Early-onset Colorectal Cancer Patients Research Articles

The health-related quality of life of early-onset colorectal cancer patients: an Australian cross-sectional study.

Early-onset colorectal cancer (EOCRC) patients are more likely to have advanced disease and undergo more aggressive treatment modalities. However, current literature investigating the health-related quality of life (HRQoL) of EOCRC patients is scarce. This study aimed to determine the HRQoL of an Australian cohort of EOCRC patients including a subset who underwent pelvic exenteration (PE) or cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). A cross-sectional study of EOCRC patients treated at the Royal Prince Alfred Hospital, Sydney Australia was performed. Patients were divided into groups based on the time interval from their index operation: ≤2 years and >2 years. HRQoL was evaluated using the SF-36v2 questionnaire. A total of 50 patients were included. For patients ≤2 years from surgery, the median physical component summary (PCS) and mental health component summary (MCS) scores were 53.3 (36.4-58.9) and 47.3 (37.5-55.7). In the >2 years group, the median PCS and MCS scores were 50.6 (43.3-57.7) and 50.2 (39.04-56.2), respectively. Stage I (vs. stage II) disease and emergency (vs. elective) surgery conferred poorer PCS scores in patients ≤2 years from surgery. No other variables impacted PCS or MCS scores in EOCRC patients in either group. HRQoL of EOCRC patients was equivocal to the Australian population. Having an earlier stage of diagnosis and emergency index operation was associated with poorer levels of physical functioning in patients ≤2 years from surgery. However, because of the limitations of this study, these findings require validation in future large-scale prospective research.

Molecular characteristics of early-onset compared with late-onset colorectal cancer: A case controlled study.

Early-Onset Colorectal Cancer (EOCRC) is associated with a poorer prognosis relative to Late-Onset Colorectal Cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC. A total of 11,344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10,766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel). Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status. This study revealed a significantly higher MSI-H distribution rate in early-onset colorectal cancer, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.

Early-Onset Colorectal Cancer Patients Do Not Require Shorter Intervals for Post-Surgical Surveillance Colonoscopy

Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC to average onset colorectal cancer (AO-CRC) patients to help define surveillance outcomes in these groups. Single institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps (adenoma/sessile serrated)) were examined. For each group, three serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards. A total of 1259 CRC patients were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared to AO-CRC patients, EO-CRC patients had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (HR=0.71, 95% CI 0.52 - 1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (p=0.003), and EO-CRC were found to have less advanced neoplasia compared to AO-CRC counterparts (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that while EO-CRC patients returned for follow-up surveillance colonoscopy earlier than AO-CRC patients, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas. EO-CRC patients do not have an increased risk of advanced neoplasia compared to AO-CRC patients and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend.

Do treatment patterns differ in those with early-onset colorectal cancer?

ABSTRACT Background The incidence of early-onset colorectal cancer (EOCRC) is increasing. International guidelines state that treatment should not differ from that of older patients. Several studies have shown that patients under 50 years are receiving more aggressive treatment, without any survival benefit. We aim to determine if treatment for stages 2 and 3 EOCRC differs from those of late-onset colorectal cancer (LOCRC) patients. Methods This was a retrospective, population-based, cohort study of the treatment patterns of patients diagnosed with colorectal cancer in Canterbury, New Zealand, from 2010 to 2021 age <50 years, compared to those aged 60–74 years. Results A total of 3263 patients were diagnosed with CRC between 2010 and 2021. Following exclusions, we identified 130 EOCRC and 668 LOCRC patients. Stage 2 EOCRC patients are more likely to be offered adjuvant chemotherapy (p = <0.001). Furthermore, EOCRC patients with either stage 2 or 3 disease are more likely to receive multi-agent therapy (p =  <0.01), without any associated increase in survival. Conclusion EOCRC patients are given more adjuvant chemotherapy, without a corresponding improvement in outcomes, highlighting a potential for increased treatment-related harms, particularly in stage 2 disease. Clinicians should be mindful of these biases when treating young cancer patients and need to carefully consider treatment-related harms.

Identification of differentially expressed genes and splicing events in early-onset colorectal cancer.

The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC. We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens. We identified an eight-gene signature in EOCRC comprised of ALDOB, FBXL16, IL1RN, MSLN, RAC3, SLC38A11, WBSCR27 and WNT11, from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, HOTAIRM1. Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens. Our transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets.

