Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features among Commercially Insured Adults in the United States

Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features among Commercially Insured Adults in the United States | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features among Commercially Insured Adults in the United States Christopher Tait, Ankoor Patel, Alexander Chen, You Li, Carlos Minacapelli, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3284102/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The incidence of colorectal cancer in patients younger than 50 has been rising in the last 30 years, accounting for up to 25% of total cases. Despite the screening age recently being lowered to 45, a significant proportion of cases would still arise at younger ages prior to screening. Nonfamilial early onset colorectal cancer remain a particular concern. Identification of risk factors and clinical features in this age group is needed to improve detection. Methods In this retrospective cohort analysis using claims data from the Truven Health MarketScan insurance database from 2007–2017, patients were identified with colon and rectal cancer, compared across three age groups (ages 18–40, 40–50 and > 50), and analyzed for risk factors and clinical features. Results Females sex was more prevalent in the younger age group compared to age > 50 (54% and 51.9% vs 49.6%), with little change noted between rectal cancer age groups by sex. A higher percentage of younger patients were in the obese age groups compared with older groups for colon cancer, particularly the morbidly obese with BMI > 40 (24.94%, 25.75%, and 21.34% in the three age groups). Abdominal pain was a common presenting symptom identified in the age groups 50 (25% and 19% vs 14%) along with hematochezia, weight loss, and anemia. Conclusions Morbid obesity and female sex may be important risk factors among patients with early onset CRC. The presence of abdominal pain was more common among the early onset CRC cohort. Figures Figure 1 INTRODUCTION Young adults with colorectal cancer represent an emerging epidemic among cancer patients in the United States over the last three decades. Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer mortality in both genders [ 1 ]. The incidence of colorectal cancer across all age groups in high-income countries has been stable or decreased in the past several decades due to widespread screening programs and changing risk factors, including decreased smoking [ 1 ]. Screening tests and preventive management strategies for colorectal cancer in patients older than 50 have resulted in incidence rates that have decreased by 2–3% per year in both men and women since 2000 in the United States [ 2 ]. While detection and prevention of colorectal cancer in this age group represents a major public health milestone, an increasing number of cases in patients age < 50, which are termed early-onset colorectal cancers, is forcing physicians and epidemiologists to refocus management on this younger demographic [ 3 ]. Additionally, there are increasing reports of patients diagnosed with very early-onset colorectal cancer, seen in the age group of adults aged younger < 40, including in many patients with no known genetic or familial predisposition [ 4 ]. The median age of patients with colon cancer and rectal cancer is 70 years and 63 years, respectively. [ 5 , 6 ] Among all US adults with colon and rectal cancer between 1975 and 2010 [ 7 ], cases in patients younger than age 50 accounted for 4.8% and 9.5% of colon and rectal cancer cases respectively [ 8 , 9 ]. [ 10 ] Epidemiological studies indicate that since 1994, the incidence rate of CRC in patients age less than 55 has increased by 2% annually, with the highest increase in rectosigmoid cancers between the ages of 18 and 35. [ 8 ] Current modeling of these trends predict the proportional incidence of both cancers will double to an estimated 11% and 22% for colon and rectal cancer, respectively, by 2030 in this younger age demographic. Personal history of inflammatory bowel disease, family history of colorectal cancer, and hereditary colorectal cancer syndromes have all been identified and are accounted in current screening models [ 11 , 12 ]. These hereditary colorectal cancer syndromes account for a significant proportion of early-onset cancers, with some series identifying up to 33% of cases diagnosed earlier than age 50. [ 13 ] While these risk factors help identify certain patients at high risk for early-onset CRC, the majority of these cases remain sporadic, accounting for over 50% of early-onset cases. [ 14 ]. Additionally, previous series have not gone into detail regarding features of very-early onset adults with colorectal cancer in the age group 18–40, leaving risk factors in this demographic unaccounted for in screening models outside of the previously mentioned inflammatory bowel disease, genetic syndromes, or certain features of family history. Multiple factors have been hypothesized to account for this proportional increase in early-onset CRC, including obesity, non-Mediterranean Western diet, sedentary lifestyle, low fiber intake and dysbiosis. [ 15 ] Some associated genetic loci have been accounted for, including differential expression of genes in early-onset sporadic CRC include TNFR1 , EIF4E , CLC and IFNAR1 [ 16 , 17 ]. There is a possible relationship between microsatellite instability of tumors in younger patients with CRC [ 18 ]. Nonetheless, there remains a lack of consensus on whether early-onset CRC has distinct molecular/immunologic entity from CRC in older patients [ 18 – 22 ]. Some data already support possible benefit in screening younger adults for CRC based on microstimulation analyses [ 23 ]. In the last three years, the American Cancer Society and the American College of Gastroenterology, as well as the US Protective Task Force, have issued recommendations in support of earlier screening at age 45 [ 7 ]. A deeper understanding of the demographics and risk factors associated with gastrointestinal cancers in younger patient populations can help improve screening practices. It can also provide impetus to interventions aimed at reversal of potentially modifiable risk factors. Several recent reviews have addressed the epidemic of early-onset cancers, and identified multiple risk factors including obesity during adolescence and early adulthood, sedentary lifestyle, metabolic syndrome, alcohol use, and diet related factors [ 24 ] [ 25 ]. Most previous series looking into younger age groups have looked into risk factors for patients age < 50, but identification of specific risk features in the very early onset group (age < 40) remains to be studied and is one of the major focuses of this analysis. Further analysis at large scale is needed to identify demographic groups, clinical features, and risk factors that may help further guide screening guidelines. Consequently, we sought to evaluate demographic, clinical features, and co-morbidity risk factors associated with colon and rectal cancers in younger patient populations, including stratification into early-onset (age 40 to 50) and very-early onset (age 18 to 40) groups based upon database analysis of insurance claims (Truven Health MarketScan®) to help identify these risk factors and clinical features at scale and compare across different age groups as well as against control groups. METHODS Data Source The Truven Health MarketScan® Commercial Claims (MSCC) database from January 1, 2007, to December 31, 2017 was accessed to extract retrospective claims-based healthcare data. The claims data represent health care records from government and public organizations, large employers, and health plans from approximately 350 payers annually. The MSCC database includes longitudinal individual-level data for health insurance claims including inpatient, outpatient, and prescription drugs. The MSCC database contains de-identified data that is compliant with all United States patient confidentiality requirements, including the Health Insurance Portability and Accountability Act of 1996. The Internal Review Board (IRB) of Rutgers Robert Wood Johnson Medical School