Performance of a blood-based test for colorectal cancer screening adjusted to the US census age and sex distribution.

18 Background: Despite availability of various screening options, nearly 40% of eligible U.S. adults were not up to date with the colorectal cancer (CRC) screening. Blood-based testing offers a promising complementary approach and may enhance patient adherence among unscreened individuals. In the PREEMPT CRC study, we evaluated clinical performance of an investigational blood-based screening test for detecting molecular signals of advanced colorectal neoplasia (ACN) in an average-risk population. Freenome blood-based CRC screening test met all primary endpoints demonstrating 79.2% sensitivity for CRC, 91.5% specificity for ACN, 90.8% negative predictive value (NPV) for ACN and 15.5% positive predictive value (PPV) for ACN. Sensitivity for advanced precancerous lesions (APLs) was 12.5%. To evaluate how the test would perform in the standard U.S. population, an analysis of test performance weighted to the U.S. census sex and age distribution was prespecified and performed. Methods: Between May 2020 and April 2022, the study enrolled participants aged 45-85 at average risk for CRC. Enrolled participants had a blood drawn before the bowel preparation for the standard of care screening colonoscopy (CS). CS and applicable histopathology reports underwent central pathologist review. Blood samples were processed blind to clinical findings. Primary endpoints included sensitivity for CRC, specificity for ACN, NPV for ACN and PPV for ACN. A secondary endpoint was sensitivity for APLs. Results: A subset of 32,731 sequentially enrolled participants were included in the clinical validation cohort. Out of those, 27,010 (82.5%) had evaluable blood samples and CS. The median age of the evaluable participants was 57.0 years, and 55.8% were women versus 50.5% in the U.S. Census. Age distribution included 11.0% participants in the 45-49 age group versus 15.3% in the U.S. Census, 33.0% in the 50-54 age group versus 15.6%, and 32.3% in the 55-64 age group versus 32.3%, 20.8% in the 65-74 age group versus 24.3%, 3.0% participants aged 75 or older versus 12.5%. After performance was weighted to match U.S. Census sex and age distributions, sensitivity for CRC was 81.1% (95% CI 71.3%-88.1%), specificity for those without ACN was 90.4% (95% CI 90.0%-90.7%), NPV for those without ACN was 90.5% (95% CI 90.5%-90.7%), and PPV for ACN was 15.5% (95% CI 13.8%-16.2%). Sensitivity for APL was 13.7% (95% CI 12.4%-15.0%). Conclusions: PREEMPT CRC is the largest study evaluating a CRC screening blood-based test to date. The study successfully met all primary endpoints, demonstrating acceptable clinical performance of the investigational blood-based test. The U.S. census sex-age adjusted clinical performance estimates showed improvement in CRC and APL sensitivity. This blood-based test may provide a convenient and effective option for CRC screening in the average-risk U.S. population. Clinical trial information: NCT04369053 .