develop secondary malignancies. Long-term screening should be recommended for these patients and integrated into their survivorship plans. Citation Format: Deepak Vadehra, Kristopher Attwood, Anthony George, Shailesh Advani, Sahithi Sonti, Sarbajit Mukherjee. Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients [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 7449.

Background: In 2024, colorectal cancer (CRC) emerged as the leading cause of cancer death in men under 50 and the second leading cause in women (referred to as early-onset CRC (EOCRC). The incidence of EOCRC is growing by 1.4% annually. Understanding the “multidimensional spectrum of toxicities”, including the effects of the disease, treatments, and emotional and physical experiences of CRC at a young age, along with the indirect impacts on family and work life, remains poorly understood. The ColoCare Study is dedicated to investigating the interconnected factors that drive these complex toxicities. The goal is to identify high-risk EOCRC patients who could benefit from targeted strategies to improve their physical health, socioeconomic status, and overall quality of life during and after treatment. Methods: The ColoCare Study is an international, prospective cohort study including six U.S. sites and one site in Germany. Individuals ages 18 to 89 at diagnosis with newly diagnosed primary invasive CRC stage I-IV were enrolled (n=4,442 patients (1,238: age &amp;lt;50 y; 1,718: age 50-64 y; and 1,486: age 65+ y)). We collected longitudinal, repeated assessments of patient-reported symptoms, health-related quality of life, and financial health, in addition to blood-, stool-, and tumor-derived biomarkers, and linked these to medical records for clinicopathological characteristics, toxicities, comorbidities, recurrence, and vital status. Results: In our cohort, more than half of EOCRC patients face treatment-related adverse events (AEs) both during and after their treatment. Compared to older patients, those with EOCRC experience more severe symptoms such as nausea/vomiting, fatigue, pain, and sleep disturbances. Among female EOCRC patients, 72% discussed reproductive and fertility-related challenges with their clinicians, yet only 19% proceeded with fertility preservation. Alarmingly, only 13% of all patients had insurance coverage for fertility preservation. Furthermore, employment and financial stability pose significant challenges for working-age EOCRC patients. They report greater financial difficulties than those over 65 (p&amp;lt;0.001). Individuals aged 18–49 also reported more frequent challenges in mental and physical function compared to their older counterparts. Additionally, EOCRC patients experience higher rates of material and psychological hardships. Further analyses are ongoing. Conclusions: These findings highlight the need for more targeted clinical management for many early-onset colorectal cancer (EOCRC) patients, especially during the first year following diagnosis and into survivorship. Addressing specific concerns related to ongoing toxicities—such as physical, socioeconomic, and emotional issues—could greatly benefit these patients. With approximately 1,000 EOCRC patients involved, the ColoCare Study is uniquely positioned to conduct research focused on EOCRC survivorship. Citation Format: Jane C. Figueiredo, Nicole C. Loroña, Anne Kirchoff, Karely V T. Van Thiel Berghuijs, Heydon Kaddas, Mary Playdon, Patricia A. Erickson, Maria F. Gomez, Sheetal Hardikar, Mmadili N. Ilozumba, Jennifer Ose, Victoria Damerell, Vaia Florou, Mark A. Lewis, Shannon Christy, William M. Grady, Biljana Gigic, Doratha A. Byrd, Adetunji Toriola, Christopher I. Li, David Shibata, Cornelia M. Ulrich. Multidimensional assessment of toxicities and survivorship among people with early-onset colorectal cancer – Results from the ColoCare Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR015.