approved the protocol of this study. Study Sample & Variables The study sample included 18- to 65-year-old MarketScan enrollees with at least one documented inpatient admission or outpatient service diagnosis for colorectal cancer. Accordingly, between January 1, 2007, and December 31, 2017, colorectal cancer was defined according to the International Statistical Classification of Diseases and Related Health Problems (ICD), 10th Revision, Clinical Modification (ICD-10-CM) codes. The cohort breakdown is summarized in Fig. 1 . We defined the age group ≤ 40 as younger or very early-onset group, 40–50 as early-onset age group, and ≥ 50 to 65 as older age group. Symptoms such as hematochezia, anemia, dysphagia, abdominal pain, weight loss, was captured from records at any point prior to index (and including index date) by ICD codes. In addition, history of smoking, alcohol use, and body mass index (BMI) information were captured prior to index by ICD coding. Statin use and death information were captured before and after the index date. The date of the first CRC diagnosis was defined as the index date for all study participants. Baseline demographics, including age, gender, the region of residence, and the type of health insurance plan, were obtained from the index date records. A comorbidity profile was measured for each age group during the baseline period using ICD-10 codes acquired from the inpatient admissions and outpatient services. The profile included participants’ statuses on Crohn's disease (CD), ulcerative colitis (UC), polyposis syndromes including Peutz-Jeghers (PJ), benign neoplasm of colon including Juvenile Polyposis (JP), family history of colonic polyps including familial adenomatous polyposis (FAP), and gastrointestinal hemorrhage including GI bleeding. Lynch syndrome status could not be extrapolated reliably from the database based on search parameters and as such was not included. Familial vs non-familial cancer status was extrapolated based on coding history for family history of colorectal cancer, and personal or family history of juvenile polyposis syndrome, Peutz-Jeghers syndrome, FAP, or family history of GI cancer. In addition, a total weighted Charlson Comorbidity Index (CCI) score was estimated for each age group during the baseline period using algorithms provided by Quan et al. [ 26 ]. Control Group Patients An available claims-based control group consisting of patients with chronic liver disease (CLD) with one primary or secondary ICD-9/ICD-10 codes (during the period of 2015–2017) for HCC, compensated cirrhosis, HCV, Chronic Hepatitis B (HBV), HDV, alcoholic fatty liver, Non-alcoholic Fatty Liver Disease (NAFLD), hepatic encephalopathy, autoimmune hepatitis, hepatitis E virus, Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC) and malignant neoplasm of intrahepatic bile ducts. This was an established, well-studied cohort used in previous analyses and analyzed for differences in risk factors [ 27 ]. Statistical Analysis We compared GI cancer baseline characteristics and comorbidity profiles for those under the specific age groups of age 18 to 40, age 40–50, and age 50 to 65 and classifying the ≥ 50 as the control group. We analyzed between cancer patients in each group and examined outcomes compared with control patients. We also performed subgroup analysis based upon history of familial/hereditary GI cancer, which included verifiable heritable GI genetic cancer syndromes and family history of GI cancer. Wald Chi-square tests were performed to test the associations between age ≤ 40, 40–50 to the age ≥ 50 age group and reported as p-values, with a significance threshold defined as < 0.05. RESULTS Colon Cancer A total of 61,690 patients were identified based on ICD-10 codes for colorectal cancer with patients identified by age group (Fig. 1 ). Among these patients, 44,217 were identified with colon cancer. The demographics, comorbidities, and clinical features of these patients by age group with colon cancer in comparison with control group patients is described in Table 1. The majority of patients diagnosed with colon cancer were in the non-familial group (94.78%) and were above age 50 (75.97%). Among all patients with colon cancer, 7.58% were diagnosed before age 40 years, 16.45% of patients were diagnosed between 40 and 50 years, and 75.97% were diagnosed after age 50 years. A subgroup analysis excluding patients with hereditary syndromes and a family history of GI cancer was performed (Supplemental Table 1), with 7.58% of cases age 50. All p-values reported between age groups reach significance. The average age of onset for very-early colon cancers was 33.99 years, and 45.78 in the age 40–50 group. The majority of cases in all groups were from the South by region of residence, and this did not vary appreciably across age groups (48.39–49.58%). Very-early onset colon cancer patients had a significantly higher proportion of females compared to middle and older age groups (54.03% vs 51.80% vs 49.72%), and an increase in female proportion compared with controls in these groups. Very early-onset and early-onset colon cancer patients had a lower Charlson comorbidity index than older colon cancer patients (CCI 4+; 3.15% vs 4.44% vs. 10.28%; P < 0.001). Compared with control patients, a higher percentage of cancer patients had 2 or more comorbidities noted. The majority of colon cancer patients were in the overweight and obese classes, with slightly increased proportion in the highest BMI categories in the early-onset and middle age groups compared with the oldest cohort (BMI > 40; 24.82% and 25.48% vs 21.22%). Compared with control group patients, the very-early onset and early-onset colon cancer groups had generally lower obesity rates than the control groups in the measured BMI categories, including in the highest BMI groups. The prevalence of Crohn’s (1.76% vs 0.88% vs 0.57%) and UC (2.52% vs 1.20% vs 0.97%) was higher in the older age cohort compared to early-onset and middle age groups, and more prevalent among cancer patients than controls than all age groups. Older patients had greater smoking and alcohol consumption rates compared to very early-onset and early-onset CC patients, with all p-values reported significant. Regarding clinical features, findings of hematochezia were noted in 8.04% of very-early onset and 8.67% of early-onset colon cancers, and 4.18% of age > 50 colon cancers. Anemia was noted in 15.69% and 15.82% of very early and early colon cancer patients, and 13.80% of age > 50 patients. Abdominal pain was more common in very early-onset (25.88%) and early-onset (19.86%) compared with age > 50 patients (14.55%). Comparing symptoms with age-matched controls, hematochezia, weight loss, and anemia were all more common in cancer patients. Abdominal pain was less common in the very-early onset and early-onset cancer patients compared with control patients (25.88% vs 28.01% and 19.86% vs 25.88%). The prevalence of familial adenomatous polyposis (FAP) was higher in the early-onset and middle age cohorts compared to the older age cohort. The prevalence of juvenile polyposis (JP) was higher in older patients with the colon cancer cohort. Death was not significantly different across the age groups during the follow-up period. Death was more common in colon cancer patients in the very-early onset group compared with controls (0.18% vs 0.09%), with all p-values reported reaching significance. Rectal Cancer A total of 17,473 patients with rectal cancer were identified by claims for ICD codes and stratified by age groups. The demographics, comorbidities, and clinical features of all patients with rectal cancer are described in Table 2. The majority of patients diagnosed with rectal cancer were non-familial (96.04%) and most were above the age of 50 (75.40%). 