Construction and validation of a nomogram for predicting overall survival of patients with stage III/IV early-onset colorectal cancer.

This study aimed to identify prognostic factors and develop a nomogram for predicting overall survival (OS) in stage III/IV early-onset colorectal cancer (EO-CRC). Stage III/IV EO-CRC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The datasets were randomly divided (2:1) into training and validation sets. A nomogram predicting OS was developed based on the prognostic factors identified by Cox regression analysis in the training cohort. Moreover, the predictive performance of the nomogram was assessed using the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Subsequently, the internal validation was performed using the validation cohort. Finally, a risk stratification system was established based on the constructed nomogram. Of the 10,387 patients diagnosed with stage III/IV EO-CRC between 2010 and 2015 in the SEER database, 8,130 patients were included. In the training cohort (n=3,071), sex, marital status, race/ethnicity, primary site, histologic subtypes, grade, T stage, and N stage were identified as independent prognostic variables for OS. The 1-, 3-, and 5-year area under the curve (AUC) values of the nomogram were robust in both the training (0.751, 0.739, and 0.723) and validation cohorts (0.748, 0.733, and 0.720). ROC, calibration plots, and DCA indicated good predictive performance of the nomogram in both the training and validation sets. Furthermore, patients were categorized into low-, middle-, and high-risk groups based on the nomogram risk score. Kaplan-Meier curve showed significant survival differences between the three groups. We developed a prognostic nomogram and risk stratification system for stage III/IV EO-CRC, which may facilitate clinical decision-making and individual prognosis prediction.

Nomogram model for predicting cancer-specific mortality in patients with early-onset colorectal cancer: a competing risk analysis insight from the SEER database and an external validation cohort.

Early-onset colorectal cancer (EOCRC) is increasing in incidence and poses a growing threat. Urgent research is needed, especially in survival analysis, to enhance comprehension and treatment strategies. This study aimed to explore the risk factors associated with cancer-specific mortality (CSM) and other-cause mortality (OCM) in patients with EOCRC. Additionally, the study aimed to develop a nomogram predicting CSM using a competitive risk model and validate its accuracy through the use of training, using internal and external cohorts. Data from EOCRC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017). EOCRC patients who were treated at a tertiary hospital in northeast China between 2014 and 2020 were also included in the study. The SEER data were divided into the training and validation sets at a 7:3 ratio. A univariate Cox regression model was employed to identify prognostic factors. Subsequently, multivariate Cox regression models were applied to ascertain the presence of independent risk factors. A nomogram was generated to visualize the results, which were evaluated using the concordance index (C-index), area under the curve (AUC), and calibration curves. The clinical utility was assessed via decision curve analysis (DCA). Multivariable Cox regression analysis demonstrated that factors such as race, tumor differentiation, levels of carcinoembryonic antigen (CEA), marital status, histological type, American Joint Committee on Cancer (AJCC) stage, and surgical status were independent risk factors for CSM in EOCRC patients. In addition, age, gender, chemotherapy details, CEA levels, marital status, and AJCC stage were established as independent risk factors for OCM in individuals diagnosed with EOCRC. A nomogram was developed using the identified independent risk factors, demonstrating excellent performance with a C-index of 0.806, 0.801, and 0.810 for the training, internal validation, and external validation cohorts, respectively. The calibration curves and AUC further confirmed the accuracy and discriminative ability of the nomogram. Furthermore, the DCA results indicated that the model had good clinical value. In this study, a competing risk model for CSM was developed in EOCRC patients. The model demonstrates a high level of predictive accuracy, providing valuable insights into the treatment decision-making process.

Sexual Functioning and Impact on Quality of Life in Patients with Early-Onset Colorectal Cancer: A Systematic Review.

