Prior studies have reported the prevalence of colorectal cancer (CRC) in average-risk screening population ages 50 to 75 to be 0.7% to 1.0%.1, 2 However, no estimates from studies enrolling individuals undergoing screening colonoscopy have been reported. The experience of ongoing studies enrolling average risk individuals is that the prevalence rates are substantially lower. A 2020 study from a community-based cohort undergoing CRC screening with fecal immunochemical testing (FIT) followed by diagnostic colonoscopy reported a CRC prevalence rate of 1.46 per 1000, or 0.15%.3 The aim of our study is to report the screen-detected prevalence of CRC and advanced neoplasia in an average-risk asymptomatic individuals from selected academic and community medical centers in the US, Canada, and Germany and describe associated risk factors.
The NCI-funded Early Detection Research Network’s Great Lakes/New England Clinical Validation Center, GLNE 010 was a prospective multicenter study aimed at validating biomarkers of risk of CRC and advanced neoplasia with 29 geographically dispersed study sites across the US, and one each in Canada and Germany (Supplementary Table 1). There were two discrete time periods for the study (2011-2017 and 2018-2019). During the second period, three additional US sites were added. Between 2011 and 2019 the study enrolled two groups of individuals: 1) average-risk (asymptomatic and no family or personal history of CRC or advanced neoplasia) men and women between the ages of 50 and 85 years scheduled for screening colonoscopy (i.e., no prior CRC screening or last colonoscopy screening at least 5 years ago with no known prior adenomas) and 2) individuals due for surveillance colonoscopy, for follow-up of adenomas. The study followed the STROBE guidelines and used rigorous data collection protocols.4 Participants completed baseline demographic and lifestyle questionnaires and provided blood and stool samples prior to bowel preparation for their screening colonoscopy. The colonoscopies were performed by gastroenterologists at the study sites. Colonoscopy records and associated histopathology reports were collected. Participants with complete colonoscopies and adequate preparation were included in the analysis. For cancers staging information was collected from the medical records.
CRC was defined as a primary adenocarcinoma of the colon or rectum and staged using the American Joint Commission on Cancer (AJCC) classification system (8th edition). Polyps removed during colonoscopy were classified using the World Health Organization (WHO) classification as hyperplastic polyps, tubular, villous, or tubulovillous adenomas, or sessile serrated lesions. Advanced adenomas were defined as any adenoma either 10mm or larger or with villous features or high-grade dysplasia. Advanced sessile serrated lesions were sessile serrated lesions 10mm or larger, or a traditional serrated adenoma of any size. Aspirin and non-steroidal anti-inflammatory drugs (NSAID) use were classified as regular use, occasional use, or not used and based on participant’s self-report.
For the study, we defined CRC, advanced adenomas and advanced sessile serrated lesions as advanced colorectal neoplasia (ACRN). Cross tabulations of individual risk factors with ACRN are presented. A generalized estimating equations (GEE) logistic regression model was fit with ACRN as the response variable to examine effects of multiple risk factors while accounting for potential correlations attributable to clustering by study site. The GEE model employed an exchangeable working correlation structure. Since study site factors are potentially associated with the project time periods (2011-2017, 2018-2019), the GEE model included time period as a covariate. Race was categorized as white, Black, and other. All statistics employed R software, version 4.0.4.
The study enrolled 6,811 individuals, 5,291 undergoing screening and 1,520 undergoing surveillance colonoscopy. Of the 5,291 participants enrolled for screening, 410 did not undergo colonoscopy and were excluded, leaving 4,881 participants with complete outcome data. The average age was 59.9 years and 43.2% of participants were men (Table 1). Ten individuals were found to have CRC for a prevalence rate of 0.20% (95% CI 0.080%, 0.32%). Two CRCs were in the proximal colon, four in the distal colon and four in the rectum. One was AJCC stage 0, five stage I, two stage IIA, and one each of stage IIIA and IVA.
Table 1.