6.89% were diagnosed prior to age 40 years (very-early onset), 17.70% of patients were diagnosed between 40 and 50 years (early-onset) and 75.40% were diagnosed after age 50 years. There were no significant gender differences noted across the age groups. Young and middle age rectal patients had a lower Charlson comorbidity index than older rectal patients (CCI > 4; 2.16% vs 3.70% vs 8.65%; P < 0.0001). The majority of the patients with rectal cancer were in the overweight and obese class, with no significant differences across the age groups or in comparison to control group. The prevalence of Crohn’s and UC was higher in the very-early onset cohort followed by the early-onset and age > 50 cohort in that order. Findings of hematochezia (11.28% vs 11.83% vs 6.18%), anemia (10.2% vs 10.6% vs 8.80%), and weight loss (3.57% vs 3.16% vs 2.48%) were more common in very-early and early-onset groups than the age > 50 patients. Abdominal pain (19.1% vs 15.1% vs 9.68%) and family history of GI malignancy (5.1% vs 5.45% vs 4.43%) was most common early-onset group followed by very-early onset and age > 50 group. Older patients had an increase in smoking (19.9% vs 14.4% vs 15.5%) and alcohol consumption rates (2.99% vs 2.16% vs 2.00%) compared to very early-onset and early-onset rectal cancer patients. The demographics, comorbidities, and presentation of all patients with rectal after excluding patients with familial gastrointestinal diseases is described in Supplemental Table 2. There were similar demographics trends across age groups in rectal patients without familial gastrointestinal diseases compared to all rectal patients described in the previous paragraph. Trends were noticed across gender, Charlson comorbidity index, and body mass index (BMI), various clinical findings, smoking and alcohol as described previously across all rectal cancer patients. Limited analysis between age matched non-cancer affected controls and cancer patients revealed few novel features between these groups, and was limited to comparison with control with chronic liver disease so served primarily as surrogate baseline demographic. DISCUSSION Data presented in this analysis further emphasizes the increasing prevalence of colorectal cancer in young patients over the last 30 years [ 2 ]. The goal of this retrospective claims-based analysis was to expand on previous series by using the large MarketScan insurance claims database to examine age-based cohorts for both colon and rectal cancer within the United States for additional trends, risk factors, and clinical features. Differences in morbidity and treatment for rectal cancer made this differentiation significant and has not been consistently reported in previous series. Considering case series had shown a significant number of cases in patients age < 40, this group was analyzed separately in a group termed “very early-onset,” to help differentiate any features in this group currently not recommended for routine screening [ 3 ]. Among colon cancer patients in our cohort, we found 24.03% presented at age 18 to 50, a slight increase in prevalence in this population compared with previous SEER database analysis showing this group made up 21.2% of total colorectal cancer cases up to 2013 [ 28 ]. 7.58% of patients were diagnosed age 18 to 40 years old, and in this group < 10% reported a family history of GI malignancy. Subgroup analysis excluding for familial syndromes and patients with family history did not show an appreciable change in these age-based percentages, indicating that the vast majority of early and very-early onset cases were sporadic in nature. Among total rectal cancer patients, 6.85% of cases were in the age 18 to 40 group, closely in line with previous series [ 27 ]. A higher proportion of females was noted in the two early-onset colon cancer groups compared with the age > 50 group, although it should be noted our control group had similarly increased proportion of females in the younger groups as well. This suggests that female sex is a risk factor for early-onset colon cancer, although comparison with a more standardized control group is needed to solidify this correlation. Recent studies have demonstrated an association with sex hormones and genetic variants in hormone metabolic pathways that contributed to susceptibility to CRC, which could explain difference in the incidence between the sexes [ 29 ]. Gender was less significant a risk factor for rectal cancer, which showed a slight male predominance. Comorbidity analysis in the early and very early-onset colon cancer groups revealed a significant proportion with at least 2 comorbidities by the Charlson index, with the highest percentage having 3 or 4 comorbidities. Obesity has been implicated in previous series as a likely risk factor for colorectal cancer, and in our series the majority of both colon and rectal cancer patients in all groups were in the overweight, obese or morbidly obese weight categories. Of note, morbidly obese patients with BMI > 40 were highly represented in the colon cancer population across all age groups, representing 24.94%, 25.75%, and 21.34% of colon cancer cases in age ≤ 40, 40–50, and ≥ 50 groups, respectively. Interestingly, the proportion of patients in the obese groups was similar between the rectal cancer age groups, which is in contrast to previous series which implicated obesity as a rectal cancer risk factor [ 30 ]. The nature of claims analysis for obesity makes tracking these trends cumbersome, as there are multiple ICD codes used by different providers that may not have been captured in this analysis which could make correlations less clear. Comparison with controls was also not helpful in this case, as our control population was enriched with a significant proportion of cases with non-alcoholic fatty liver disease and higher proportion of obesity than the cancer groups in most age groups. Regarding clinical features in colon cancer patients, a larger proportion of age 18 to 40 and age 40 to 50 patients presented with abdominal pain compared with age 50 to 65 group (25% vs 19% and 14%, respectively). While abdominal pain is common in control groups and a frequent feature of an ultimately benign work-up by gastroenterologists, this suggests a high index of suspicion is warranted even in younger patients when tracking this symptom over time. Weight loss and hematochezia were also significantly more common in the younger age groups compared with older cancer patients. Age 18–40 and 40–50 patients with rectal cancer were more likely to present with hematochezia than age 50–65 patients. Previous series have noted that patients with early-onset (age < 50) colorectal cancer experience symptoms for a longer duration of time and longer delay in diagnosis compared with late-onset CRC [ 31 , 32 ], likely a result of lower index suspicion with younger patients in the past. Broadening understanding of this rising incidence and high index of suspicion are important points for clinicians ruling our early-onset colorectal cancer cases. The main strengths of this analysis include the very large cohort analyzed, including > 15,000 colorectal cancer cases in patients age < 50, with novel analysis of very early-onset cases in patients age < 40 for both colon and rectal cancers. This is larger in size than recent MarketScan analysis focusing mainly on metabolic syndrome and obesity [ 33 ], and larger than recent VA series which included 12,229 total cases with 97% men [ 34 ]. Previous analysis all focused on adults aged 18–49 as the early-onset colon cancer group, so focusing on the age group 18–40 represents a large cohort not previously cited in other series. Claims data allowed for analysis of clinical complaints and symptoms identified, which has also not been a focus of recent large series in younger age groups. The analysis doeshave weaknesses, including that Lynch syndrome was not easily extracted from the claims database and was not included in this analysis, which excludes an important cause of early-onset genetic cancer syndromes. The analysis was also weakened by lack of an easily comparable control group from which reliable odds ratios could be calculated, making generalizability of associations less reliable. Recent series mentioned in this paper previously have already highlighted some of these risk factors compared with controls, particularly with respect to obesity and diet, making some of these features noted less novel. This analysis does emphasize that further comparison of sex differences and clinical symptoms in these populations compared with controls is