Colorectal cancer (CRC) screening reduces incidence and mortality but participation in the USA remains suboptimal and unequally distributed across sociodemographic groups. National screening prevalence cited in the protocol is approximately 59% overall with lower rates among many racial/ethnic minoritised groups and other disadvantaged populations. Lower screening is associated with disparities by race/ethnicity, immigration status, insurance and income.
Non-invasive screening approaches may improve uptake. The protocol focuses on a recently US Food and Drug Administration-approved blood test that analyses circulating cell-free DNA (cfDNA) for methylation and fragmentation patterns and for somatic variants in genes such as KRAS and APC. Published accuracy data referenced in the protocol report about 83% sensitivity and 90% specificity for CRC detection compared with colonoscopy as the reference. Given the convenience of a blood draw, cfDNA testing is hypothesised to increase screening participation, particularly in populations with historically low uptake.
However, important evidence gaps remain. Prior studies of cfDNA uptake have been conducted in largely white, well insured populations and may not generalise to Federally Qualified Health Centers (FQHCs) or other settings serving low-income, racially/ethnically diverse patients. In addition, cfDNA has lower sensitivity for advanced precancerous polyps than some established tests, and population benefit will depend on net increases in screening participation without undue substitution away from more sensitive modalities. Colonoscopy follow-up after abnormal non-invasive tests is often suboptimal nationally, and follow-up after abnormal cfDNA has not been well characterised.
The overarching aim stated in the protocol is to determine whether offering a cfDNA blood-based strategy as an option can reduce screening disparities by increasing CRC screening participation among patients within an FQHC system.
The protocol lists several strengths:
The protocol also acknowledges limitations:
Primary objective
The primary objective is to compare the impact of offering usual care versus expanded options that include a cfDNA test on CRC screening participation among 340 age-eligible patients who are not up-to-date with screening.
Primary hypothesis
The investigators prespecified that screening completion within 60 days of randomisation will be greater by more than 15 percentage points in the intervention group compared with usual care; a difference greater than 15% was defined as the minimal clinically important difference.
Secondary objective
Among individuals with abnormal test results, the trial will compare rates of colonoscopy referral, scheduling and completion between arms. The distribution of screening test types (FIT, colonoscopy, cfDNA, or both cfDNA and FIT) among participants completing screening will also be summarised.
Exploratory hypothesis
The protocol notes an expectation that numerically more patients in the intervention group will have colonoscopy referral, scheduling and completion, but frames this as exploratory.
This is a pragmatic, two-arm randomised controlled trial enrolling 340 patients at the Family Health Centers of San Diego (FHCSD), a Federally Qualified Health Center network serving a racially and ethnically diverse, low-income patient population. Eligible participants are aged 45–75 and not up-to-date with CRC screening. Randomisation is 1:1 to intervention versus usual care.
Intervention arm
Patients randomised to the intervention arm will be offered a choice among three options: colonoscopy, an at-home fecal immunochemical test (FIT), or an in-clinic cfDNA blood test together with an at-home FIT. The in-clinic cfDNA option reflects incorporation of the FDA-approved blood-based assay into the primary care workflow.
Usual care arm
Participants randomised to usual care will be offered the standard options available in the clinic: colonoscopy or at-home FIT.
All participants in both arms will receive education on the importance of CRC screening and reminders to complete testing, consistent with the pragmatic, workflow-embedded trial design.
Primary outcome
The primary outcome is completion of any CRC screening test within 60 days of enrolment/randomisation, analysed as the proportion of randomized patients completing screening in each group. Group comparisons will be performed using a χ2 test of proportions.
Secondary outcomes
Secondary measures include the number of abnormal results for each modality, test result distributions, the number of patients with abnormal tests who are referred for follow-up, and the number who complete diagnostic colonoscopy within 90 days of an abnormal non-invasive test result.
Rationale and contextual considerations
The protocol emphasises that population-level benefits of cfDNA depend on increasing overall screening participation while avoiding excessive substitution away from tests with higher sensitivity for advanced neoplasia, such as colonoscopy or FIT. The study setting—an FQHC treating populations with known screening disparities—was selected to address gaps in generalisability of prior cfDNA uptake studies.
The trial was approved by the University of California, San Diego Office of Institutional Review Board Administration (protocol number as reported in the source). A waiver of documented (signed) consent was granted to permit a pragmatic design mirroring usual-care offering of screening options. The investigators plan to report test results to participants and disseminate main results via peer-reviewed publication. The trial is registered under the identifier NCT06929481 as reported in the protocol.