A multi-cancer early detection blood test using machine learning detects early-stage cancers lacking USPSTF-recommended screening.

US Preventive Services Task Force (USPSTF) guidelines recommend single-cancer screening for select cancers (e.g., breast, cervical, colorectal, lung). Advances in genome sequencing and machine learning have facilitated the development of blood-based multi-cancer early detection (MCED) tests intended to complement single-cancer screening. MCED tests can interrogate circulating cell-free DNA to detect a shared cancer signal across multiple tumor types. We report real-world experience with an MCED test that detected cancer signals in three individuals subsequently diagnosed with cancers of the ovary, kidney, and head/neck that lack USPSTF-recommended screening. These cases illustrate the potential of MCED tests to detect early-stage cancers amenable to cure.

Stage-Stratified Incidence Rates of Colorectal Adenocarcinoma Among Patients Aged 46 to 49 in the United States.

This cross-sectional study uses Surveillance, Epidemiology, and End Results registry data to analyze colorectal adenocarcinoma staging incidence of patients aged 46 to 49 years from 2000 to 2020.

Spectrum of Advanced Colorectal Neoplasia and Anticipated Yield of Average-Risk Screening in Veterans Under Age 50.

The incidence of early onset colorectal cancer, or colorectal cancer (CRC) diagnosed before age 50, is increasing.1 In response, multiple societal guidelines in the United States now recommend initiating CRC screening at age 45 in average-risk individuals (ie, those without high-risk clinical characteristics, such as bleeding, or iron deficiency anemia), inflammatory bowel disease, or family history of colorectal neoplasia.2 The Veterans Health Administration (VHA) is the largest integrated health system in the United States and is contending with how best to expand CRC screening access to this younger population in the setting of limited colonoscopy resources. Understanding the rate and anatomic location of colorectal neoplasia in Veterans younger than age 50 can inform the expected yield of different screening modalities. Prior work has shown that individuals undergoing colonoscopy for low-risk diagnostic indications have equivalent risk of colorectal neoplasia as those undergoing average-risk screening.3 This study and a recent meta-analysis4 reported that 3.6% (95% confidence interval, 1.9%-6.7%) to 3.7% (95% confidence interval, 3.0%-4.7%) of average-risk individuals age 45-49 have advanced colorectal neoplasia (ACN), defined as an advanced polyp or carcinoma; however, data specific to the VHA population are lacking.

The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection.

The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented.

Shifts in the Proportion of Distant Stage Early-Onset Colorectal Adenocarcinoma in the United States.

BACKGROUND: Carcinoids, frequently classified as "colorectal cancer" contribute to rising early-onset colorectal cancer (EOCRC) incidence rates (IR) and have distinct staging distributions compared to often advanced stage adenocarcinomas (screening target). Thus, assessing temporal shifts in early-onset distant stage adenocarcinoma can impact public health. METHODS: 2000-2016 Surveillance Epidemiology and End Results (SEER) 18 yearly adenocarcinoma IRs were stratified by stage (in situ, localized, regional, distant), age (20-29, 30-39, 40-49, 50-54-year-olds), subsite (colorectal, rectal-only, colon-only), and race [non-Hispanic whites, non-Hispanic Blacks (NHB), Hispanics] in 103,975 patients. Three-year average annual IR changes (pooled 2000-2002 IRs compared with 2014-2016) and cancer stage proportions (percent contribution of each cancer stage) were calculated. RESULTS: Comparing 2000-2002 with 2014-2016, the steepest percent increases are in distant stage cancers. Colon-only, distant adenocarcinoma increased most in 30-39-year-olds (49%, 0.75/100,000→1.12/100,00, P < 0.05). Rectal-only, distant stage increases were steepest in 20-29-year-olds (133%, 0.06/100,000→0.14/100,000, P < 0.05), followed by 30-39-year-olds (97%, 0.39/100,000→0.77/100,000, P < 0.05) and 40-49-year-olds (48%, 1.38/100,000→2.04/100,000, P < 0.05). Distant stage proportions (2000-2002 to 2014-2016) increased for colon-only and rectal-only subsites in young patients with the largest increases for rectal-only in 20-29-year-olds (18%→31%) and 30-39-year-olds (20%→29%). By race, distant stage proportion increases were largest for rectal-only in 20-29-year-old NHBs (0%→46%) and Hispanics (28%→41%). Distant colon proportion increased most in 20-29-year-old NHBs (20%→34%). CONCLUSIONS: Youngest patients show greatest burdens of distant colorectal adenocarcinoma. Although affecting all races, burdens are higher in NHB and Hispanic subgroups, although case counts remain relatively low. IMPACT: Optimizing earlier screening initiatives and risk-stratifying younger patients by symptoms and family history are critical to counteract rising distant stage disease.