warranted. CONCLUSION Colorectal cancer in patients age < 50 represents a growing proportion of cases. Current screening guidelines are adapting to capture more of these patients, however identification of additional risk factors is needed to help identify those at highest risk that may warrant earlier screening. Our cohort contributes to the data demonstrating a significant proportion (~ 25%) of colon and rectal cancer patients being diagnosed under the age of 50 years, with 8% presenting younger than age 40. We found notable differences among gender across various age groups, including higher proportion of female colon cancer cases among patients under age 40. Obesity and high BMI levels remain an important risk factor across age groups with a high proportion of these patients in the highest BMI category in colon cancer. Clinical differences were noted among younger patients, including more colon and rectal cancer cases reporting abdominal pain, hematochezia and weight loss compared with cases older than 50. Many patients reported a family history in this cohort, but the majority of cases were sporadic with proportion of cases not changing by age group after excluding familial cases, highlighting the importance of a high index of suspicion even outside of a strong family history. Further analysis of risk features in this young cohort can help improve earlier clinical detection and limit time to diagnosis in patients who may be at risk. Declarations Conflict of Interest Disclosures : No conflicts of interest, financial, personal, or otherwise, are declared by the authors. Author contributions: All authors worked in all 4 aspects of authorship as per ICMJE guidelines. C.T. had substantial contributions to the conception and study design, analysis & interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript. A.P . had substantial contributions to the conception and study design, analysis & interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript. Y.L . contributed to the study design, statistical analysis, interpretation of data, creating figures/tables, and revised and approved manuscript. A.C. contributed to study design, acquisition and analysis of data, drafting manuscript, revised and approved manuscript. C.D.M . contributed to study design, acquisition and analysis of data, created figures/tables, revised and approved manuscript. V.R. had substantial contributions to the conception and study design, analysis & interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript All authors reviewed the manuscript. Funding : This work received no external funding References Brenner H, Chen C. The colorectal cancer epidemic: challenges and opportunities for primary, secondary and tertiary prevention. 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Clin Gastroenterol Hepatol. 2017;15(5):728–737e3. Scott RB, et al. Rectal cancer in patients under the age of 50 years: the delayed diagnosis. Am J Surg. 2016;211(6):1014–8. Chen H, et al. Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer. Gut. 2021;70(6):1147–54. Zullig LL et al. Colorectal Cancer Statistics From the Veterans Affairs Central Cancer Registry. Clin Colorectal Cancer, 2016. 15(4): p. e199-e204. Supplementary Table 1. Non-familial Patients with Colon Cancer Supplementary Table 2. Non-familial Patients with Rectal Cancer. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Patel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIiWNgGAWjYDACCQbGBwkVDAyMDSjCbHi1MBt8OAPXYkCUFjbBmW1wLhFa+Gf3HmPmnXcvsXna8QfMlW1/7Pqljz9g+FB2GLcld86lPebdVpzYODvHgPFsm0HyzD4gY8Y53FoYbuSYG/NuS8gFamFgbARqMTjDw8DM24Zbi/yNHDNp3jkgLekPwFrsz7A/YP6LR4sBUIvkzAaQlgQDkBY7Ax4GA2ZGPFoMb+QlG3w4llAP8svBhnPGCRJneAwO9pxLx6lF7kbuwQcJNQnGhrPTHz5sKJOz5+9hf/jgR5k1bu8z8ECta2BgOACkE4E0mEFYizyUa49f9SgYBaNgFIxEAABrDVm8c6TlFQAAAABJRU5ErkJggg==","orcid":"","institution":"Rutgers Robert Wood Johnson School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ankoor","middleName":"","lastName":"Patel","suffix":""},{"id":229339970,"identity":"3666c92a-1e2a-48e4-a0eb-44ad795860f1","order_by":2,"name":"Alexander Chen","email":"","orcid":"","institution":"Rutgers Robert Wood Johnson School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Chen","suffix":""},{"id":229339972,"identity":"be18f7c1-4cbb-498c-968f-2165d6590d98","order_by":3,"name":"You Li","email":"","orcid":"","institution":"Rutgers Robert Wood Johnson School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"You","middleName":"","lastName":"Li","suffix":""},{"id":229339973,"identity":"007ca097-ba13-4807-a808-e3d649395c05","order_by":4,"name":"Carlos Minacapelli","email":"","orcid":"","institution":"Rutgers Robert Wood Johnson School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Minacapelli","suffix":""},{"id":229339975,"identity":"5f84ae58-9f83-4169-8cca-31b618c98011","order_by":5,"name":"Vinod Rustgi","email":"","orcid":"","institution":"Rutgers Robert Wood Johnson School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Vinod","middleName":"","lastName":"Rustgi","suffix":""}],"badges":[],"createdAt":"2023-08-22 02:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3284102/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3284102/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":42433108,"identity":"691f9839-7e8e-41de-bab6-2b7b2633e81d","added_by":"auto","created_at":"2023-08-31 14:40:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":219913,"visible":true,"origin":"","legend":"\u003cp\u003ePatient Extraction and Cohort Selection for Gastrointestinal Cancers\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3284102/v1/1987eb97907427311f8ac07a.png"},{"id":44964644,"identity":"a3b6f843-c211-4e2b-9db2-855a8108439f","added_by":"auto","created_at":"2023-10-20 06:07:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":446352,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3284102/v1/a7e3b29f-be7a-4ff8-b968-1eb5f45c6fb0.pdf"},{"id":42433107,"identity":"c6af42c1-bc47-4968-ad4a-e19b06639d75","added_by":"auto","created_at":"2023-08-31 14:40:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27622,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3284102/v1/761779ce4e6bf0c6b5187022.docx"},{"id":42434772,"identity":"b8694f3a-f8e0-4758-be0a-68c17b880b0d","added_by":"auto","created_at":"2023-08-31 14:48:44","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":51304,"visible":true,"origin":"","legend":"","description":"","filename":"Table12.docx","url":"https://assets-eu.researchsquare.com/files/rs-3284102/v1/036f318444ff3feea9c2003b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features among Commercially Insured Adults in the United States","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eYoung adults with colorectal cancer represent an emerging epidemic among cancer patients in the United States over the last three decades. Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer mortality in both genders [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence of colorectal cancer across all age groups in high-income countries has been stable or decreased in the past several decades due to widespread screening programs and changing risk factors, including decreased smoking [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Screening tests and preventive management strategies for colorectal cancer in patients older than 50 have resulted in incidence rates that have decreased by 2\u0026ndash;3% per year in both men and women since 2000 in the United States [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While detection and prevention of colorectal cancer in this age group represents a major public health milestone, an increasing number of cases in patients age\u0026thinsp;\u0026lt;\u0026thinsp;50, which are termed early-onset colorectal cancers, is forcing physicians and epidemiologists to refocus management on this younger demographic [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Additionally, there are increasing reports of patients diagnosed with very early-onset colorectal cancer, seen in the age group of adults aged younger\u0026thinsp;\u0026lt;\u0026thinsp;40, including in many patients with no known genetic or familial predisposition [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe median age of patients with colon cancer and rectal cancer is 70 years and 63 years, respectively. