Colorectal cancer (CRC) screening participation is suboptimal and associated with inequities in CRC outcomes by race/ethnicity and socioeconomic position. A novel, cell free DNA (cfDNA) blood test has potential to increase participation, but has not been studied in groups at highest risk for adverse CRC outcomes. Among patients age-eligible for colorectal cancer screening, not up-to-date, we propose a 2-arm, pragmatic, randomized controlled trial comparing offers of standard screening options (at home fecal immunochemical test (FIT) or colonoscopy) vs. offers of expanded options (at home FIT, colonoscopy, or in clinic cfDNA plus at home FIT), set at a large Federally Qualified Health Center serving individuals at increased risk for inequities in CRC outcomes. Results will inform guideline and policy makers on whether cfDNA should be supported as a screening option, and support planning for a large-scale trial examining impact of a cfDNA option for screening on CRC and advanced neoplasia detection.

Patients assigned to usual care will be offered options for screening using a standardized script outlining: 1) importance of screening; 2) option of screening with at home FIT or colonoscopy, including key characteristics. Description of key characteristics will include 1) test completion steps; 2) test performance, stating that colonoscopy picks up 9 out of 10 colorectal cancers and important growths called polyps, and that FIT picks up 3 in 4 cancers and 1 in 4 important polyps (we define "important polyps" as adenomas 1 centimeter or larger in size or containing villous/tubulovillous histology or high-grade dysplasia). The script will note abnormal FIT requires a colonoscopy to check for CRC and important growths. Patients assigned to the intervention group will receive an identical offer, but with additional option of screening with an in clinic cfDNA plus an at home FIT. The script will state cfDNA is a blood test meant to be complementary to current screening with ability to detect 8 out of 10 CRCs and 1 in 10 important polyps, and offers advantage of having a same day test for CRC detection to complement the FIT that they will do at home. The script will also state colonoscopy is required if either cfDNA or FIT is abnormal. For patients who opt for the cfDNA plus at home FIT option, the study team will coordinate same day blood draw. Following manufacturer's instructions, 40 mL of blood (4 tubes each with 10 mL of blood) will be collected and sent to Guardant Health for the Guardant Shield test. Patients will be instructed to complete the FIT as soon as possible and within 5 days, and, to minimize the influence of cfDNA result on likelihood of FIT completion, cfDNA results will not be disclosed to the patient for 14 days after the clinic visit. For all subjects, demographic characteristics, coded data on primary provider of record, and outcomes will be collected. Because this is planned as a pragmatic trial to mimic the potential impact of introducing the cfDNA test into usual care, and because the study poses minimum risk and promotes potentially lifesaving colorectal cancer screening, a waiver of informed consent for study screening and randomization to study group assignment, and for written documentation of informed consent has been approved. An informed consent sheet with the option to "opt out" of the study will be provided to all potential subjects.

Inclusion Criteria:

1. Persons, aged 45 to 75 years old
2. Not up-to-date with screening, defined based on an existing electronic health record (EHR)-based flag that indicates absence of FIT within the last 12 months, colonoscopy within the last 10 years, sigmoidoscopy within the last 5 years or multi-target stool DNA (Cologuard) test within 3 years.
3. Attending primary care visits during the 2 months of recruitment. According to routine practice, screening status will be confirmed by primary care providers as part of routine visits.
4. Being provided the informed consent form.

Exclusion Criteria:

1. Personal history of colorectal cancer (CRC), adenomas, or other related cancers.

2. Prior history of colorectal surgery

3. Family history of CRC, defined as having one or more first-degree relative (parent, sibling, or child) diagnosed with CRC at any age.

4. Up-to-date with colorectal cancer screening, defined as:

   • Fecal occult blood test (FOBT) or FIT within the last 12 months
   • FIT-DNA (Cologuard) or FIT-RNA (Colosense) test within 3 years
   • cfDNA (Shield) within the last year
   • CT colonography within the last 5 years
   • Sigmoidoscopy within the last 5 years
   • Colonoscopy within the last 10 years

5. Abnormal FIT, FOBT, cfDNA, FIT-DNA, or FIT-RNA test within the last 3 years.

6. Personal history of any of the following high-risk conditions for colorectal cancer:

   • Inflammatory Bowel Disease (IBD), including chronic ulcerative colitis (CUC) and Crohn's disease

   • Familial adenomatous polyposis (FAP)

   • Other hereditary cancer syndromes including but not limited to:

     • Hereditary non-polyposis colorectal cancer syndrome (HNPCC) or "Lynch Syndrome", Peutz-Jeghers Syndrome, MUTYH Polyposis (MAP), Familial Adenomatous Polyposis (FAP), Cowden's Syndrome, Juvenile Polyposis, Serrated Polyposis Syndrome

7. Uninsured patients will be excluded because of inability to ensure follow up. Because of recently expanded Medi-Cal eligibility, exclusions due to insurance are expected to be minimal.

The trial results will be submitted for peer review publication. A limited, de-identified dataset for replication of analyses will be made available upon request to the corresponding author, and with execution of a data use agreement, if permitted by the human subjects protection programs at UCSD and FHCSD.