Cost-Effectiveness of Outreach Strategies for Stool-Based Colorectal Cancer Screening in a Medicaid Population.

Outreach, including patient navigation, has been shown to increase the uptake of colorectal cancer (CRC) screening in underserved populations. This analysis evaluates the cost-effectiveness of triennial multi-target stool DNA (mt-sDNA) versus outreach, with or without a mailed annual fecal immunochemical test (FIT), in a Medicaid population. A microsimulation model estimated the incremental cost-effectiveness ratio using quality-adjusted life years (QALY), direct costs, and clinical outcomes in a cohort of Medicaid beneficiaries aged 50-64 years, over a lifetime time horizon. The base case model explored scenarios of either 100% adherence or real-world reported adherence (51.3% for mt-sDNA, 21.1% for outreach with FIT and 12.3% for outreach without FIT) with or without real-world adherence for follow-up colonoscopy (66.7% for all). Costs and outcomes were discounted at 3.0%. At 100% adherence to both screening tests and follow-up colonoscopy, mt-sDNA costed more and was less effective compared with outreach with or without FIT. When real-world adherence rates were considered for screening strategies (with 100% adherence for follow-up colonoscopy), mt-sDNA resulted in the greatest reduction in incidence and mortality from CRC (41.5% and 45.8%, respectively) compared with outreach with or without FIT; mt-sDNA also was cost-effective versus outreach with and without FIT ($32,150/QALY and $22,707/QALY, respectively). mt-sDNA remained cost-effective versus FIT, with or without outreach, under real-world adherence rates for follow-up colonoscopy. Outreach or navigation interventions, with associated real-world adherence rates to screening tests, should be considered when evaluating the cost-effectiveness of CRC screening strategies in underserved populations.

Impact of Relative Dose Intensity of FOLFOX Adjuvant Chemotherapy on Risk of Death Among Stage III Colon Cancer Patients.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines have recommended tailored chemotherapy for stage III high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) colon cancer since 2018. Studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on stage III colon cancer survival, however, none has performed a stratified analysis by risk profiles. This study aims to identify the FOLFOX optimal RDI for high-risk and low-risk stage III colon cancer patients. METHODS: Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by 8 population-based cancer registries. Multivariable Cox model and Fine-Gray competing risks model were employed to explore Optimal RDI defined as the lowest RDI administered without significant differences in either overall or cause-specific death. RESULTS: Among the 168 high-risk patients, the optimal RDI cut-off was 70% (HR = 1.59 with 95% CI: 0.69-3.66 in overall mortality; HR = 1.24 with 95% CI: 0.42-3.64 in cause-specific mortality when RDI < 70% vs. RDI ≥ 70%). Among the 239 low-risk patients, none of the evaluated cut-offs were associated with significant differences in risk of death between comparison groups. The lowest assessed RDI was 45%, HR = 0.80; 95% CI: 0.24 to 2.73 for overall mortality and HR = 0.53; 95% CI: 0.06 to 4.95 for cause-specific mortality, when RDI <45% versus RDI ≥45%. CONCLUSIONS: There is no significant harm on the risk of death when reducing RDI by <30% for high-risk patients. For the low-risk patients, we found that RDI as low as 45% did not significantly affect the risk of death.

Trends in the Incidence of Early-Onset Colorectal Adenocarcinoma Among Black and White US Residents Aged 40 to 49 Years, 2000-2017.

