Analysis of Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database

This cohort study compares the survival among individuals with early-onset vs later-onset colorectal cancer using data from the US National Cancer Database.


Introduction
Among adults aged younger than 50 years in the US, colorectal cancer (CRC) represents the second most common cancer diagnosis and the third leading cause of cancer death. 1 Although there is no unequivocal definition of early-onset CRC, age younger than 50 years appears to be a common criterion in the published literature. 2,36][7][8][9][10][11] Early-onset CRC (ie, CRC diagnosed at age <50 years) has been characterized by unique clinical, genetic, and epigenetic characteristics, 2,3 and thus it may be associated with different survival from CRC diagnosed among individuals older than 50 years.3][14][15][16][17][18][19][20][21][22][23] Inclusion of individuals aged 60 years and older in the comparison can introduce substantial mortality events unrelated to CRC diagnosis, thereby complicating these analyses. 24us, an ideal comparison group may be individuals diagnosed at or shortly after age 50 years, such as those aged 50 to 55 years, especially when CRC-specific survival could not be calculated owing to unavailability of causes of death.However, a 2020 study 25 in the US Surveillance, Epidemiology, and End Results registries reported a steep incidence increase from age 49 to 50 years, consistent with previously undetected CRCs diagnosed through recommended screening uptake at age 50 years.In addition to this steep incidence increase, we hypothesized that CRC diagnosed specifically at age 50 years may have a higher proportion of early stage at diagnosis than CRC diagnosed at most ages.
Therefore, diagnosis at age 50 years may have superior survival in all ages (ie, ages 0-90 years) of the study population owing to more intensive screening.Accordingly, we excluded individuals diagnosed at age 50 years from the comparison group and selected individuals diagnosed with CRC at ages 51 through 55 years to compare the survival differences for individuals diagnosed with early-onset CRC.
Additionally, individuals with early-onset CRC have been found to be more likely to be diagnosed at advanced stage. 2,3Therefore, we also hypothesized that stage at diagnosis would be associated with the comparison of survivals and may also contribute to heterogeneity of survival.
Moreover, given that "younger than age 50 years" is a wide age range, there may be heterogeneity in early-onset CRC survival by age.Thus, we conducted the analyses using the National Cancer Database (NCDB), a large nationally representative cancer database, to verify our hypotheses of (1)   superior survival associated with CRC diagnosis at age 50 years, (2) a survival advantage associated with early-onset CRC after primarily adjusting for stage, and (3) heterogeneity within earlyonset CRC.

Methods
Because NCDB data were deidentified, the Yale Institutional Review Board approved this cohort study as exempt human research and determined that informed consent was not required.This

Data Source and Study Population
Jointly sponsored by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, the NCDB is a clinical oncology database that captures 70% or more of new cancer diagnoses in the US and undergoes strict monitoring to ensure data quality and completeness. 26,27The NCDB and participating hospitals have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors in this study.
The NCDB was analyzed for individuals diagnosed with primary CRC from January

Study Population Characteristics
Characteristics of individuals in the study population were collected.

Statistical Analysis
In addition to descriptive analysis of individuals by age group, the characteristics of individuals with early-onset and later-onset CRC were compared using χ 2 tests for categorical variables and the Mann-Whitney U test for continuous variables. 30,31Differences in overall survival between earlyonset and later-onset CRC were assessed via the Kaplan-Meier method and the log-rank test, 32,33 and we further conducted these analyses by stage.
We applied Cox proportional hazards regression to calculate hazard ratios (HRs) of overall mortality associated with age at diagnosis. 34,35 1.
Additionally, we assessed overall survival by 1-year increments in all ages, observing a decrease in

Subgroup Analyses
We further assessed for heterogeneity in survival among individuals with early-onset CRC (