e15711 Background: The incidence of early-onset colorectal cancer (EOCRC) is rising, but little is known about the immune microenvironment. Our prior work has shown altered transcriptomic signatures in EOCRC patients compared to their average-age counterparts, particularly the downregulation of certain immune checkpoint inhibitor pathways in EOCRC. In this analysis, we seek to elucidate the expression of common immunotherapy targets in EOCRC patients (younger than 50 years old at diagnosis) compared to average onset colorectal cancer (AOCRC) patients (defined as 50 years or older at diagnosis). We also seek to compare the immune cell composition between EOCRC and AOCRC tumor microenvironments. Methods: We queried The Cancer Genome Atlas ( TCGA ) CRC dataset. Patients were separated into younger and older populations. Participant transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), with particular attention to common immunotherapy targets (TNFRSF9/4-1BB, LAG3, CD40, CD 276/B7-H3, PD-L1, PD-L2, CD70, TIM-3, CD27, CTLA4, ICOS, TIGIT, BTLA, OX40, GITR, and CD47). The proportions of different cell populations were estimated using the cell fraction analysis module from CIBERSORT. The Wilcoxon signed-rank test was used for the group comparison with significance set at p≤0.05. Results: Across the TCGA database, we assessed a total of 397 patient samples (n = 349 AO n = 48 EO). Amongst the patients in the database, BTLA expression was increased in EOCRC patients (p = 0.01). CD47 expression was noted to be less in the EOCRC cohort (p = 0.03). While looking at the immune cell composition, M1 macrophages were found to be less abundant in the EOCRC cohort, however this was not statistically significant. Other differences in immune cell composition were also noted in this analysis, however they lacked statistical significance. Conclusions: Our analysis shows differential expression of common immunotherapy targets between EOCRC and AOCRC patients in the TCGA database. Available data suggests decreased CD 47 expression may lead to decreased immune cell infiltration which may cause a decreased anti-tumor immune response in EOCRC patients. In addition, available data suggests BTLA expression can inhibit the function of CD8 cancer specific T cells further contributing to decreased immune function and suggesting potential decreased immunotherapy response. The present analysis complements our previous work, suggesting that EOCRC patients may have an altered immune environment which may lead to decreased response to immunotherapy compared to AOCRC patients. Further studies are needed to confirm our hypothesis.

Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients. Methods: We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3412 patients were included in the study, comprising 302 H/L patients and 3110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer-LOCRC: ≥50 years) and ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW EOCRC patients. Results: Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%, p = 0.01), ACVR1 (2.9% vs. 0%, p = 0.04), and MAP2K1 (3.6% vs. 0%, p = 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%, p = 9.1 × 10-4) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%, p = 0.03), MAPK3 (3.6% vs. 0.7%, p = 6.83 × 10-3), NF1 (11.6% vs. 6.1%, p = 0.02), and PDGFRB (5.8% vs. 2.1%, p = 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway alterations may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response. Conclusions: These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnicity-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific alterations. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients.

Background/Objectives:Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients.Methods:We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3,412 patients were included in the study, comprising 302 H/L patients and 3,110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer –LOCRC: ≥50 years) and ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW EOCRC patients.Results:Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%, p = 0.01), ACVR1 (2.9% vs. 0%, p = 0.04), and MAP2K1 (3.6% vs. 0%, p = 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%, p = 9.1e-4) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%, p = 0.03), MAPK3 (3.6% vs. 0.7%, p = 6.83e-3), NF1 (11.6% vs. 6.1%, p = 0.02), and PDGFRB (5.8% vs. 2.1%, p = 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway disruptions may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response.Conclusions:These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnic-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific disruptions. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients.

Our objective was to describe differences in treatment patterns and survival between early-onset (< 50years old) and late-onset colorectal cancer (CRC) patients in community-based health systems. We used tumor registry and electronic health record data to identify and characterize patients diagnosed with adenocarcinoma of the colon or rectum from 2010 to 2014 at six US health systems in the patient outcomes to advance learning (PORTAL) network. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset versus late-onset CRC. Cox regression models were used to estimate adjusted hazard ratios (HRs) and CIs comparing survival between early- and late-onset CRC patients. There were 1,424 early-onset and 10,810 late-onset CRC cases in our analyses. Compared to late-onset CRC, early-onset CRC was significantly associated with advanced-stage disease, high-grade histology, signet ring histology, and rectal or left colon location. After adjusting for differences in tumor and patient characteristics, early-onset patients were more likely than late-onset patients to have > 12 lymph nodes examined (OR 1.60, CI 1.37-1.87), to receive systemic therapy (chemotherapy or immunotherapy) within 6months of diagnosis (OR 2.84, CI 2.40-3.37), and to have a reduced risk of CRC-specific death (HR 0.66, CI 0.56-0.79). Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use. Despite some adverse risk factors, these patients tend to have better survival than older onset patients.