This systematic review investigates the intersection of early-onset colorectal cancer (EOCRC), sexual functioning, and associated quality of life (QoL), aiming to understand the comprehensive impact of EOCRC on these critical dimensions. Through an extensive search across PubMed, Scopus, and Embase up until November 2023, this study synthesized evidence from the literature while adhering to PRISMA guidelines. The studies included EOCRC patients under 50 years, which examined sexual functioning and QoL using validated instruments, and were published in English. After a rigorous screening process, five relevant studies were identified from an initial pool of 2184 articles. This review includes data from five studies involving 2031 EOCRC patients. The key findings revealed a high prevalence of sexual dysfunction, with up to 50% of men experiencing impotence and 58% reporting sexual dysfunction, alongside 36% of women in some studies. Pain was described by 12% to 31% of patients. Anxiety and depression were notably prevalent, affecting up to 69% of participants. EOCRC profoundly impacts sexual functioning and QoL, with a significant prevalence of sexual dysfunction and psychological distress among affected individuals. These findings suggest the need for oncological management strategies that include not only medical treatment but also psychological support and sexual health interventions. This systematic review emphasizes the importance of holistic patient care approaches, advocating for further research and clinical attention to address the complex needs of younger EOCRC patients.

Abstract 7449: Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients

Abstract 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.

Abstract 7017: Increased epigenetic age acceleration in young adult and early onset colorectal cancer patients post-treatment: A ColoCare Pilot Study

Abstract Introduction: Advanced biological age relative to chronological age has been observed in individuals with colorectal cancer (CRC), and there is growing evidence that cancer treatments can further accelerate biological aging. However, the influence of age at diagnosis on these relationships has yet to be examined in detail. This pilot study used data from the ColoCare Study to explore pre- and post-treatment differences in age acceleration by chronological age at CRC diagnosis. Methods: The ColoCare Study is a prospective cohort study of newly-diagnosed CRC patients enrolled across seven U.S. and European sites. Participants in this pilot study were from the ColoCare site in Tampa, Florida who had available pre-treatment blood DNA. Young adult (YA, aged 18-39) and early onset (EO, aged 40-49) participants were matched with average onset (AO, aged 50-64) and late onset (LO, aged &amp;gt;64) participants on stage, sex, race and microsatellite instability status. Genome-wide DNA methylation profiles were assayed on buffy coat DNA using MethylationEPIC v2 BeadChips. PhenoAgeAccel and GrimAgeAccel were calculated on all samples to quantify the difference between DNA methylation-predicted biological age and chronological age (i.e., age acceleration). Linear regression models were used to estimate the associations of age at diagnosis and treatment with PhenoAgeAccel and GrimAgeAccel, adjusted for sex, race, and site (rectal, colon). Results: The sample (n=60) included n=19 YA, n=15 EO, n=11 AO, and n=15 LO participants with pre-treatment blood DNA. Over half (n=15 YA/EO, n=20 AO/LO) had a paired post-treatment blood sample available. Half of participants were female and had colon tumors, and 76% were diagnosed with stage I-III disease. Pre-treatment, PhenoAgeAccel and GrimAgeAccel were similar across age groups (P &amp;gt; 0.05). In the subset of participants with pre- and post-treatment samples, age acceleration appeared to increase post-treatment (pre- and post-treatment differences, PhenoAgeAccel: 1.44, SD: 5.55, P= 0.13; GrimAgeAccel: 0.92, SD: 2.80, P= 0.06). Increases were largest among YA/EO participants. In adjusted models, the predicted differences in pre-to post-treatment PhenoAgeAccel were 2.89 (95% CI: -0.13, 5.90) in YA/EO and 0.36 (95% CI: -2.25, 2.96) in AO/LO (P-difference= 0.20). The predicted differences in GrimAgeAccel were 1.75 (95% CI: 0.25, 3.25) in YA/EO and 0.30 (95% CI: -1.00, 1.60) in AO/LO (P-difference= 0.15). Conclusions: In this pilot study of CRC patients, pre-treatment age acceleration did not vary by age at diagnosis. Post-treatment, patients diagnosed at age 49 or younger had larger increases in age acceleration than patients diagnosed at age 50 or older. These findings warrant further investigation in larger samples and to determine if increases in post-treatment age acceleration as associated with patient outcomes and treatment response. Citation Format: Erin M. Siegel, Jacob K. Kresovich, Amanda M. Bloomer, Anders Berglund, Esther Jean-Baptiste, Gillian Trujillo, Rachel Carmella, Julaxis Love, Seth Felder, Jennifer Ose, Biljana Gigic, Christopher I. Li, Jane C. Figueiredo, Adetunji T. Toriola, Cornelia M. Ulrich, David Shibata, Laura B. Oswald. Increased epigenetic age acceleration in young adult and early onset colorectal cancer patients post-treatment: A ColoCare Pilot Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7017.