Discussion
In this cohort study using a large US database, we observed an increase in incident CRC diagnoses at age 50 years, with an increased proportion of individuals with earlier stage disease and a transient decrease in mortality.These findings motivated us to select individuals diagnosed with CRC at ages 51 to 55 years as the comparison group for early-onset CRC, and we found that individuals with earlyonset CRC were more likely to be diagnosed at advanced stage and experienced inferior unadjusted overall survival rates.However, following adjustment for other predictors associated with mortality, most notably stage, we found that individuals with early-onset CRC had a superior survival compared with those diagnosed at ages 51 to 55 years.That advantage was greatest for individuals diagnosed from ages 35 to 39 years, however, and was largely limited to individuals diagnosed at stage I and II.
However, considering that younger people are generally healthier, with more years remaining to live, 24 the survival advantage should be interpreted cautiously, especially given that the advantage has a small magnitude and is heterogeneous by ages and stage.
Early-onset CRC is often characterized by more advanced stage, poorer cell differentiation, increased prevalence of mucosal and signet ring cell histology, left-sided (ie, distal colon and rectum) location of primary tumors, loss of DNA methylation, increased rate of KRAS and TP53 mutations, and increased proportion of cancer family syndromes. 2,3,41,42These distinguishing characteristics suggest that early-onset CRC may exhibit unique biologic features and a potentially different prognosis when compared with CRC diagnosed among older individuals.and is often diagnosed in individuals from ages 35 to 45 years. 45,46In contrast, adenomatous polyposis coli syndrome is more common in individuals who are diagnosed with CRC at age younger than 20 years (10%) compared with those diagnosed at later ages (0.1%), 47 and adenomatous polyposis coli syndrome is not associated with a survival advantage. 48,49 given that there is limited information to distinguish curative vs palliative types of surgical treatment, chemotherapy, and radiotherapy in the NCDB, we could not fully address how treatment types (eg, curative vs palliative) may be associated with survival.Fourth, given that molecular signatures were unavailable in the NCDB, we could not verify biological distinctiveness within early-onset CRC in etiology and progression.However, our analysis of segmented early-onset CRC may encourage future molecular studies to investigate biological distinctiveness and heterogeneity in the early-onset CRC population.Fifth, given that this is an observation study, residual confounding cannot be ruled out.

Conclusions
This study's finding that younger individuals with CRC had increased mortality in unadjusted analyses, which was associated with being diagnosed at later stages of illness, suggests that more attention in screening given to younger individuals may reduce their mortality if their diseases can be detected at earlier stage.Our finding of a survival advantage associated with early-onset CRC among younger individuals should be interpreted cautiously, given that the advantage had a small magnitude and was heterogeneous by age and stage.Further study is needed to understand the underlying heterogeneity of survival by age and stage among individuals with early-onset CRC.

Table 1 .
Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database Demographic and Clinical Characteristics of Individuals by Age at Diagnosis Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database Compared with the 1-year prior age, an increase was observed at the transition at age 50 years (Figure 1A), from 11 597 CRC diagnoses at age 49 years to 16 365 diagnoses at age 50 years, which represented 41.1% increase in incidence.In contrast, although the number of incident CRC diagnoses increased continuously until age 65 years, the mean 1-year increase in incident CRC diagnoses was 11.5% (95% CI, 10.9%-12.4%)for ages 45 to 49 years.We further assessed stage at diagnosis across 1-year age increments, finding a transient step-up in JAMA Network Open | Oncology JAMA Network Open.2021;4(6):e2112539.doi:10.1001/jamanetworkopen.2021.12539(Reprinted) June 16, 2021 5/14 Downloaded From: https://jamanetwork.com/ on 09/29/2023 earlier stage (ie, I and II) at age 50 years.Specifically, 2296 of 11 597 individuals with CRC at age 49 years (19.8%) and 4876 of 16 365 individuals with CRC at age 50 years (29.8%) had stage I disease, reflecting a 50.5% relative increase at this transition (Figure

Table 1 .
Demographic and Clinical Characteristics of Individuals by Age at Diagnosis (continued) individuals diagnosed at age 50 years (eTable 2 in the Supplement), which was also verified by the restricted cubic splines plot (eFigure 2 in the Supplement).Therefore, based on these findings, we excluded individuals diagnosed at age 50 years from the referent group and selected individuals with CRC diagnosed at ages 51 to 55 years as the comparison group.

Table 2
).Compared with individuals diagnosed at ages 51 to 55 years, the unadjusted HR for overall mortality among individuals with early-onset CRC was 1.04 (95% CI, 1.02-1.05;P < .001).However, with progressive multivariable adjustment, most notably with adjustment for stage, individuals with early-onset CRC had a reduction in mortality.Within the fully adjusted model, the multivariable HR for overall mortality for individuals with early-onset CRC was 0.95 (95% CI, 0.93-0.96;P < .001)compared with individuals diagnosed from age 51 to 55 years.In the model adjusted for stage, the HR for individuals with early-onset CRC was 0.89 (95% CI, 0.88-0.90;P < .001).