The proportion of early onset colorectal cancer (EOCRC) is alarming in adults, including in African Americans (AA). To investigate differences between EOCRC compared to late-onset colorectal cancer (LOCRC) among AA patients. This retrospective study reviewed demographic, clinical presentations, colonoscopy, and pathology reports of patients at Howard University Hospital from 1959 to 2023. The study included 176 EOCRC cases (< 45years) and 2034 LOCRC cases (> 45years). Both EOCRC and LOCRC groups were predominantly AA (> 80%) with slightly more females (53%) than males. The mean age was 38years for EOCRC and 66years for LOCRC cases. EOCRC cases increased as a proportion of total detected CRC cases since 2010 (over 13%) after several decades of just above 6%. Family history of CRC in first degree relatives was higher among EOCRC (15.5% vs.3.4% in LOCRC patients, p < 0.01). Symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). EOCRC patients exhibited higher incidence of abdominal pain (23.3% vs. 17.2%, p = 0.05) and changes in bowel habits (24.4% vs. 14%, p < 0.01) compared to LOCRC patients. Other symptoms such as melena, hematochezia, and weight loss were less prevalent in EOCRC patients. Comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent among EOCRC patients. EOCRC was primarily observed in the sigmoid and rectosigmoid regions (p = 0.02). Metastasis at index colonoscopy was more prevalent with EOCRC compared to LOCRC (p = 0.04), with a higher proportion of patients at stage 3 cancer (p < 0.05). Significant differences were noted in the timeline for undergoing surgery after the diagnosis of colorectal cancer, with EOCRC patients taking longer than LOCRC patients (p = 0.03). Presentation of EOCRC over LOCRC increased proportionally in our cohort since 2010 and is associated with family history, and symptoms such as abdominal pain and change in bowel habits. Likely because of age at presentation, there are less comorbidities among EOCRC patients who predominantly present in the outpatient setting, and more likely diagnosed with advanced stage lesions that are predominantly sigmoid or rectosigmoid. These findings are similar to observations seen in the general population with EOCRC, albeit African American patients have commonly had earlier age presentation of CRC than White American patients.

BackgroundThe incidence of colorectal cancer (CRC) in patients under age 50 is rising for unclear reasons. We examined the effects of socioeconomic factors on outcomes for patients with early‐onset CRC compared to late‐onset CRC.MethodsPatients with CRC from 2004 to 2015 in the National Cancer Database were included and categorized by age (under or over 50 years). Differences in demographic and socioeconomic factors, disease characteristics, and survival outcomes between early‐onset versus late‐onset CRC patients were assessed by Chi‐squared test and Cox models.ResultsThe study population included 1,061,204 patients, 108,058 (10.2%) of whom were under age 50. The proportion of patients diagnosed under age 50 increased over time: 9.4% in 2004–2006, 10.1% in 2007–2009, 10.5% in 2010–2012, and 10.7% in 2013–2015 (p < 0.0001). Early‐onset CRC patients were more likely to be Black (15.1% vs. 11.3%) or Hispanic (8.6% vs. 4.6%) and to present with stage 4 disease (24.9% vs. 17.0%), p < 0.0001 for all. Black patients had the worst median OS (58.3 months) compared to White (67.0 months), Hispanic (91.6 months), or Asian (104.9 months) patients, p < 0.0001. Within the subgroup of early‐onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status.ConclusionsEarly‐onset CRC continues to increase. Patients with early‐onset CRC are more likely to be Black or Hispanic and to present with stage 4 cancer. Early‐onset Black patients showed worse OS compared to White patients in all income subgroups, even with private insurance.

