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Principal Investigator
Laura Hester
Ph.D., Sc.M.
Janssen Research and Development, LLC
Position Title
Associate Director, Epidemiology
About this CDAS Project
PLCO (Learn more about this study)
Project ID
Initial CDAS Request Approval
Nov 17, 2020
Using clinicopathological data to determine risk of metachronous advanced colorectal neoplasia among patients with adenomas
Chemoprophylaxis uses pharmaceuticals to prevent colorectal neoplasia development and is a promising strategy for reducing colorectal cancer (CRC) incidence and mortality.[1] Chemoprophylaxis has benefits over screening by intercepting colorectal neoplasia development rather than relying on identification and removal of neoplasia that has already commenced. Effective clinical implementation of chemoprophylactics requires identifying who has a high near-term risk of metachronous advanced colorectal neoplasia (ACN) and will benefit most from chemoprophylaxis. Prior research suggests that approximately 12% of patients with an adenoma present with metachronous ACN within a median of 4 years, indicating that having any adenoma confers a higher risk of ACN.[2] Prior predictive models for metachronous ACN using clinical/lifestyle characteristics among patients with an adenoma had low performance, suggesting models with additional pathology or laboratory data are needed.[3] Studies on histopathological characteristics have found that adenoma number and size were the most significant risk factors for ACN.[2,4,5] Two studies used both clinical/lifestyle and histopathological data to develop a risk model but combined overly heterogenous trial data or were based only on single center data from a non-Western population.[2,4] To inform chemoprophylaxis implementation, a high-performing risk prediction model and scoring system that includes both clinical/lifestyle and histopathological covariates is needed to identify patients with a high near-term risk of ACN.

The overall objective is to identify patients with an adenoma at highest risk for metachronous high-risk adenoma (HRA) or ACN within 3 or 5 years. We will use a retrospective observational study among participants aged 18+ who were randomized to receive the flexible sigmoidoscopy screening intervention in the PLCO trial and had an adenoma at baseline. The primary outcome will be HRA (>2 adenomas of any histology) or ACN (tubular adenoma ≥10 mm, adenoma with villous features or high grade dysplasia of any size, or invasive CRC) within 3 or 5 years of the first adenoma depending on year of randomization.[5] The secondary outcome will be CRC diagnosis within 10 years. Covariates will include demographic, BMI, comorbidity, familial history, and lifestyle/diet predictors from baseline questionnaires, as well as colorectal adenoma location, size, number, and histology from the PLCO colorectal screening study. We plan to explore the following aims:

Aim 1: To develop, internally validate, and select the highest performing parametric or machine learning models to predict risk of HRA/ACN within 3 or 5 years among train and test cohorts of patients with an adenoma at the index flexible sigmoidoscopy.
Aim 2: To assess variable importance in the best performing model from Aim 1 to develop and assess the performance of a simplified model that can be applied in patients with an adenoma at screening.
Aim 3: To use probability from the simplified model in Aim 2 to stratify patients into low, medium, and high risk groups of HRA/ACN in 3 or 5 years and to assess model reclassification versus existing models.

External validation of the simplified model will be conducted.

1. The Use of Aspirin for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):365-375.
2. Martinez ME, Baron JA, Lieberman DA, et al. A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy. Gastroenterology. 2009;136(3):832-841.
3. Peng L, Weigl K, Boakye D, Brenner H. Risk Scores for Predicting Advanced Colorectal Neoplasia in the Average-risk Population: A Systematic Review and Meta-analysis. Am J Gastroenterol. 2018;113(12):1788-1800.
4. Chung SJ, Kim YS, Yang SY, et al. Five-year risk for advanced colorectal neoplasia after initial colonoscopy according to the baseline risk stratification: a prospective study in 2452 asymptomatic Koreans. Gut. 2011;60(11):1537-1543.
5. Gupta S, Lieberman D, Anderson JC, et al. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2020;158(4):1131-1153.


Laura Hester, Janssen R&D, LLC
Justin Callaway, Janssen R&D, LLC
Hari Singhal, Janssen R&D, LLC
Janeta Nikolovski, Janssen R&D, LLC
Gary Borzillo, Janssen R&D, LLC