Abstract 7005: Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients

Abstract Objective: Early onset colorectal cancer (EO CRC) is rising at an alarming rate. While average onset colorectal cancer (AO CRC) affects patients mostly above 65 years of age, EO CRC affects patients under 50 years of age, disproportionately affecting males from low-income communities and racial/ethnic minorities. Chronic inflammation has been identified as a strong contributor to pathogenesis. We hypothesize that methylation of DNA may serve as a potential mechanism associated with chronic inflammation that contributes to the etiology differentially between EO and AO CRC. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue specimens from four AO and EO CRC patients each were retrieved from the Tissue Repository. Paraffin curls containing tumor and adjacent normal tissues were generated from appropriate EO and AO CRC patient tissues. The Qiagen GeneRead DNA FFPE genomic DNA kit was then used to extract the DNA from the paraffin curls. Illumina Methylation EPIC v2.0 kit was used to evaluate DNA methylation (DNAm) patterns after the restoration process from deamination in the fixed/embedded sample using the Uracil-N-Glycosylase enzyme. Unreliable and non-specific probes were removed before statistical analysis for differentially methylated CpG sites. Age acceleration for each tissue was calculated by comparing the estimated DNAm age with chronological age using the Horvath approach. Results: A clear clustering of DNAm patterns by age of onset were observed for both normal and tumor tissues. However, there was no difference when comparing tumor and normal tissues after multiple corrections. Four-way ANCOVA adjusting for race, gender, BMI, and tissue type suggested that age onset was the most significant factor. We also found that age acceleration in EO CRC tissue is greater than in AO CRC. After applying Bonferroni correction, significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SNTB1, NFATC3, SLC25A24, RABGAP1L, WDSUB1, WWOX, SELB, SLC28A3, and PPP6R2 in EO CRC patients when compared to AO CRC. SNTB1 regulates colorectal cancer progression and stemness, while NFATC3 has been associated with inflammation and cancer. Conclusions: The preliminary results from this study showed a significant difference in the DNAm profile of FFPE samples between AO and EO CRC. The finding suggests that epigenetics may play a role in the etiology of CRC, potentially involved in the chronic inflammation pathway. The analysis of a larger patient number is underway to strengthen these findings. Citation Format: L. Joseph Su, Ping-Ching Hsu, Aniruddha Rathod, Yulun Liu, Jacopo Ferruzzi, Syed Kazmi, Emina Huang. Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer 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 7005.

Abstract 4409: FBXW7 and BCL9L altered pathways as hallmarks of early-onset colorectal cancer

Abstract Background: The incidence of early-onset colorectal cancer (EO-CRC) has been alarmingly increasing, particularly among non-Hispanic Whites (NHWs), resulting in similar rates to ones in African Americans (AAs). Overall, the median age of diagnosis has decreased from 72 to 66 years. The molecular features that could potentially distinguish this phenotype are still not well-established. This study aimed to identify genetic, epigenetic, and transcriptomic factors associated with EO-CRC. Methods: 510 patients with microsatellite-stable tumors analyzed for somatic mutations, targeting 20 cancer driver genes. We included a cohort of 175 AAs from the Yale New Haven Health System, a previously studied cohort of 51 AAs from the Chicago Colorectal Cancer Consortium, and the publicly available molecular data from TCGA COAD-READ PanCancer cohort (50 AAs and 229 NHWs). We analyzed the transcriptomic and methylation profiles from the Yale cohort using Tempo-SeqTM and Illumina EPIC array, respectively. Results: Of the 510 patients, 18% were diagnosed with EO-CRC. Using a multiple variant analysis, adjusting for sex, race, tumor location, and stage, EO-CRC patients were less likely to be male (OR = 0.59, 95% CI: 0.37-0.94, p-value = 0.03), their tumors lacked mutations in APC (OR = 0.37, 95% CI: 0.22-0.63, p-value = 0.0002), and they were more likely to have mutations in FBXW7 (OR = 3.1, 95% CI: 1.60-6.00, p-value = 0.0007) and BCL9L (OR = 3.1, 95% CI: 1.00-8.72, p-value = 0.04). We compared tumors with and without mutations in FBXW7 or BCL9L in two independently analyses. Combining transcriptomics and methylation data, we identified 10 candidate genes that showed significant gene downregulation with hypermethylation or upregulation with hypomethylation. Among FBXW7 mutant tumors, we found the Cartilage oligomeric matrix protein (COMP) gene was significantly downregulated and hypermethylated. In CRC, COMP has been associated with a crosstalk between the TGF-β pathway and immune cell infiltration. Moreover, inactivation of FBXW7 resulted in the accumulation of phosphorylated TGIF1 molecules and repression of TGFβ-dependent transcription in cancer cell lines. Deficiency of FBXW7 is a key element in the phosphorylation-dependent ubiquitination and subsequent proteasome degradation of oncoproteins, such as c-MYC, NOTCH, and Cyclin E. Among BCL9L mutant tumors, keratin 20 (KRT20), the intermediate filament protein and marker of intestinal differentiation in CRC, was downregulated and hypermethylated. BCL9L plays an important role in tumorigenesis induced by aberrant Wnt signaling or aneuploidy tolerance. Conclusion: Our findings further demonstrate the importance of specific etiologic mechanisms in EO-CRC at the level of somatic alterations, providing new ways to understand the biology of EO-CRC and prospects for the development of targeted therapies. Citation Format: Reger Mikaeel, Dante Bellomo, Seeta Rajpara, David Buckley, Mary Yagle, Baris Kerimoglu, Curtis Thorne, Megha Padi, Bodour Salhia, Nathan A. Ellis, Xavier Llor, Rosa Xicola. FBXW7 and BCL9L altered pathways as hallmarks of early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4409.