Importance: Early-onset colorectal cancer incidence rates are rising faster in White individuals than Black individuals. However, prior National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) racial stratification analyses used smaller SEER 13 databases, combined patients under age 50 years, did not stratify by sex, and did not focus on adenocarcinoma histologic subtypes (screening target). Objective: To perform a race- and sex-stratified adenocarcinoma incidence rate analysis in individuals aged 40 to 49 years using larger SEER 18 databases with expanded race data to better understand the colorectal cancer burden in those at or approaching screening age. Design, Setting, and Participants: This cross-sectional study used 2000 to 2017 SEER 18 annual age-adjusted colorectal cancer incidence rates stratified by anatomic subsite (colon or rectum), adenocarcinoma histology, race (non-Hispanic Black or non-Hispanic White), and sex for individuals aged 40 to 49 years, and yearly annual percent change (APC) incidence rates were calculated. Annual rate ratios (ARRs) between subgroups were determined. Statistical analysis was performed from January to March 2021. Main Outcomes and Measurements: Early-onset colorectal cancer incidence rates, APCs, and ARRs. Results: In this study, a total of 46 728 colorectal cancer cases were identified in 45 429 patients aged 40 to 49 years from 2000 to 2017. Among the 45 429 patients included in this study, 6480 (14.2%) were Black and 27 426 (60.4%) were White; the mean (SD) age was 45.5 (2.8) years. Among White individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates increased from 19.6 per 100 000 person-years in 2000 to 25.2 per 100 000 person-years in 2017 (APC, 1.6; 95% CI, 1.3 to 1.9). Among Black individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates were not significantly changed (26.4 per 100 000 person-years in 2000 and 25.8 per 100 000 person-years in 2017 [APC, -0.03; 95% CI, -0.5 to 0.5]). There were no significant differences in ARRs of absolute colorectal incidence rates between White and Black individuals from 2014 to 2017. Rectal-only absolute adenocarcinoma incidence rates in Black and White individuals remained similar from 2000 to 2008 but significantly diverged in 2009. As of 2017, rectal absolute incidence rates were 39% higher among White individuals than among Black individuals with increasing APC (APC, 2.2; 95% CI, 1.6 to 2.8) whereas rectal adenocarcinoma incidence rates among Black individuals were decreasing, although the APC was not statistically significant (APC, -1.4; 95% CI, -2.6 to 0.1). Absolute colonic adenocarcinoma incidence rates remained higher in Black individuals. The study subgroups with the largest divergence in APCs were rectal adenocarcinoma in White vs Black women (APC of 2.2 [95% CI, 1.6 to 2.8] vs APC of -1.7 [95% CI, -3.6 to 0.3], respectively). Conclusions and Relevance: This study found that colorectal adenocarcinoma incidence rates in people aged 40 to 49 years were increasing among White individuals but stabilized among Black individuals with absolute incidence rates becoming equivalent. Absolute rectal adenocarcinoma incidence rates were 39% lower in Black individuals with a widening disparity in rectal cancer between White and Black women. Possible contributors include introduction of a screening threshold of age 45 years in Black individuals in 2008. Although the average-risk screening age has now shifted to age 45 years in all racial groups, these data can help motivate real-world implementation of guidelines to maximize screening rates that have historically been suboptimal in younger individuals.

Genetic Analysis of Archived Tumor Specimens for Hereditary Colorectal Cancer Syndromes in the Cajuns of Louisiana, a US Founder Population.

INTRODUCTION: The Louisiana Acadian region (population 1.2 million), home of the Cajuns, has among the highest US colorectal cancer (CRC) rates. Although Cajuns are a known genetic founder population, studies assessing for hereditary CRC have not been performed. METHODS: A retrospective review of 2 hospital cancer registries was performed to identify young (<55) Cajun CRC patients in Lafayette, Louisiana (the Acadian region population center), diagnosed from 2003 to 2016. Men were studied because of the higher likelihoods of retaining Cajun surnames for ancestry identification compared with women. Immunohistochemistry for mismatch repair proteins associated with the Lynch syndrome (LS) was performed on tumors. Germline sequencing was performed on adjacent normal tissue of these archived formalin-fixed paraffin-embedded surgical resection specimens for pathogenic variants underlying CRC-associated syndromes, including LS, familial adenomatous polyposis, and others. RESULTS: Of 9 young Cajuns, a germline analysis revealed LS in 2 (MLH1 frameshift, MLH1 missense pathogenic variants). Both had immunohistochemistry-deficient MLH1. Two others had the same adenomatous polyposis coli variant of unknown significance (2 algorithms predicting deleterious and probably damaging change), making this a potential familial adenomatous polyposis founder effect candidate. DISCUSSION: This is the first study assessing for hereditary CRC in a large US regional founder population. This small study did not identify clear Cajun founder pathogenic variants. However, larger studies are warranted, which could also help clarify the clinical significance of the adenomatous polyposis coli variant of unknown significance. This study is important because it demonstrates that a retrospective tumor analysis can be used to ascertain the prevalence of genetic susceptibility in specific populations.

