Optimal Colorectal Cancer Surveillance Strategy for Lynch Syndrome by Genotype

The overall goal of the proposed research is to optimize colorectal cancer (CRC) screening strategies for individuals at the highest risk for CRC development attributable to Lynch Syndrome (LS). Germline alterations in one of four DNA mismatch repair (MMR) genes causes LS, an autosomal dominant condition associated with multiple malignancies and the most common inherited CRC syndrome. LS affects nearly 1/300 individuals and ~1 million individuals in the US, similar to BRCA-related hereditary breast and ovarian cancer syndrome. Current CRC surveillance recommendations for LS involve colonoscopy every 1-2 years starting at age 25 years; in their lifetime, individuals with LS will have completed ~50 colonoscopies (vs. 3 for average-risk screening). This intensive strategy is based on inflated lifetime CRC risk estimates and do not account for variable risk based on genotype. As a result, the current “one-size-fits-all” approach to CRC surveillance in LS individuals with the less aggressive genotypes subjects them to over-testing and overtreatment, with a negative impact on quality of life and significant resource utilization. The overarching hypothesis of our proposal is that CRC surveillance in LS should be tailored to the risk of CRC incidence and mortality associated with each genotype to improve individual health outcomes, resource utilization, and acceptability to providers and patients alike. The hypothesis will be tested with three aims: Aim 1: Determine the optimal gene-specific colonoscopy regimen in LS and estimate the improved resource utilization (colonoscopy demand) with a personalized LS surveillance approach. Using simulation modeling, we will refine the LS-CRC model to project the long-term outcomes for numerous strategies for each of the four MMR genes (MLH1, MSH2, MSH6, and PMS2) with varying (a) surveillance intervals. This will allow us to estimate the number of colonoscopies with current and various regimens evaluated. Aim 2: Evaluate the impact of incorporating non-invasive CRC screening modalities, such as stool studies (fecal immunohistochemical testing (FIT) and FIT-fecal DNA) to colonoscopy surveillance for LS carriers. We will use our model to evaluate a novel, hybrid approach to CRC surveillance that will incorporate non-invasive approaches to colonoscopy to minimize overutilization of colonoscopy, potentially improving outcomes by increasing adherence and saving costs. Aim 3: Assess barriers, facilitators, and attitudes towards current and new, personalized, gene-specific CRC surveillance strategies. We will assess attitudes towards colonoscopy with or without non-invasive CRC screening tests among healthcare providers and patients. Impact: By award period end, we will have produced personalized risk-tailored CRC surveillance regimens with LS that optimize effectiveness and cost-effectiveness. Results of this proposal will provide evidence to support the de-implementation of colonoscopy overuse in LS.