Development and Clinical Validation of a Blood Test for Early Detection of Colorectal Adenomas and Cancer for Screening and Post-Polypectomy Surveillance

ABSTRACT BACKGROUND & AIMS There is a lack of convenient, sensitive, non-invasive strategies for screening and surveillance for colorectal neoplasia. An assay combining the results of circulating gastrointestinal epithelial cells (CEC) and somatic mutations of cell-free DNA adjusting for age/sex using a unique algorithm is evaluated in patients requiring colonoscopy. METHODS A prospective single-site 458-subject study (asymptomatic: 43% screening/43% surveillance, enriched with 65 symptomatic subjects) undergoing colonoscopy was conducted. The test analyzed CEC and somatic mutations. The probability of advanced neoplasia (advanced adenoma (AA) and CRC) was determined by logistic regression methods adjusted for expected CRC incidence rate, prior history of AA, patient age and sex on a training subset. A linear predictor was developed to generate a score scaled from 0-100. The test performance was evaluated on an independent set of subjects using pre-specified algorithms and cutpoint. RESULTS Based on a pre-defined clinical threshold and predictive model derived from the training set (n=232), analysis of an independent asymptomatic validation set (n=194) yielded 89% (Lower exact one-sided 95% CI: 80%) specificity and 100% (95% CI: 37%)/78% (95% CI: 61%) sensitivity for detection of CRC/AA. In a secondary analysis, excluding surveillance subjects, the 97-subject screening cohort yielded 91% (95% CI: 79%) specificity and CRC/AA sensitivity at 100% (95% CI:37%)/83% (95% CI: 56%, 87% for advanced neoplasia 95% CI: 64%). Significant associations, (p CONCLUSIONS A multimodal blood test that included CEC and somatic mutations with adjustment for age and sex demonstrated high sensitivity for the diagnosis of advanced colorectal neoplasia. The resulting score captures prognostic information for CRC progression of index adenoma size and number and has the potential to enable stratification of patients for screening or post- polypectomy surveillance colonoscopy.