Impact of Patient Adherence to Stool-Based Colorectal Cancer Screening and Colonoscopy Following a Positive Test on Clinical Outcomes.

Colorectal cancer-screening models commonly assume 100% adherence, which is inconsistent with real-world experience. The influence of adherence to initial stool-based screening [fecal immunochemical test (FIT), multitarget stool DNA (mt-sDNA)] and follow-up colonoscopy (after a positive stool test) on colorectal cancer outcomes was modeled using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model. Average-risk individuals without diagnosed colorectal cancer at age 40 undergoing annual FIT or triennial mt-sDNA screening from ages 50 to 75 were simulated. Primary analyses incorporated published mt-sDNA (71%) or FIT (43%) screening adherence, with follow-up colonoscopy adherence ranging from 40% to 100%. Secondary analyses simulated 100% adherence for stool-based screening and colonoscopy follow-up (S1), published adherence for stool-based screening with 100% adherence to colonoscopy follow-up (S2), and published adherence for both stool-based screening and colonoscopy follow-up after positive mt-sDNA (73%) or FIT (47%; S3). Outcomes were life-years gained (LYG) and colorectal cancer incidence and mortality reductions (per 1,000 individuals) versus no screening. Adherence to colonoscopy follow-up after FIT had to be 4%-13% higher than mt-sDNA to reach equivalent LYG. The theoretical S1 favored FIT versus mt-sDNA (LYG 316 vs. 297; colorectal cancer incidence reduction 68% vs. 64%; colorectal cancer mortality reduction 76% vs. 72%). The more realistic S2 and S3 favored mt-sDNA versus FIT (S2: LYG 284 vs. 245, colorectal cancer incidence reduction 61% vs. 50%, colorectal cancer mortality reduction 69% vs. 59%; S3: LYG 203 vs. 113, colorectal cancer incidence reduction 43% vs. 23%, colorectal cancer mortality reduction 49% vs. 27%, respectively). Incorporating realistic adherence rates for colorectal cancer screening influences modeled outcomes and should be considered when assessing comparative effectiveness. PREVENTION RELEVANCE: Adherence rates for initial colorectal cancer screening by FIT or mt-sDNA and for colonoscopy follow-up of a positive initial test influence the comparative effectiveness of these screening strategies. Using adherence rates based on published data for stool-based testing and colonoscopy follow-up yielded superior outcomes with an mt-sDNA versus FIT-screening strategy.

Real-world cost-effectiveness of stool-based colorectal cancer screening in a Medicare population.

AIM: Multiple screening strategies are guideline-endorsed for average-risk colorectal cancer (CRC). The impact of real-world adherence rates on the cost-effectiveness of non-invasive stool-based CRC screening strategies remains undefined. METHODS: This cost-effectiveness analysis from the perspective of Medicare as a primary payer used the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) to estimate cost and clinical outcomes for triennial multi-target stool DNA (mt-sDNA), annual fecal immunochemical test (FIT) and annual fecal occult blood test (FOBT) screening strategies in a simulated cohort of US adults aged 65 years, who were assumed to either be previously unscreened or initiating screening upon entry to Medicare. Reported real-world adherence rates for initial stool-based screening and colonoscopy follow up (after a positive stool test result) were defined as 71.1% and 73.0% for mt-sDNA, 42.6% and 47.0% for FIT, and 33.4% and 47.0% for FOBT, respectively. The incremental cost-effectiveness ratio using quality-adjusted life years (QALY) was defined as the primary outcome of interest; other cost and clinical outcomes were also reported in secondary analyses. Multiple sensitivity and scenario analyses were conducted. RESULTS: When reported real-world adherence rates were included only for initial stool-based screening, mt-sDNA was cost-effective versus FIT ($62,814/QALY) and FOBT ($39,171/QALY); mt-sDNA also yielded improved clinical outcomes. When reported real-world adherence rates were included for both initial stool-based screening and follow-up colonoscopy (when indicated), mt-sDNA was increasingly cost-effective compared to FIT and FOBT ($31,725/QALY and $28,465/QALY, respectively), with further improved clinical outcomes. LIMITATIONS: Results are based on real-world cross-sectional adherence rates and may vary in the context of other types of settings. Only guideline-recommended stool-based strategies were considered in this analysis. CONCLUSION: Comparisons of the effectiveness and benefits of specific CRC screening strategies should include both test-specific performance characteristics and real-world adherence to screening tests and, when indicated, follow-up colonoscopy.