3580 Background: The incidence of colorectal cancer (CRC) in young adults (age at diagnosis &lt; 50 years old) has been rapidly increasing. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as Western diet may be associated with increased incidence of sporadic EO CRC. The gut microbiota decomposes and ferments dietary fibers to produce microbial metabolites, which play important roles in maintaining the intestinal epithelium integrity. A high-fat, low-fiber diet has been associated with intestinal dysbiosis, which disrupts intestinal bacterial homeostasis. An increased inflammation state characterizes dysbiosis and may promote an immunosuppressive tumor microenvironment (TME) and suppress antitumor immune surveillance. In addition, epigenetic modifications are influenced by environmental changes and therefore epigenetics may bridge the knowledge gap in understanding the development of sporadic EOCRC. Methods: We obtained RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Oncology Research Information Exchange Network (ORIEN) from the Ohio State University biospecimen services to characterize intra-tumor microbiota composition, tumor-infiltrating lymphocytes (TILs) and differential pathways in EO CRC. We used Infinium HM450 methylation array in The Cancer Genome Atlas (TCGA) and performed genome-wide analyses using reduced representation bisulfite sequencing (RRBS) method to identify differentially methylated regions (DMRs) in EO CRC. Results: Gene expression analysis is consistent with Fusobacterium promoting inflammation in EO CRC. Intra-tumor microbes are positively correlated with M2 macrophages. Compared to late onset (LO) CRC, EO CRC patients have unique gene signatures of phagosome formation, S100 family signaling pathway and CREB signaling in neurons by using ingenuity pathway analysis (IPA). In addition, we found that methylation ages predicted by epigenetic clocks in EO CRC patients were 15 years older on average than their chronological ages, whereas methylation ages in late onset (LO) CRC patients were comparable with chronological ages. The enriched pathways based on DMRs associated with EO CRC have significant overlap with canonical pathways based on differentially expressed genes (DEGs), including CREB signaling in neurons and S100 family signaling pathways. Conclusions: These data suggest that pathogenic microbes may induce inflammation, which leads to accelerated aging in EO CRC.

The incidence of colorectal cancer (CRC) in individuals under the age of 50 has increased. Liver metastasis (LM) is the most common metastasis in CRC patients and is associated with a poor prognosis. This study aimed to use public databases to identify the risk factors for LM in early-onset colorectal cancer (EOCRC) patients and develop a nomogram to quantify the risk of LM. We retrospectively collected data of EOCRC patients diagnosed from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic analysis were used to screen and validate the risk factors for LM in EOCRC patients, and a nomogram was established based on these factors. Calibration curve, area under the receiver operating curve (AUC), and decision curve analysis (DCA) were developed to evaluate the accuracy of the model. A total of 2567 EOCRC patients were included and randomly divided into a training set (n = 1797) and a validation set (n = 770) at a ratio of 7:3. Univariate and multivariate analyses showed that N stage, pretreatment CEA, bone metastasis, and lung metastasis were independent risk factors. The AUCs of the training set and validation set were 0.7958 and 0.7653, respectively, and the calibration curve also demonstrated good accuracy and predictive ability. DCA indicated that it was more clinically relevant than the traditional TN staging. We constructed a Random Forest model, and calculated the SHapley Additive exPlanations (SHAP) values to determine variables importance and visualize the results. We developed a nomogram to predict the risk of LM in EOCRC patients, and the model was internally validated with good accuracy and reliability. It can assist doctors in risk assessment and clinical decision-making.

Background and Objectives: Early-onset colorectal cancer (EO-CRC) has become a significant public health concern due to its alarming rise in incidence and the poor prognosis associated with this disease. The aim of our study was to identify epidemiological, clinical, and paraclinical characteristics that could explain the more aggressive evolution of EO-CRC compared to late-onset colorectal cancer (LO-CRC). Materials and Methods: We conducted a retrospective study over a two-year period, including 204 patients diagnosed with colorectal cancer (CRC). The patients were divided into two subgroups: those with EO-CRC and those with LO-CRC. Statistical analysis was performed using IBM SPSS Statistics, Version 29.0. Results: EO-CRC was identified in 11.3% of the patients included in the study. Compared to LO-CRC patients, EO-CRC patients exhibited a tendency for more distal tumor localization and a stenotic endoscopic appearance (43.5% vs. 29.3%). Regarding histopathological diagnosis, EO-CRC patients demonstrated a higher proportion of the mucinous histologic subtype (34.8% vs. 14.4%) and a significantly greater percentage of poorly differentiated tumors (39.1% vs. 14.5%; p = 0.010). Immunohistochemical results, available for a limited number of patients, revealed higher CDX2 positivity in LO-CRC patients (p = 0.012) and higher HER2 positivity in EO-CRC patients (p = 0.002). Smoking (p = 0.006) and hypertension (p = 0.002) were more prevalent in EO-CRC patients than in LO-CRC patients. Conclusions: Patients with EO-CRC exhibit distinct histopathological and molecular characteristics compared to those with LO-CRC, which may contribute to their poorer prognoses. The higher prevalence of the mucinous histological subtype, poor tumor differentiation, increased HER2 expression, and reduced CDX2 expression suggest potential molecular pathways driving the aggressive nature of EO-CRC. These findings highlight the need for tailored screening strategies and personalized therapeutic approaches in younger CRC patients. Future studies should further investigate the underlying mechanisms and potential biomarkers that could guide early diagnoses and targeted treatments.