Baseline characteristics of participating individuals and associations with Advanced Colorectal Neoplasia
| Variable | No ACRN (n=4380) |
ACRN (n=501) |
OR (95%CI) |
|---|---|---|---|
| Age [mean (SD)] | 59.8 (8.1) | 60.5 (8.0) | |
| 50-54 | 1,483 (33.9) | 132 (26.3) | 1.00 |
| 55-59 | 818 (18.7) | 128 (25.5) | 1.18 (0.86, 1.64) |
| 60-64 | 722 (16.5) | 88 (17.6) | 1.30 (0.93, 1.82) |
| 65-69 | 665 (15.2) | 76 (15.2) | 1.50 (1.09, 2.08) |
| 70-74 | 473 (10.8) | 47 ( 9.4) | 1.69 (1.13, 2.54) |
| 75-79 | 203 ( 4.6) | 25 ( 5.0) | 1.90 (1.24, 2.92) |
| 80-85 | 16 ( 0.4) | 5 ( 1.0) | 3.61 (1.58, 8.23) |
| Gender | |||
| Female | 2,532 (57.8) | 239 (47.7) | 1.00 |
| Male | 1,848 (42.2) | 262 (52.3) | 1.37 (1.16, 1.62) |
| Race | |||
| White | 3,908 (90.5) | 459 (93.7) | 1.00 |
| Black | 256 ( 5.9) | 17 ( 3.5) | 0.72 (0.44, 1.18) |
| Other | 155 ( 3.6) | 14 ( 2.9) | 1.10 (0.61, 1.98) |
| Refused | 11 ------- | 1 ------- | |
| Unknown | 50 ------- | 10 ------- | |
| Ethnicity | |||
| Non-Hispanic | 4,215 (96.3) | 489 (98.2) | 1.00 |
| Hispanic | 162 ( 3.7) | 9 ( 1.8) | 0.38 (0.19, 0.75) |
| Refused | 1 ------- | 0 ------- | |
| Unknown | 2 ------- | 3 ------- | |
| Smoking Status [mean* (SD)] | 16.9 (20.5) | 19.8 (17.0) | |
| Never Smoked | 2,730 (62.4) | 248 (49.5) | 1.00 |
| Former Smoker | 1,357 (31.0) | 181 (36.1) | 1.35 (1.05, 1.73) |
| Current Smoker | 291 ( 6.6) | 72 (14.4) | 2.11 (1.68, 2.65) |
| Unknown | 2 ------- | 0 ------- | |
| Prior screening or colonoscopy | |||
| No prior colonoscopy | 2,642 (60.3) | 374 (74.7) | 1.00 |
| Prior colonoscopy | 1,738 (39.7) | 127 (25.3) | 0.60 (0.48,0.75) |
| Alcohol Use [mean** (SD)] | 5.9 (6.6) | 6.3 (8.3) | |
| Never Drink | 1,263 (29.0) | 128 (25.9) | 1.00 |
| Alcohol Consumer | 3,087 (71.0) | 367 (74.1) | 1.02 (0.85, 1.23) |
| Unknown | 30 ------- | 6 ------- | |
| Aspirin | |||
| Do not use | 3,184 (72.7) | 402 (80.2) | 1.00 |
| Occasional use | 129 ( 2.9) | 11 ( 2.2) | 0.96 (0.59, 1.56) |
| Regular use | 1,067 (24.4) | 88 (17.6) | 0.85 (0.66, 1.10) |
| NSAID | |||
| Do not use | 3,518 (80.3) | 421 (84.0) | 1.00 |
| Occasional use | 670 (15.3) | 62 (12.4) | 1.02 (0.82, 1.28) |
| Regular use | 192 ( 4.4) | 18 ( 3.6) | 1.01 (0.60, 1.70) |
| GLNE 010 version | |||
| Version 1 (2011-2017) | 3,034 (69.3) | 246 (49.1) | 1.00 |
| Version 2 (2018-2019) | 1,346 (30.7) | 255 (50.9) | 1.28 (1.03, 1.60) |
ACRN: Advanced Colorectal Neoplasia
Mean pack-years among smokers
Mean drinks per week among consumers
One or more ACRN was reported in 501 individuals (ACRN prevalence rate of 10.3%; supplementary table 2). Factors associated with ACRN were older age (OR 1.50; 95% CI 1.09-2.08 for ages 65-69, OR 1.69; 95% CI 1.13-2.54 for ages 70-74 and OR 1.90; 95% CI 1.24-2.92 for ages 75-79, respectively, compared with ages 50-54). The OR for male sex was 1.37 (95% CI 1.16-1.62), for current smoking 2.11 (95% CI 1.68-2.65) and former smoking 1.35 (95% CI 1.05, 1.73) (Table 1). Compared to first-time colonoscopy, prior colonoscopy was associated with a lower risk of ACRN at screening (12.4% vs. 6.8% respectively, OR 0.60; 95% CI 0.48, 0.75). There was no interaction between prior colonoscopy and age. Compared to non-Hispanic ethnicity, Hispanic ethnicity was associated with a lower risk of ACRN at screening (OR 0.38; 95% CI 0.19-0.75). We did not find an association with Black race, use of alcohol, aspirin or NSAIDs.
