Personalizing Post-Polypectomy Surveillance for Colorectal Cancer Prevention

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PROJECT SUMMARY AND ABSTRACT Screening is an established method for decreasing colorectal cancer (CRC) incidence and mortality. However, despite guidance supporting CRC screening initiation (i.e., 45 years), relatively little is known about what to do after a precancerous polyp is detected and removed. This is particularly concerning given that over 40% of individuals who undergo CRC screening are found to have a precancerous polyp and then instructed to undergo frequent colonoscopies (termed surveillance) every 3-10 years for CRC risk reduction. Current guidelines utilize a risk-stratification scheme that categorizes patients as high or low risk based only on polyp characteristics from their initial colonoscopy. However, polyp-based risk stratification methods are imprecise, with a sensitivity and specificity of 59-81% and 43-58%, respectively, for predicting subsequent advanced neoplasia after polyp removal. Thus, our current guideline-based risk stratification methods both miss high-risk individuals who may benefit from early surveillance and subject many low-risk individuals to unnecessary colonoscopies and its associated harms. Recent studies from our group and others have identified several clinical and genetic (i.e., polygenic risk score) risk factors associated with CRC; these may further optimize risk stratification following CRC screening and polyp removal, but remain understudied. For this R01 proposal, we will first develop and validate a practical, clinically useful risk prediction tool that incorporates both detailed polyp characteristics and other important predictors known to play an important role in CRC risk, such as clinical and genetic (i.e., polygenic risk score) risk factors (Aims 1 and 2). Second, we will identify optimal strategies for CRC surveillance given individual risk estimates defined in Aims 1-2 and evaluate the cost- effectiveness of different risk-stratified surveillance strategies compared to current guideline recommended polyp-based surveillance strategies (Aim 3). This Aim will leverage our ongoing collaboration with an established, internationally recognized micro-simulation model (MISCAN-Colon) that informs U.S. Preventative Task Force recommendations. Lastly, we will gain patient, clinician, and service provider’s perspectives on these novel comprehensive risk prediction methods, to optimize potential adoption, and assess potential implementation barriers and facilitators (Aim 4). This aim will incorporate group experiences with mixed methods techniques to identify attitudes and barriers of implementation. The overall aims will leverage comprehensive data from an extremely large contemporary community-based cohort and an independent cohort for validation. These cohorts’ detailed data include genome-wide genotype arrays coupled with prior screening, pathologic and clinical data, and surveillance outcomes. This study can substantially transform how we manage care for over 7 million patients diagnosed annually with precancerous polyps, personalize post- polypectomy surveillance using a new, novel, comprehensive, patient-centered risk prediction model, and optimize post-polypectomy surveillance to reduce CRC incidence and mortality.