Contributions of Adenocarcinoma and Carcinoid Tumors to Early-Onset Colorectal Cancer Incidence Rates in the United States.

BACKGROUND: Early-onset colorectal cancer (EOCRC) incidence rates (IRs) are rising, according to previous cancer registry analyses. However, analysis of histologic subtypes, including adenocarcinoma (the focus of CRC screening and diagnostic testing) and carcinoid tumors (which are classified as "colorectal cancer" in SEER [Surveillance, Epidemiology, and End Results] databases but have a distinct pathogenesis and are managed differently from adenocarcinoma), has not been reported. OBJECTIVE: To assess EOCRC IRs and changes in IRs over time, stratified by histology. DESIGN: Retrospective analysis. SETTING: Yearly IRs according to SEER 18 data from 2000 to 2016 on age-specific colon-only, rectal-only, and combined-site CRC cases, stratified by histology ("overall" CRC [all histologic subtypes], adenocarcinoma, and carcinoid tumors) and age. PATIENTS: 119 624 patients with CRC. MEASUREMENTS: IRs per 100 000 population, changes in 3-year average annual IRs (pooled IRs from 2000 to 2002 vs. those from 2014 to 2016), and annual percentage change (APC) in persons aged 20 to 29, 30 to 39, 40 to 49, and 50 to 54 years. RESULTS: The steepest changes in adenocarcinoma 3-year average annual IRs were for rectal-only cases in persons aged 20 to 29 years (+39% [0.33 to 0.46 per 100 000]; P < 0.050) and 30 to 39 years (+39% [1.92 to 2.66 per 100 000]; P < 0.050) and colon-only cases in those aged 30 to 39 years (+20% [3.30 to 3.97 per 100 000]; P < 0.050). Corresponding APCs were 1.6% (P < 0.050), 2.2% (P < 0.050), and 1.2% (P < 0.050), respectively. In persons aged 40 to 49 years, 3-year average annual IRs increased in both colon-only (+13% [12.21 to 13.85 per 100 000]; P < 0.050) and rectal-only (+16% [7.50 to 8.72 per 100 000]; P < 0.050) subsites. Carcinoid tumors were common, representing approximately 4% to 20% of all colorectal and 8% to 34% of all rectal cancer cases, depending on age group and calendar year. Colon-only carcinoid tumors were rare. Colorectal carcinoid tumor IRs increased more steeply than adenocarcinoma in all age groups, thus affecting the contribution of carcinoid tumors to overall cancer cases over time. These changes were driven by rectal subsites and were most pronounced in persons aged 50 to 54 years, in whom rectal carcinoid tumors increased by 159% (2.36 to 6.10 per 100 000) between 2000 to 2002 and 2014 to 2016, compared with 10% for adenocarcinoma (18.07 to 19.84 per 100 000), ultimately accounting for 22.6% of all rectal cancer cases. LIMITATION: Population-based data. CONCLUSION: These findings underscore the importance of assessing histologic CRC subtypes independently. Doing so may lead to a better understanding of the drivers of temporal changes in overall CRC incidence and a more accurate measurement of outcomes from efforts to reduce adenocarcinoma risk, and can guide future research. PRIMARY FUNDING SOURCE: None.

Primary Care Provider Knowledge and Practice in Risk Assessment for Early Age Onset Colorectal Cancer: Opportunities for Improvement.