Abstract 4979: Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location

Abstract Background: Here, we describe analyses towards identifying and comparing genetic variations between the primary and metastatic sites in early-onset metastatic colorectal cancer patients. Methods: We selected patients with early-onset metastatic colorectal cancer (under 50 years old) using data from the American Association for Cancer Research Project GENIE (version 14.1). We used the Fisher exact test to compare genetic mutations between the primary tumor and metastatic sites, complemented by the Benjamini-Hochberg adjustment method. Results: In a total of 1,791 patients with early-onset metastatic colorectal cancer, 27.1% had tumor samples from metastatic sites, while the majority, 72.9%, were from the primary tumor location. The most common mutations found were in the TP53 gene (77.6%), followed by APC (76.0%), KRAS (42.4%), and PIK3CA (19.0%). Notably, the metastatic samples had a significantly higher occurrence of SMAD4 mutations compared to their primary site counterparts (20.8% vs. 14.0%, p&amp;lt;0.001, q&amp;lt;0.001). Conversely, the primary tumor samples exhibited higher frequencies of TCF7L2 and ARID1A mutations (16.9% vs. 10.6%, p&amp;lt;0.001, q&amp;lt;0.001, and 13.0% vs. 6.4%, p&amp;lt;0.001, q&amp;lt;0.001, respectively). Conclusion: Determining the specific genes responsible for the formation of metastatic tumors is crucial for a deeper understanding of the disease's underlying biology in early-onset metastatic colorectal cancer. Such genomic details are crucial to pave the way to the discovery of potential biomarkers for diagnosis and the development of new cancer therapeutics. Citation Format: Muhammet Ozer, Suleyman Y. Goksu, Busra Bacik Goksu, Nina N. Sanford, Amy Jones, Nilesh Verma, Syed Kazmi. Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location [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 4979.

Surgical and survival outcomes of early-onset colorectal cancer patients: a single-centre descriptive Australian study.

Early-onset colorectal cancer (EOCRC) incidence is increasing in Australia. However, no Australian studies have reported on EOCRC patients' surgical management and survival patterns. A retrospective study of 111 EOCRC patients treated at the Royal Prince Alfred Hospital (RPAH), Sydney, Australia between January 2013 and December 2021 was performed. RPAH is a quaternary referral centre for pelvic exenteration (PE) and cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Most patients had left-sided tumours (76.58%) and stage IV disease at the time of presentation (37.85%). 27.93% of patients underwent either CRS/HIPEC and PE and 72.07% of patients underwent other colorectal resections of which the most common was low anterior resection (19.82%). A stoma was fashioned in 50.54% of patients. Complications occurred in 54.95% of patients of which most were Clavien-Dindo grade II (47.54%). Absolute 1-, 3- and 5-year time intervals were 93.69%, 87.39% and 85.48%. Disease-free and overall survival were poorer in stage IV patients who had PE, followed by CRS/HIPEC then other colorectal resections (P < 0.001 and P = 0.003). Stoma formation, PE and CRS/HIPEC and minor postoperative complications were common in our EOCRC cohort. Despite this, the 5-year absolute survival rate was acceptable. Thus, an aggressive surgical approach in EOCRC patients at a quaternary referral centre may be feasible at the cost of greater postoperative morbidity. This information is imperative in the surgical consent and preoperative counselling of EOCRC patients and highlights the need for further research to assess the postoperative functional outcomes and quality of life of EOCRC patients.