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Among all US adults with colon and rectal cancer between 1975 and 2010 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], cases in patients younger than age 50 accounted for 4.8% and 9.5% of colon and rectal cancer cases respectively [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Epidemiological studies indicate that since 1994, the incidence rate of CRC in patients age less than 55 has increased by 2% annually, with the highest increase in rectosigmoid cancers between the ages of 18 and 35. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Current modeling of these trends predict the proportional incidence of both cancers will double to an estimated 11% and 22% for colon and rectal cancer, respectively, by 2030 in this younger age demographic. Personal history of inflammatory bowel disease, family history of colorectal cancer, and hereditary colorectal cancer syndromes have all been identified and are accounted in current screening models [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These hereditary colorectal cancer syndromes account for a significant proportion of early-onset cancers, with some series identifying up to 33% of cases diagnosed earlier than age 50. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] While these risk factors help identify certain patients at high risk for early-onset CRC, the majority of these cases remain sporadic, accounting for over 50% of early-onset cases. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, previous series have not gone into detail regarding features of very-early onset adults with colorectal cancer in the age group 18\u0026ndash;40, leaving risk factors in this demographic unaccounted for in screening models outside of the previously mentioned inflammatory bowel disease, genetic syndromes, or certain features of family history.\u003c/p\u003e \u003cp\u003eMultiple factors have been hypothesized to account for this proportional increase in early-onset CRC, including obesity, non-Mediterranean Western diet, sedentary lifestyle, low fiber intake and dysbiosis. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Some associated genetic loci have been accounted for, including differential expression of genes in early-onset sporadic CRC include \u003cem\u003eTNFR1\u003c/em\u003e, \u003cem\u003eEIF4E\u003c/em\u003e, \u003cem\u003eCLC\u003c/em\u003e and \u003cem\u003eIFNAR1\u003c/em\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. There is a possible relationship between microsatellite instability of tumors in younger patients with CRC [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nonetheless, there remains a lack of consensus on whether early-onset CRC has distinct molecular/immunologic entity from CRC in older patients [\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Some data already support possible benefit in screening younger adults for CRC based on microstimulation analyses [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the last three years, the American Cancer Society and the American College of Gastroenterology, as well as the US Protective Task Force, have issued recommendations in support of earlier screening at age 45 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA deeper understanding of the demographics and risk factors associated with gastrointestinal cancers in younger patient populations can help improve screening practices. It can also provide impetus to interventions aimed at reversal of potentially modifiable risk factors. Several recent reviews have addressed the epidemic of early-onset cancers, and identified multiple risk factors including obesity during adolescence and early adulthood, sedentary lifestyle, metabolic syndrome, alcohol use, and diet related factors [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Most previous series looking into younger age groups have looked into risk factors for patients age\u0026thinsp;\u0026lt;\u0026thinsp;50, but identification of specific risk features in the very early onset group (age\u0026thinsp;\u0026lt;\u0026thinsp;40) remains to be studied and is one of the major focuses of this analysis.\u003c/p\u003e \u003cp\u003e Further analysis at large scale is needed to identify demographic groups, clinical features, and risk factors that may help further guide screening guidelines. Consequently, we sought to evaluate demographic, clinical features, and co-morbidity risk factors associated with colon and rectal cancers in younger patient populations, including stratification into early-onset (age 40 to 50) and very-early onset (age 18 to 40) groups based upon database analysis of insurance claims (Truven Health MarketScan\u0026reg;) to help identify these risk factors and clinical features at scale and compare across different age groups as well as against control groups.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Source\u003c/h2\u003e \u003cp\u003eThe Truven Health MarketScan\u0026reg; Commercial Claims (MSCC) database from January 1, 2007, to December 31, 2017 was accessed to extract retrospective claims-based healthcare data. The claims data represent health care records from government and public organizations, large employers, and health plans from approximately 350 payers annually. The MSCC database includes longitudinal individual-level data for health insurance claims including inpatient, outpatient, and prescription drugs. The MSCC database contains de-identified data that is compliant with all United States patient confidentiality requirements, including the Health Insurance Portability and Accountability Act of 1996. The Internal Review Board (IRB) of Rutgers Robert Wood Johnson Medical School approved the protocol of this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Sample \u0026amp; Variables\u003c/h2\u003e \u003cp\u003eThe study sample included 18- to 65-year-old MarketScan enrollees with at least one documented inpatient admission or outpatient service diagnosis for colorectal cancer. Accordingly, between January 1, 2007, and December 31, 2017, colorectal cancer was defined according to the International Statistical Classification of Diseases and Related Health Problems (ICD), 10th Revision, Clinical Modification (ICD-10-CM) codes. The cohort breakdown is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe defined the age group\u0026thinsp;\u0026le;\u0026thinsp;40 as younger or very early-onset group, 40\u0026ndash;50 as early-onset age group, and \u0026ge;\u0026thinsp;50 to 65 as older age group. Symptoms such as hematochezia, anemia, dysphagia, abdominal pain, weight loss, was captured from records at any point prior to index (and including index date) by ICD codes. In addition, history of smoking, alcohol use, and body mass index (BMI) information were captured prior to index by ICD coding. Statin use and death information were captured before and after the index date.