on 09/29/2023 finding
Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database Figure 2. Kaplan-Meier Mortality Estimates for Early-Onset and Later-Onset Colorectal Cancer (CRC) by Stage Overall mortality of early-onset and later-onset CRC by stage is listed for 180 980 individuals at all stages, 40 192 individuals at stage I, 38 015 individuals at stage II, 55 428 individuals at stage III, and 47 345 individuals at stage IV.The P-value was calculated using the log-rank test. of an increased proportion of earlier stage disease among individuals diagnosed at age 50 years and is associated with an improved survival for individuals aged 50 years.Few studies have specifically investigated the survival of individuals diagnosed with CRC at age 50 years, and our findings may suggest a higher burden of undetected preclinical early-onset CRC among individuals aged younger than 50 years, especially those ages 45 to 49 years.We would hypothesize that CRC diagnosed at ages 45 to 49 years may not be biologically different from CRC diagnosed at age 50 years. 2,3Thus, we would expect similar survival advantages from screening in the age range of 45 to 49 years.Recently, the draft CRC screening guideline of the US Preventive Services Task Force recommended starting CRC screening at age 45 years. 40Our findings may have policy implications and may inform the current debate on whether to decrease the age of initial CRC screening.Prior studies 12-23 assessing the survival differences of individuals with early-onset CRC used different ages (ie, Ն50, 50-75, 60-80, >65, or 65-75 years) as comparison groups, which may partly explain the inconsistent findings across prior studies.In contrast, we selected a relatively comparable age group (ages 51-55 years) that excluded individuals diagnosed at age 50 years for comparison and reported worse survival rates in all years for individuals with early-onset CRC.However, after adjustment for stage at diagnosis, individuals with early-onset CRC actually had better survival, with a relative 5% reduction in mortality (adjusted HR, 0.95 [95% CI, This may reinforce the importance of early CRC detection the younger population, especially given that we are in the midst of a shift in the recommended age for CRC screening. 2,3This is further supported by our JAMA Network Open | Oncology JAMA Network Open.2021;4(6):e2112539.doi:10.1001/jamanetworkopen.2021.12539(Reprinted) June 16, 2021 7/14 Downloaded From: https://jamanetwork.com/ on 09/29/2023 JAMA Network Open.2021;4(6):e2112539.doi:10.1001/jamanetworkopen.2021.12539(Reprinted) June 16, 2021 8/14 Downloaded From: https://jamanetwork.com/

Table 2 .
Overall Mortality Comparing Early-Onset and Later-Onset CRC a Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database Specifically, the survival advantage was greatest among individuals diagnosed from ages 35 to 39 years and was absent among those diagnosed at age 25 years or younger.Interestingly, hereditary nonpolyposis colorectal cancer, owing to underlying mismatch repair deficiency, is associated with superior survival a Demographic characteristics included sex, race, geographic location, and residence setting.Socioeconomical status included median income in zip code of residence by quartiles, percentage of residents by zip code graduating from high school, and primary health insurance.Clinical factors included stage, tumor location, and Charlson-Deyo Comorbidity Index score.Treatment factors included facility type and use of surgical treatment, radiation, chemotherapy, and immunotherapy.b Adjusted for stage.c Adjusted for demographic characteristics, socioeconomical status, clinical factors (not including stage), and treatment factors.d Adjusted for demographic characteristics, socioeconomical status, clinical factors (including stage), and treatment factors.JAMA Network Open | Oncology JAMA Network Open.2021;4(6):e2112539.doi:10.1001/jamanetworkopen.2021.12539(Reprinted) June 16, 2021 9/14 Downloaded From: https://jamanetwork.com/ on 09/29/2023 50,51 high penetrance syndromes could partly account for the relative in survival across ages among individuals with early-onset CRC.Supportive of this hypothesis, previous findings also reported an increased prevalence of somatic mutations in CTNNB1 among individuals with CRC who were younger than age 30 years and the highest proportion of consensus molecular subtype-1 (CMS-1; ie, microsatellite instability immune subtype) among individuals with CRC who were younger than age 40 years.50,51LimitationsThisstudy has several limitations.First, since the NCDB did not collect information on screening, we could confirm that increases in diagnoses from age 49 to 50 years and the survival advantage associated with diagnosis at age 50 years necessarily reflected screening practices.Second, because data on causes of death were not available, we could not calculate CRC-specific mortality.Thus, to address the association of early-onset CRC with survival among young individuals, we selected a relatively young and comparably aged (ie, ages 51-55 years) CRC population for comparison.Third,