Survival outcome and prognostic factors for early-onset and late-onset metastatic colorectal cancer: a population based study from SEER database

Colorectal cancer is the third most common cancer worldwide and there has been a concerning increase in the incidence rate of colorectal cancer among individuals under the age of 50. This study compared the survival outcome between early-onset and late-onset metastatic colorectal cancer to find the differences and identify their prognostic factors. We obtained patient data from SEER database. Survival outcome was estimated using Kaplan–Meier survival curves and compared using the log-rank test. Univariate and multivariate analyses were conducted utilizing COX models to identify their independent prognostic factors. A total of 10,036 early-onset metastatic colorectal (EOCRC) cancer patients and 56,225 late-onset metastatic colorectal cancer (LOCRC) patients between 2010 and 2019 were included in this study. EOCRC has more survival benefits than LOCRC. Tumor primary location (p < 0.001), the location of metastasis (p < 0.001) and treatment modalities (p < 0.001) affect the survival outcomes between these two groups of patients. Female patients had better survival outcomes in EOCRC group (p < 0.001), but no difference was found in LOCRC group (p = 0.57). In conclusion, our study demonstrated that EOCRC patients have longer survival time than LOCRC patients. The sex differences in survival of metastatic colorectal cancer patients are associated with patients’ age. These findings contribute to a better understanding of the differences between metastatic EOCRC and LOCRC, and can help inform the development of more precise treatment guidelines to improve prognosis.

A161 IMPACT OF EARLY-ONSET COLORECTAL CANCER ON DISABILITY-ADJUSTED LIFE YEARS IN CANADA: 1990 TO 2019

Abstract Background Colorectal cancer is the third most common malignancy and remains a leading cause of potentially preventable morbidity and mortality. Early-onset colorectal cancer (EOCRC) is a growing public health focus, particularly in North America, where incidence rates have increased over time. Aims Recognizing that EOCRC affects patients in the prime of their life, we aimed to estimate the impact of EO-CRC on disability-adjusted life years (DALYs) lost in Canada between 1990 and 2019. Methods We used the Global Burden of Diseases (GBD) Study to assess temporal trends in incidence, mortality and DALYs for EOCRC (patients ampersand:003C50 years old) in Canada between 1990 and 2019. Point estimates are available from http://ghdx.healthdata. org/gbd-results-tool. Rates were estimated per 100 0000 individuals at risk and stratified by age and sex. Annual percentage changes (APC) were estimated using joinpoint regression with 95% confidence intervals (CIs). Results In 2019, the incidence, mortality and corresponding DALYs rates for EOCRC were 15.67 (95% CI 11.58, 20.81), 3.19 (95% CI 2.81, 3.61), and 161.88 (95% CI 142.50, 183.53) per 100,000 individuals, respectively. Overall incidence increased significantly during the study period by 1.12%/year (95% CI 0.91%, 1.62%). An analysis of the temporal trends demonstrates that the most significant increase in incidence in EOCRC occurred between 2000 - 2006 with an APC of 3.19% (95% CI 2.40%, 3.99%), which was primarily driven by an increased incidence in men. Mortality (APC 3.30%, 95% CI 2.41%, 4.19%) and DALYs (APC 3.28%, 95% CI 2.34%, 4.22%) for EOCRC also significantly increased for males between 2001 - 2006. Conclusions Our study reveals a substantial burden in early-onset colorectal cancer in Canada, with a significant increase in incidence over time and over 160 DALYs/100,000 population. Figure 1: Incidence (A), Mortality (B) and DALYs (C) for EOCRC in Canada between 1990 and 2019 with 95% CIs. Funding Agencies None

Distinct plasma molecular profiles between early-onset and late-onset colorectal cancer patients revealed by metabolic and lipidomic analyses

