Risk factors and prediction models for colorectal cancer in older US individuals

Background: Colorectal cancer (CRC) has high incidence and mortality in older adults, yet routine screening after age 75 is generally not recommended and current guidelines are limited. Risk factors for CRC diagnosed after age 75 and the subgroups of older individuals at highest risk are not well defined. Methods: We conducted a prospective cohort analysis within the Nurses' Health Study and the Health Professionals Follow-Up Study among participants free of CRC through age 75. Established CRC risk factors were assessed up to age 75, with modifiable factors averaged across repeated questionnaires. We calculated age- and sex-standardized incidence rates (standardized to the 2000 US standard population) and used Cox proportional hazards regression to estimate associations and build a risk prediction model. Model discrimination was evaluated using the C-statistic. Results: Among 92,773 participants, 848 developed CRC after age 75. A history of lower endoscopy by age 75 was associated with substantially lower CRC risk (incidence, 113 vs 237 per 100,000), and this association was consistent regardless of indication (screening or symptoms). When considering endoscopy timing by age 75, participants whose last endoscopy occurred between ages 66 and 75 had lower CRC incidence than those whose last endoscopy was before age 66 (i.e., missing at least one recommended endoscopy; 102 vs 163 per 100,000). Risk was higher in men and in those with a family history of CRC. Modifiable factors showed positive associations for heavy smoking, alcohol consumption, body mass index (BMI), and processed meat intake. Some subgroups had incidence rates comparable to those without prior endoscopy, such as individuals with ≥2 affected first-degree relatives, >2 alcoholic drinks/day, and BMI ≥35 kg/m 2 (210 to 243 per 100,000). No significant associations were observed for height, waist circumference, history of diabetes, physical activity, unprocessed red meat, dietary fiber, or whole grain intake. Compared to a model including only prior lower endoscopy, adding last-endoscopy timing, sex, family history, and modifiable factors significantly improved discrimination (C-statistic from 0.55 to 0.66; p < 0.001). Conclusion: In two large prospective cohorts, lower endoscopy by age 75, particularly between ages 66 and 75, was associated with substantially lower CRC incidence after age 75, and family history and modifiable factors further stratify risk. Incorporating these factors improved risk prediction and may guide individualized prevention beyond age 75.