Background: The causes of the rising incidence of early-onset colorectal cancer (EOCRC), defined as CRC in patients aged &amp;lt;50, remain unknown. In this study, we evaluated tumor genomic differences in patients with EOCRC versus late-onset CRC (LOCRC, age &amp;gt;60). Methods: The international cohort included 13,262 patients diagnosed with stages I-III colon or rectal cancer who had ctDNA testing using a personalized and tumor-informed multiplex PCR assay (Signatera™ 16-plex bespoke mPCR NGS assay), from which whole-exome sequencing (WES) on the surgically resected tumor was performed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from WES analysis. The prevalence of gene-wide mutations, pathogenic gene variants, and mutations in known oncogenic pathways was compared between EOCRC and LOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between the groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 3,093 patients with EOCRC (70.8% colon, 27.4% rectal, 1.9% unknown) and 10,169 patients with LOCRC (79.9% colon, 18.3% rectal, 1.7% unknown) were included, where 9.0%/37.3%/53.7% were AJCC stages I, II, and III, respectively. Early-onset patients compared to late-onset patients had fewer cases of stage II CRC (30.7% vs. 39.3%, p&amp;lt;0.01) and more cases of stage III CRC (60.9% vs 51.6%, p&amp;lt;0.01). Adjusted by stage, patients with EOCRC were less likely to be MSI-H compared to patients with LOCRC (10% vs. 17%, p&amp;lt;0.01), or have high tumor mutational burden (TMB-H) (15% vs. 19%, p&amp;lt;0.01). Genes of the Hippo, NOTCH, WNT, and RTK-RAS oncogenic pathways were less commonly mutated in the EOCRC cohort (p&amp;lt;0.01). The BRAF V600E mutation was less prevalent in the EOCRC group (3% vs. 15%, p&amp;lt;0.01), regardless of TMB and MSI status. In the TMB-low/MSS group, TP53 mutations were more common in EOCRC (8% vs. 5%, p&amp;lt;0.01), but APC gene mutations were less common in EOCRC (56% vs. 66%, p&amp;lt;0.01). When comparing EOCRC and LOCRC in the TMB-H/MSI-H group, BRAF V600E (4% vs. 60%), RNF43 G659V (16% vs. 45%), and WNT1 G619A (6% vs. 20%) mutations were less prevalent in EOCRC (p&amp;lt;0.01 for all mutations); however, patients with EOCRC had more mutations in PIK3CA H1047R (22% vs. 9%), APC R1468* (11% vs. 3%), and KRAS A146T (7% vs. 2%) gene variants (p&amp;lt;0.01 for all mutations). In the TMB-H/MSS group, EOCRC patients were more likely to have driver mutations in the PI3K pathway (74% vs. 56%, p&amp;lt;0.01). Further, POLE P286R mutations were more common in TMB-H/MSS patients with EOCRC compared to LOCRC (38% vs. 13%, p&amp;lt;0.01), whereas ACVR2A K437R was less common (11% vs. 30%, p&amp;lt;0.01). Conclusion: Patients with LOCRC were more likely to have pathogenic gene variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases harbored unique genomic alterations that varied between the TMB-low/MSS, TMB-H/MSI-H, and TMB-H/MSS subpopulations. Citation Format: Eric M. Lander, Samuel Rivero-Hinojosa, Vasily N. Aushev, Jesús Izaguirre-Carbonell, Adham Jurdi, Minetta C. Liu, Cathy Eng. Genomic alterations associated with early-onset and late-onset colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6696.