\u003c/p\u003e \u003cp\u003eThe date of the first CRC diagnosis was defined as the index date for all study participants. Baseline demographics, including age, gender, the region of residence, and the type of health insurance plan, were obtained from the index date records. A comorbidity profile was measured for each age group during the baseline period using ICD-10 codes acquired from the inpatient admissions and outpatient services. The profile included participants\u0026rsquo; statuses on Crohn's disease (CD), ulcerative colitis (UC), polyposis syndromes including Peutz-Jeghers (PJ), benign neoplasm of colon including Juvenile Polyposis (JP), family history of colonic polyps including familial adenomatous polyposis (FAP), and gastrointestinal hemorrhage including GI bleeding. Lynch syndrome status could not be extrapolated reliably from the database based on search parameters and as such was not included. Familial vs non-familial cancer status was extrapolated based on coding history for family history of colorectal cancer, and personal or family history of juvenile polyposis syndrome, Peutz-Jeghers syndrome, FAP, or family history of GI cancer. In addition, a total weighted Charlson Comorbidity Index (CCI) score was estimated for each age group during the baseline period using algorithms provided by Quan et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eControl Group Patients\u003c/h2\u003e \u003cp\u003eAn available claims-based control group consisting of patients with chronic liver disease (CLD) with one primary or secondary ICD-9/ICD-10 codes (during the period of 2015\u0026ndash;2017) for HCC, compensated cirrhosis, HCV, Chronic Hepatitis B (HBV), HDV, alcoholic fatty liver, Non-alcoholic Fatty Liver Disease (NAFLD), hepatic encephalopathy, autoimmune hepatitis, hepatitis E virus, Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC) and malignant neoplasm of intrahepatic bile ducts. This was an established, well-studied cohort used in previous analyses and analyzed for differences in risk factors [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eWe compared GI cancer baseline characteristics and comorbidity profiles for those under the specific age groups of age 18 to 40, age 40\u0026ndash;50, and age 50 to 65 and classifying the \u0026ge;\u0026thinsp;50 as the control group. We analyzed between cancer patients in each group and examined outcomes compared with control patients. We also performed subgroup analysis based upon history of familial/hereditary GI cancer, which included verifiable heritable GI genetic cancer syndromes and family history of GI cancer. Wald Chi-square tests were performed to test the associations between age\u0026thinsp;\u0026le;\u0026thinsp;40, 40\u0026ndash;50 to the age\u0026thinsp;\u0026ge;\u0026thinsp;50 age group and reported as p-values, with a significance threshold defined as \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eColon Cancer\u003c/h2\u003e\n \u003cp\u003eA total of 61,690 patients were identified based on ICD-10 codes for colorectal cancer with patients identified by age group (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Among these patients, 44,217 were identified with colon cancer. The demographics, comorbidities, and clinical features of these patients by age group with colon cancer in comparison with control group patients is described in Table\u0026nbsp;1. The majority of patients diagnosed with colon cancer were in the non-familial group (94.78%) and were above age 50 (75.97%). Among all patients with colon cancer, 7.58% were diagnosed before age 40 years, 16.45% of patients were diagnosed between 40 and 50 years, and 75.97% were diagnosed after age 50 years. A subgroup analysis excluding patients with hereditary syndromes and a family history of GI cancer was performed (Supplemental Table\u0026nbsp;1), with 7.58% of cases age\u0026thinsp;\u0026lt;\u0026thinsp;40, 16.45% age 40\u0026ndash;50, and 75.97% age\u0026thinsp;\u0026gt;\u0026thinsp;50. All p-values reported between age groups reach significance.\u003c/p\u003e\n \u003cp\u003eThe average age of onset for very-early colon cancers was 33.99 years, and 45.78 in the age 40\u0026ndash;50 group. The majority of cases in all groups were from the South by region of residence, and this did not vary appreciably across age groups (48.39\u0026ndash;49.58%). Very-early onset colon cancer patients had a significantly higher proportion of females compared to middle and older age groups (54.03% vs 51.80% vs 49.72%), and an increase in female proportion compared with controls in these groups. Very early-onset and early-onset colon cancer patients had a lower Charlson comorbidity index than older colon cancer patients (CCI 4+; 3.15% vs 4.44% vs. 10.28%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared with control patients, a higher percentage of cancer patients had 2 or more comorbidities noted. The majority of colon cancer patients were in the overweight and obese classes, with slightly increased proportion in the highest BMI categories in the early-onset and middle age groups compared with the oldest cohort (BMI\u0026thinsp;\u0026gt;\u0026thinsp;40; 24.82% and 25.48% vs 21.22%). Compared with control group patients, the very-early onset and early-onset colon cancer groups had generally lower obesity rates than the control groups in the measured BMI categories, including in the highest BMI groups. The prevalence of Crohn\u0026rsquo;s (1.76% vs 0.88% vs 0.57%) and UC (2.52% vs 1.20% vs 0.97%) was higher in the older age cohort compared to early-onset and middle age groups, and more prevalent among cancer patients than controls than all age groups. Older patients had greater smoking and alcohol consumption rates compared to very early-onset and early-onset CC patients, with all p-values reported significant.\u003c/p\u003e\n \u003cp\u003eRegarding clinical features, findings of hematochezia were noted in 8.04% of very-early onset and 8.67% of early-onset colon cancers, and 4.18% of age\u0026thinsp;\u0026gt;\u0026thinsp;50 colon cancers. Anemia was noted in 15.69% and 15.82% of very early and early colon cancer patients, and 13.80% of age\u0026thinsp;\u0026gt;\u0026thinsp;50 patients. Abdominal pain was more common in very early-onset (25.88%) and early-onset (19.86%) compared with age\u0026thinsp;\u0026gt;\u0026thinsp;50 patients (14.55%). Comparing symptoms with age-matched controls, hematochezia, weight loss, and anemia were all more common in cancer patients. Abdominal pain was less common in the very-early onset and early-onset cancer patients compared with control patients (25.88% vs 28.01% and 19.86% vs 25.88%). The prevalence of familial adenomatous polyposis (FAP) was higher in the early-onset and middle age cohorts compared to the older age cohort. The prevalence of juvenile polyposis (JP) was higher in older patients with the colon cancer cohort. Death was not significantly different across the age groups during the follow-up period. Death was more common in colon cancer patients in the very-early onset group compared with controls (0.18% vs 0.09%), with all p-values reported reaching significance.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eRectal Cancer\u003c/h2\u003e\n \u003cp\u003eA total of 17,473 patients with rectal cancer were identified by claims for ICD codes and stratified by age groups. The demographics, comorbidities, and clinical features of all patients with rectal cancer are described in Table\u0026nbsp;2. The majority of patients diagnosed with rectal cancer were non-familial (96.04%) and most were above the age of 50 (75.40%). 6.89% were diagnosed prior to age 40 years (very-early onset), 17.70% of patients were diagnosed between 40 and 50 years (early-onset) and 75.40% were diagnosed after age 50 years. There were no significant gender differences noted across the age groups. Young and middle age rectal patients had a lower Charlson comorbidity index than older rectal patients (CCI\u0026thinsp;\u0026gt;\u0026thinsp;4; 2.16% vs 3.70% vs 8.65%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The majority of the patients with rectal cancer were in the overweight and obese class, with no significant differences across the age groups or in comparison to control group. The prevalence of Crohn\u0026rsquo;s and UC was higher in the very-early onset cohort followed by the early-onset and age\u0026thinsp;\u0026gt;\u0026thinsp;50 cohort in that order. Findings of hematochezia (11.28% vs 11.83% vs 6.18%), anemia (10.2% vs 10.6% vs 8.80%), and weight loss (3.57% vs 3.16% vs 2.48%) were more common in very-early and early-onset groups than the age\u0026thinsp;\u0026gt;\u0026thinsp;50 patients. Abdominal pain (19.1% vs 15.1% vs 9.68%) and family history of GI malignancy (5.1% vs 5.45% vs 4.43%) was most common early-onset group followed by very-early onset and age\u0026thinsp;\u0026gt;\u0026thinsp;50 group. Older patients had an increase in smoking (19.9% vs 14.4% vs 15.5%) and alcohol consumption rates (2.99% vs 2.16% vs 2.00%) compared to very early-onset and early-onset rectal cancer patients.