Colorectal cancer (CRC) incidence in younger adults has been steadily rising, warranting an in-depth investigation into the distinctions between early-onset CRC (EOCRC, < 50 years) and late-onset CRC (LOCRC, ≥ 50 years). Despite extensive study of clinical, pathological, and molecular traits, differentiating EOCRC from LOCRC and identifying potential biomarkers remain elusive. We analyzed plasma samples from healthy individuals, EOCRC, and LOCRC patients using liquid-chromatography mass spectrometry (LC/MS)-based metabolomics and lipidomics. Distinct polar metabolite and lipid profiles with significant metabolites altered in CRC group (e.g., choline and DG 40:4) were identified. Notably, EOCRC exhibited distinct polar metabolomic and differential lipidomic profiles compared to LOCRC, with polar metabolites like aminoadipate and uridine contributing significantly to the difference, and originating from pathways such as lysine biosynthesis and nucleotide metabolism. Furthermore, gene set enrichment analysis (GSEA) using independent TCGA gene expression data identified pathways significantly enriched in either EOCRC or LOCRC. Integrating gene expression and metabolomics data revealed numerous associations differentiating EOCRC and LOCRC. Our multi-omics integration underscores critical molecular distinctions, offers insights into the EOCRC development mechanisms and potential plasma biomarkers for diagnosis.

Racial/ethnic disparities in inpatient palliative care utilization and hospitalization outcomes among patients with colorectal cancer.

Research has shown that racial/ethnic disparities exist in outcomes for colorectal cancer (CRC) patients, but there are no studies assessing inpatient palliative care utilization and hospitalization outcomes in this population. We examined racial/ethnic disparities in palliative care utilization and hospitalization outcomes among CRC and early-onset CRC patients. Using National Inpatient Sample (NIS) data collected between 2016 and 2018, cross-sectional analyses were performed. Descriptive analyses were done, stratified by race/ethnicity. Multivariable logistic and linear regression models were used to examine racial/ethnic differences in palliative care utilization, inpatient mortality, chemotherapy/radiotherapy use, length of stay and total hospital charges among hospitalized patients with CRC and early-onset CRC. Blacks had higher odds (AOR: 1.09; 95% CI: 1.03-1.16) of receiving palliative care consultation while Hispanics had lower odds (AOR: 0.90; 95% CI: 0.84-0.96) compared to Whites. Blacks had 1.1 times higher odds (95% CI: 1.01-1.18) of inpatient mortality relative to Whites while Hispanics had 16% (AOR: 0.84; 95% CI: 0.76-0.93) lower odds of inpatient mortality. Compared to Whites, Blacks (AOR: 1.99; 95% CI: 1.64-2.41), Hispanics (AOR: 2.49; 95% CI: 1.94-3.19) and colorectal cancer patients in the other category (AOR: 1.72; 95% CI: 1.35-2.18) were more likely to receive inpatient treatment with chemotherapy/radiotherapy. Furthermore, Black patients were 1.1 times (95% CI: 1.06-1.14) more likely to have a length of stay more than 5 days. Blacks (𝛃: $3,096.7; 95% CI: $1,207.0-$4,986.5) Hispanic (𝛃: $10,237.5; 95% CI: $7,558.2-$12,916.8) and other patients (𝛃: $6,332.0; 95% CI: $2,830.9-$9, 833.2) had higher hospital charges relative to their White counterparts. Among patients with early onset CRC, Blacks had higher palliative care use (AOR: 1.29; 95% CI: 1.10-1.51) and inpatient mortality (AOR: 1.38; 95% CI: 1.06-1.79) while Hispanics reported $5,589.7 (95% CI: $683.2-$10,496.2) higher total hospital charges and were more likely to receive inpatient chemotherapy/radiotherapy (AOR: 2.48; 95% CI: 1.70-3.63). Further research is needed to explore specific cultural, socioeconomic, and political factors that explain these disparities and identify ways to narrow the gap. Meanwhile, the healthcare sector will need to assess what strategies might be helpful in addressing these disparities in outcomes in the context of other socioeconomic and cultural factors that may be affecting the patients.

