Long-Term Colorectal Cancer Incidence and Mortality After Colonoscopy Screening According to Individuals' Risk Profiles

Kai Wang, MD, PhD; Wenjie Ma, MD, ScD; Kana Wu, MD, PhD; Shuji Ogino, MD, PhD; Edward L. Giovannucci, MD, ScD; Andrew T. Chan, MD, MPH; Mingyang Song, MD, ScD


J Natl Cancer Inst. 2021;113(9):1177-1185. 

In This Article

Abstract and Introduction


Background: It remains unknown whether the benefit of colonoscopy screening against colorectal cancer (CRC) and the optimal age to start screening differ by CRC risk profile.

Methods: Among 75 873 women and 42 875 men, we defined a CRC risk score (0–8) based on family history, aspirin, height, body mass index, smoking, physical activity, alcohol, and diet. We calculated colonoscopy screening-associated hazard ratios and absolute risk reductions (ARRs) for CRC incidence and mortality and age-specific CRC cumulative incidence according to risk score. All statistical tests were 2-sided.

Results: During a median of 26 years of follow-up, we documented 2407 CRC cases and 874 CRC deaths. Although the screening-associated hazard ratio did not vary by risk score, the ARRs in multivariable-adjusted 10-year CRC incidence more than doubled for individuals with scores 6–8 (ARR = 0.34%, 95% confidence interval [CI] = 0.26% to 0.42%) compared with 0–2 (ARR = 0.15%, 95% CI = 0.12% to 0.18%, P trend < .001). Similar results were found for CRC mortality (ARR = 0.22%, 95% CI = 0.21% to 0.24% vs 0.08%, 95% CI = 0.07% to 0.08%, P trend < .001). The ARR in mortality of distal colon and rectal cancers was fourfold higher for scores 6–8 than 0–2 (distal colon cancer: ARR = 0.08%, 95% CI = 0.07% to 0.08% vs 0.02%, 95% CI = 0.02% to 0.02%, P trend < .001; rectal cancer: ARR = 0.08%, 95% CI = 0.08% to 0.09% vs 0.02%, 95% CI = 0.02% to 0.03%, P trend < .001). When using age 45 years as the benchmark to start screening, individuals with risk scores of 0–2, 3, 4, 5, and 6–8 attained the threshold CRC risk level (10-year cumulative risk of 0.47%) at age 51 years, 48 years, 45 years, 42 years, and 38 years, respectively.

Conclusions: The absolute benefit of colonoscopy screening is more than twice higher for individuals with the highest than lowest CRC risk profile. Individuals with a high- and low-risk profile may start screening up to 6–7 years earlier and later, respectively, than the recommended age of 45 years.


Colorectal cancer (CRC) is the third-leading cause of cancer death in the United States.[1] Screening has been shown to decrease CRC incidence and mortality by identifying and removing precancerous polyps and early cancers.[2–14] Among the available screening options,[9,10] colonoscopy is most widely used in the United States.[15] Despite an overall increase in the uptake of CRC screening, there remains a substantial disparity in the uptake[16–19] and approximately 40% screening-eligible adult Americans not complying with the recommendations.[20,21] These data highlight the importance of tailored screening recommendations based on risk profile to optimize the benefit of screening and resource allocation at the population level.

Currently, CRC screening is recommended based only on age and family history. Although several studies have examined CRC risk prediction based on clinical, lifestyle, environmental, and genetic factors, those studies either aimed to develop screening recommendations based on the predicted CRC risk[22–26]) or examined the joint effect of predictors and screening on CRC risk.[27] To the best of our knowledge, no prior study has directly examined whether the benefit of screening differs by risk profile.

The optimal age to start screening is a critical component of screening recommendations. Since 2002, the US Preventive Services Task Force (USPSTF) recommended CRC screening to start at age 50 years in average-risk adults. Given the increasing incidence of early-onset CRC in recent years,[28] in 2020, the USPSTF released the draft recommendation that average-risk adults may initiate routine screening at age 45 years instead of 50 years.[29] A similar recommendation has been made by the American Cancer Society.[30] These recommendations for earlier screening have spurred intensive debate about the risk-benefit balance and led to greater interest in developing risk-based screening strategies.[22,31]

Therefore, in the current study, we prospectively assessed the relative and absolute risk of CRC incidence and mortality associated with colonoscopy screening according to individuals' risk profiles within 2 large cohorts in the United States, including the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). We also examined the age-specific CRC cumulative incidence and identified the ages when the threshold CRC risk at age 45 years and 50 years, respectively, was attained among individuals with different CRC risk profiles.