\u003c/p\u003e\n \u003cp\u003eThe demographics, comorbidities, and presentation of all patients with rectal after excluding patients with familial gastrointestinal diseases is described in Supplemental Table 2. There were similar demographics trends across age groups in rectal patients without familial gastrointestinal diseases compared to all rectal patients described in the previous paragraph. Trends were noticed across gender, Charlson comorbidity index, and body mass index (BMI), various clinical findings, smoking and alcohol as described previously across all rectal cancer patients. Limited analysis between age matched non-cancer affected controls and cancer patients revealed few novel features between these groups, and was limited to comparison with control with chronic liver disease so served primarily as surrogate baseline demographic.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eData presented in this analysis further emphasizes the increasing prevalence of colorectal cancer in young patients over the last 30 years [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The goal of this retrospective claims-based analysis was to expand on previous series by using the large MarketScan insurance claims database to examine age-based cohorts for both colon and rectal cancer within the United States for additional trends, risk factors, and clinical features. Differences in morbidity and treatment for rectal cancer made this differentiation significant and has not been consistently reported in previous series. Considering case series had shown a significant number of cases in patients age\u0026thinsp;\u0026lt;\u0026thinsp;40, this group was analyzed separately in a group termed \u0026ldquo;very early-onset,\u0026rdquo; to help differentiate any features in this group currently not recommended for routine screening [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong colon cancer patients in our cohort, we found 24.03% presented at age 18 to 50, a slight increase in prevalence in this population compared with previous SEER database analysis showing this group made up 21.2% of total colorectal cancer cases up to 2013 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. 7.58% of patients were diagnosed age 18 to 40 years old, and in this group\u0026thinsp;\u0026lt;\u0026thinsp;10% reported a family history of GI malignancy. Subgroup analysis excluding for familial syndromes and patients with family history did not show an appreciable change in these age-based percentages, indicating that the vast majority of early and very-early onset cases were sporadic in nature. Among total rectal cancer patients, 6.85% of cases were in the age 18 to 40 group, closely in line with previous series [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. A higher proportion of females was noted in the two early-onset colon cancer groups compared with the age\u0026thinsp;\u0026gt;\u0026thinsp;50 group, although it should be noted our control group had similarly increased proportion of females in the younger groups as well. This suggests that female sex is a risk factor for early-onset colon cancer, although comparison with a more standardized control group is needed to solidify this correlation. Recent studies have demonstrated an association with sex hormones and genetic variants in hormone metabolic pathways that contributed to susceptibility to CRC, which could explain difference in the incidence between the sexes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Gender was less significant a risk factor for rectal cancer, which showed a slight male predominance.\u003c/p\u003e \u003cp\u003eComorbidity analysis in the early and very early-onset colon cancer groups revealed a significant proportion with at least 2 comorbidities by the Charlson index, with the highest percentage having 3 or 4 comorbidities. Obesity has been implicated in previous series as a likely risk factor for colorectal cancer, and in our series the majority of both colon and rectal cancer patients in all groups were in the overweight, obese or morbidly obese weight categories. Of note, morbidly obese patients with BMI\u0026thinsp;\u0026gt;\u0026thinsp;40 were highly represented in the colon cancer population across all age groups, representing 24.94%, 25.75%, and 21.34% of colon cancer cases in age\u0026thinsp;\u0026le;\u0026thinsp;40, 40\u0026ndash;50, and \u0026ge;\u0026thinsp;50 groups, respectively. Interestingly, the proportion of patients in the obese groups was similar between the rectal cancer age groups, which is in contrast to previous series which implicated obesity as a rectal cancer risk factor [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The nature of claims analysis for obesity makes tracking these trends cumbersome, as there are multiple ICD codes used by different providers that may not have been captured in this analysis which could make correlations less clear. Comparison with controls was also not helpful in this case, as our control population was enriched with a significant proportion of cases with non-alcoholic fatty liver disease and higher proportion of obesity than the cancer groups in most age groups.\u003c/p\u003e \u003cp\u003eRegarding clinical features in colon cancer patients, a larger proportion of age 18 to 40 and age 40 to 50 patients presented with abdominal pain compared with age 50 to 65 group (25% vs 19% and 14%, respectively). While abdominal pain is common in control groups and a frequent feature of an ultimately benign work-up by gastroenterologists, this suggests a high index of suspicion is warranted even in younger patients when tracking this symptom over time. Weight loss and hematochezia were also significantly more common in the younger age groups compared with older cancer patients. Age 18\u0026ndash;40 and 40\u0026ndash;50 patients with rectal cancer were more likely to present with hematochezia than age 50\u0026ndash;65 patients. Previous series have noted that patients with early-onset (age\u0026thinsp;\u0026lt;\u0026thinsp;50) colorectal cancer experience symptoms for a longer duration of time and longer delay in diagnosis compared with late-onset CRC [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], likely a result of lower index suspicion with younger patients in the past. Broadening understanding of this rising incidence and high index of suspicion are important points for clinicians ruling our early-onset colorectal cancer cases.\u003c/p\u003e \u003cp\u003eThe main strengths of this analysis include the very large cohort analyzed, including\u0026thinsp;\u0026gt;\u0026thinsp;15,000 colorectal cancer cases in patients age\u0026thinsp;\u0026lt;\u0026thinsp;50, with novel analysis of very early-onset cases in patients age\u0026thinsp;\u0026lt;\u0026thinsp;40 for both colon and rectal cancers. This is larger in size than recent MarketScan analysis focusing mainly on metabolic syndrome and obesity [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], and larger than recent VA series which included 12,229 total cases with 97% men [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Previous analysis all focused on adults aged 18\u0026ndash;49 as the early-onset colon cancer group, so focusing on the age group 18\u0026ndash;40 represents a large cohort not previously cited in other series. Claims data allowed for analysis of clinical complaints and symptoms identified, which has also not been a focus of recent large series in younger age groups. The analysis doeshave weaknesses, including that Lynch syndrome was not easily extracted from the claims database and was not included in this analysis, which excludes an important cause of early-onset genetic cancer syndromes. The analysis was also weakened by lack of an easily comparable control group from which reliable odds ratios could be calculated, making generalizability of associations less reliable. Recent series mentioned in this paper previously have already highlighted some of these risk factors compared with controls, particularly with respect to obesity and diet, making some of these features noted less novel. This analysis does emphasize that further comparison of sex differences and clinical symptoms in these populations compared with controls is warranted.