Colorectal cancer (CRC) incidence and mortality are rising in individuals under age 50, termed early age onset (EAO) CRC. Lower endoscopy is recommended for all patients with unexplained iron deficiency anemia (IDA) or hematochezia to assess the EAO-CRC. For those without symptoms, professional societies recommend decreasing the age to start screening from 50 to 45. Primary care provider (PCP) knowledge and practices around EAO-CRC risk assessment and screening are unknown. We conducted a survey study in May, 2020 of multi-specialty PCPs from three large medical systems to assess PCP knowledge, risk stratification practices and barriers/facilitators they face to offer CRC screening in patients < 50. We conducted univariate analysis to assess factors associated with knowledge and diagnostic practices. Response rate was 27.7% (196/708). Although 77.6% of respondents were aware that EAO-CRC incidence is increasing, only 42.9% knew that EAO-CRC mortality is also increasing. Of note, 91.8% recommend starting average risk screening at age 50. For 40- to 49-year-old patients present with unexplained IDA or hematochezia, 71.9% and 50.5% of respondents, respectively, recommend a diagnostic colonoscopy. Trainees were less likely to be aware of rising EAO-CRC mortality (odds ratio, 0.42; 95% CI, 0.21 to 0.82) and non-internal medicine providers were less likely to recommend CRC screening in those with a first-degree relative with CRC (odds ratio, 0.82; 95% CI, 0.72 to 0.93). Ongoing education efforts will be required to improve recognition and management of high-risk symptoms, particularly among non-internists and trainees.

Screening for Colorectal Cancer.

Colorectal cancer screening is essential to detect and remove premalignant lesions to prevent the development of colorectal cancer. Multiple screening modalities are available, including colonoscopy and stool-based testing. Colonoscopy remains the gold standard for detection and removal of premalignant colorectal lesions. Screening guidelines by the American Cancer Society now recommend initiating screening for all average-risk adults at 45 years old. Family history of colorectal cancer, other cancers, and advanced colon polyps are strong risk factors that must be considered in order to implement earlier testing. Epidemiologic studies continue to show disparities in colorectal cancer incidence and mortality and wide variability in screening rates.

Geographic and intra-racial disparities in early-onset colorectal cancer in the SEER 18 registries of the United States.

BACKGROUND: Although early-onset colorectal cancer (EOCRC) incidence rates (IRs) are increasing, geographic and intra-racial IR disparities are not well defined. METHODS: 2000-2015 Surveillance, Epidemiology, and End Results (SEER) program CRC IR Analysis (170,434 cases) was performed from ages 30 to 60 in four US regions, 18 individual registries, metropolitan and nonmetropolitan locations and stratified by race. Analyses were conducted in 1-year and 5-year age increments. RESULTS: Wide US regional EOCRC IR variations exist: For example, age 45 IRs in the south are 26.8/100,000, 36.0% higher than the West, 19.7/100,000 (p < 0.0001). Disparities magnify between individual registries: EOCRC IRs in highest risk registries were 177-348% (Alaska Natives), 75-200% (Hawaii), 76-128% (Louisiana), and 61-125% (Kentucky) higher than lowest risk registries depending on age. EOCRC IRs are 18.2%-25.6% higher in nonmetropolitan versus metropolitan settings. Wide geographic intra-racial disparities exist. Within the White population, the greatest IR difference (78.8%) was between Kentucky (5.9/100,000) and Los Angeles (3.3/100,000) in 30- to 34-year-olds (p < .0001). Within the Black population, the greatest difference (136.2%) was between rural Georgia (30.7/100,000) and California excluding San Francisco-Oakland/San Jose-Monterey/Los Angeles (13/100,000) in 40- to 44-year-olds (p = 0003). CONCLUSION: Marked geographic EOCRC disparities exist with disproportionately high IRs in Alaska Natives, Hawaii, and southern registries. Geographic intra-racial disparities are present within White and Black populations. In Blacks, there are disproportionately high EOCRC IRs in rural Georgia. Although vigilance is required in all populations, attention must be paid to these higher risk populations. Potential interventions include assuring early investigation of symptoms, targeting modifiable risk factors and utilizing earlier age 45 screening options supported by some guidelines.