Abstract C057: Methylome-wide profiling of early-onset colorectal cancer in underrepresented populations

Abstract Colorectal cancer (CRC) is the third leading cause of death from cancer in both men and women in the United States. Late onset colorectal cancer (LOCRC) or CRC diagnosed in older adults &amp;gt;50 years old has continued to decline while early onset colorectal cancer (EOCRC) or colorectal cancer in patients under the age of 50 continues to rise at an alarming rate since the mid-1990s.  In fact, EOCRC is now the second most common cancer and the third leading cause of cancer mortality in people &amp;lt;50 years of age in the USA. The incidence of EOCRC has been on the rise over the past four decades and is expected to increase by &amp;gt;140% by 2030. Notably, Blacks and Hispanics are disproportionately affected with the EOCRC diagnosis. Despite this, minority patients remain underrepresented in clinical trials and translational research.  It has been proposed that environmental exposures including westernized diet, metabolic factors, and the microbiome might be responsible for the rise in incidence of EOCRC. Epigenetic modifications are well-known mechanisms by which the environment can modulate gene expression without changing the DNA sequence. One such modification is DNA methylation, which controls DNA accessibility, chromatin formation, and gene transcriptional activity. Unfortunately, however, little is known about the role of DNA methylation in EOCRC and much less is understood of EOCRC in minority populations. Therefore, we identified a unique cohort of 11 EOCRC patients within the Baylor College of Medicine/Harris Health System which is comprised of majority minority EOCRC population (7- Hispanic, 2 Non-Hispanic (NH) Black, and 1 NH-White EOCRC patients).  Using whole-genome bisulfite sequencing, we comprehensively characterized the DNA methylome at single-base resolution in our 11 EOCRC patient samples. Our analyses revealed distinct EOCRC methylation patterns including both global hypomethylation and promoter-specific hypermethylation, which were not previously captured in The Cancer Genome Atlas (TCGA) Analyses. Among the differentially methylated regions (DMRs), we discovered that DNA and RNA transcription pathways were enriched in EOCRCs at advanced stage. Furthermore, we identify differential DMRs patterns among ethnicities. Taken together, our work supports a pathogenic role for DNA methylation in EOCRC.  We are the first group to take this comprehensive unbiased approach to analyze the methylome in an underrepresented EOCRC cohort of patients.   Citation Format: Karen Riggins, Jason Sheng Li, Benjamin Musher, Li Yang, Patricia Castro, Wedad Alfarkh, Neda Zarrin-Kamah, Michael Scheurer, Chad Creighton, Wei Li, Lanlan Shen. Methylome-wide profiling of early-onset colorectal cancer in underrepresented populations [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 C057.

Covid-19 and Its Impact on Colorectal Cancer Diagnosis in Romania: A Single-Centered 5-year Retrospective Cohort Study.

Background: Colorectal cancer, 3rd in incidence and 2nd in mortality among cancers worldwide, represents the most common malignant tumor of the digestive tract. In Romania, it is the most frequently diagnosed type of cancer (approximately 0.06% of the population/year). During the COVID-19 pandemic the legislation preventing the SARS-CoV-2 viral transmission impairing access to outpatient healthcare services combined with patients fear of SARS-CoV-2 infection had consequences on the diagnosis and treatment of all other pathologies. Methods: A 5-year retrospective cohort study was conducted in a tertiary hospital in Arad, Romania, and included 1329 newly diagnosed colorectal cancer patients. For statistical analysis, Fisher's exact test was used for categorical data and the unpaired test with Welch's correction for continuous data. Results: The age on diagnosis decreased during the early COVID-19 pandemic to 68.50 (95% CI [67.90 69.11]) years, with the highest percentage (7.41%) of early onset colorectal cancer patients, a steady post-pandemic increase in the percentage of male (52.71% in 2019 to 62.20% in 2022) and urban (54.18% in 2018 to 70.10% in 2022) patients, admitted to the hospital due to an emergency presentation (peaking at 83.95% in 2020) and requiring a longer hospitalization period (10.03 [95% CI (8.76-11.30)] days in 2020 to 8.37 [95% CI (7.44-9.30)] days in 2022). The most common colo-rectal cancer diagnosis of patients in our reference population was malignant neoplasm of the rectum (ICD-10 code C20.0), while the most common complications were peritumoral adherence-related disorder, occlusion, and perforation, encountered in patients with comorbidities such as arterial hypertension, ischemic cardiomyopathy, diabetes mellitus, obesity, and non-alcoholic steatohepatitis. Conclusions: Regional particularities should be analyzed to better target the population at risk and to better direct the necessary healthcare resources towards the reference population, especially during crisis periods similar to the COVID-19 pandemic.