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eColorectal cancer in patients age\u0026thinsp;\u0026lt;\u0026thinsp;50 represents a growing proportion of cases. Current screening guidelines are adapting to capture more of these patients, however identification of additional risk factors is needed to help identify those at highest risk that may warrant earlier screening. Our cohort contributes to the data demonstrating a significant proportion (~\u0026thinsp;25%) of colon and rectal cancer patients being diagnosed under the age of 50 years, with 8% presenting younger than age 40. We found notable differences among gender across various age groups, including higher proportion of female colon cancer cases among patients under age 40. Obesity and high BMI levels remain an important risk factor across age groups with a high proportion of these patients in the highest BMI category in colon cancer. Clinical differences were noted among younger patients, including more colon and rectal cancer cases reporting abdominal pain, hematochezia and weight loss compared with cases older than 50. Many patients reported a family history in this cohort, but the majority of cases were sporadic with proportion of cases not changing by age group after excluding familial cases, highlighting the importance of a high index of suspicion even outside of a strong family history. Further analysis of risk features in this young cohort can help improve earlier clinical detection and limit time to diagnosis in patients who may be at risk.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e: No conflicts of interest, financial, personal, or otherwise, are declared by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eAll authors worked in all 4 aspects of authorship as per ICMJE guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC.T.\u003c/strong\u003e had substantial contributions to the conception and study design, analysis \u0026amp; interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.P\u003c/strong\u003e. had substantial contributions to the conception and study design, analysis \u0026amp; interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eY.L\u003c/strong\u003e. contributed to the study design, statistical analysis, interpretation of data, creating figures/tables, and revised and approved manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.C.\u003c/strong\u003e contributed to study design, acquisition and analysis of data, drafting manuscript, revised and approved manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC.D.M\u003c/strong\u003e. contributed to study design, acquisition and analysis of data, created figures/tables, revised and approved manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eV.R.\u003c/strong\u003e had substantial contributions to the conception and study design, analysis \u0026amp; interpretation of the data, creating figure/tables, drafting manuscript, final approval of manuscript\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work received no external funding\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrenner H, Chen C. 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Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma. Cancer. 2016;122(7):1017\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeterse EFP, et al. The impact of the rising colorectal cancer incidence in young adults on the optimal age to start screening: Microsimulation analysis I to inform the American Cancer Society colorectal cancer screening guideline. Cancer. 2018;124(14):2964\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel SG, et al. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 2022;7(3):262\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantucci C, et al. Colorectal Cancer Mortality in Young Adults Is Rising in the United States, Canada, United Kingdom, and Australia but Not in Europe and Asia. Gastroenterology. 2021;160(5):1860\u0026ndash;2. e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuan H, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRustgi VK, et al. Wilson's Disease: An Analysis of Health Care Use and Cost Burden of Commercially Insured Adults in the United States. Hepatol Commun. 2022;6(2):389\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel RL et al. \u003cem\u003eColorectal Cancer Incidence Patterns in the United States, 1974\u0026ndash;2013\u003c/em\u003e. JNCI: J Natl Cancer Inst, 2017. 109(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi S, et al. Sex hormones and genetic variants in hormone metabolic pathways associated with the risk of colorectal cancer. Environ Int. 2020;137:105543.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevi Z, et al. Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study. Cancer. 2017;123(20):4022\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen FW, et al. Advanced-Stage Colorectal Cancer in Persons Younger Than 50 Years Not Associated With Longer Duration of Symptoms or Time to Diagnosis. Clin Gastroenterol Hepatol. 2017;15(5):728\u0026ndash;737e3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott RB, et al. Rectal cancer in patients under the age of 50 years: the delayed diagnosis. Am J Surg. 2016;211(6):1014\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen H, et al. Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer. Gut. 2021;70(6):1147\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZullig LL et al. \u003cem\u003eColorectal Cancer Statistics From the Veterans Affairs Central Cancer Registry.\u003c/em\u003e Clin Colorectal Cancer, 2016. 15(4): p. e199-e204. Supplementary Table 1. Non-familial Patients with Colon Cancer Supplementary Table 2. Non-familial Patients with Rectal Cancer.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3284102/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3284102/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe incidence of colorectal cancer in patients younger than 50 has been rising in the last 30 years, accounting for up to 25% of total cases. Despite the screening age recently being lowered to 45, a significant proportion of cases would still arise at younger ages prior to screening. Nonfamilial early onset colorectal cancer remain a particular concern. Identification of risk factors and clinical features in this age group is needed to improve detection.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort analysis using claims data from the Truven Health MarketScan insurance database from 2007\u0026ndash;2017, patients were identified with colon and rectal cancer, compared across three age groups (ages 18\u0026ndash;40, 40\u0026ndash;50 and \u0026gt;\u0026thinsp;50), and analyzed for risk factors and clinical features.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFemales sex was more prevalent in the younger age group compared to age\u0026thinsp;\u0026gt;\u0026thinsp;50 (54% and 51.9% vs 49.6%), with little change noted between rectal cancer age groups by sex. A higher percentage of younger patients were in the obese age groups compared with older groups for colon cancer, particularly the morbidly obese with BMI\u0026thinsp;\u0026gt;\u0026thinsp;40 (24.94%, 25.75%, and 21.34% in the three age groups). Abdominal pain was a common presenting symptom identified in the age groups\u0026thinsp;\u0026lt;\u0026thinsp;50 compared with age\u0026thinsp;\u0026gt;\u0026thinsp;50 (25% and 19% vs 14%) along with hematochezia, weight loss, and anemia.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMorbid obesity and female sex may be important risk factors among patients with early onset CRC. The presence of abdominal pain was more common among the early onset CRC cohort.\u003c/p\u003e","manuscriptTitle":"Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features among Commercially Insured Adults in the United States","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-31 14:40:39","doi":"10.21203/rs.3.rs-3284102/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a529dc0b-dfee-4505-9ae2-55bc85116035","owner":[],"postedDate":"August 31st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-10-20T05:59:09+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-31 14:40:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3284102","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3284102","identity":"rs-3284102","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}