We found a screen-detected CRC prevalence rate of 0.20% and an ACRN prevalence rate of 10% in a multicenter prospective study of average risk individuals from multiple geographic locations. These estimates can be used by patients and clinicians to guide the informed discussion on risk and benefits of colonoscopy screening, and provide a basis to compare risk benefits to other screening modalities. Older studies overestimated the current US prevalence of CRC in average-risk individuals, and thus the benefits versus the harms of screening. In 2012, Quintero et al reported CRC prevalence of 0.5% and advanced adenoma prevalence of 9.7% in average risk asymptomatic individuals that underwent screening colonoscopy in a randomized trial comparing colonoscopy to FIT in Spain.5 In 2014, a multicenter international study on average-risk individuals age 50 and older to validate the methylated Septin 9 blood test (SEPT9) reported a CRC prevalence of 0.12%.6 As reported by others7-9 we found older age, male gender, non-Hispanic ethnicity, and smoking to be risk factors for ACRN.
The strengths of our study are the multiple sites from dispersed geographic locations, representation of both academic and community-based endoscopy practices, strict inclusion of only average-risk screen-eligible populations, and comprehensive collection of baseline risk factors. The limitations of our study are the small number of CRC, precluding a more precise estimate of CRC prevalence.
In conclusion, our study provides valuable information regarding the prevalence of CRC and advanced neoplasia for informed discussions on colonoscopy screening, calculation of required sample size for future studies, and cost-effectiveness modelling.
Supplementary Material
Acknowledgements:
We would like to thank the following individuals from the Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, for their input and support of the study: Paul Wagner, Matthew R. Young, and Sudhir Srivastava, and our participating centers (Supplementary table 1) and site investigators for their valuable contributions.
Funded by: NCI CA864009 (DEB), NCI U24CA086368 (TLM, ZF) and support from Clinical Genomics Inc., Volition LLC and, Eiken Chemical Company. Dr. Ruffin is supported by the Hershey Company Professor and Dr. and Mrs. Forney George Fellowship.
*.
Early Detection Research Network Consortium members who are co-authors:
Ziding Feng, Dale F. McLerran, Timothy R. Church, John A. Baron, Mack Ruffin and Hermann Brenner
Footnotes
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Disclosures:
Shaukat A: Research funding from Freenome Inc.
Crockett SD: Research funding from Exact Sciences, Freenome Inc and Guardant Inc.
No relevant conflicts of interest for any of the other authors
Contributor Information
Aasma Shaukat, Department of Medicine, and Masonic Cancer Center and School of Public Health Division of Environmental Health Sciences , University of Minnesota, Minneapolis, Veterans Affairs Medical Center, Minneapolis MN.
Tracey L. Marsh, Department of Biostatistics, Fred Hutch Cancer Center and University of Washington, Seattle WA
Seth D. Crockett, Department of Medicine University of North Carolina, Chapel Hill NC
Sapna Syngal, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston MA.
Robert S. Bresalier, Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston TX
Dean E. Brenner, Department of Medicine University of Michigan, Ann Arbor MI
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