Shield Post-Approval Study Protocol

The Shield post-approval study (PAS) is a prospective, longitudinal study supplemented with Real World Evidence (RWE) to evaluate the longitudinal performance of Shield in an average risk population at a second round of testing for individuals between the ages of 45 and 81 at average risk of CRC using colonoscopy as the reference method.

Colorectal cancer (CRC) is the fourth most diagnosed cancer and second leading cause of cancer-related death in the US, with an estimated 53,010 deaths attributable to CRC in 2024. The risk of CRC increases with age, with the majority of cases and deaths occurring in individuals aged 65 years or older. While the incidence of CRC in Americans 65 years of age or older has decreased over the last decade, the incidence of CRC in younger Americans aged 55 years or younger has been increasing since the mid-1990s. CRC disproportionately affects minority populations, with American Indian/Alaska Native and Black/African American populations having the highest incidence and mortality rates1; this is further exacerbated by systemic barriers to current CRC screening options.

CRC primarily arises from a precursor lesion, the adenomatous polyp (i.e., adenoma), that grows from the epithelial cells of the colorectal mucosa. Adenomas that grow larger than 10 mm or have elements indicating a risk of malignant transformation (e.g., high-grade dysplasia or villous features) are defined as advanced adenomas (AAs). The vast number of adenomas, even those with features classifying them as AAs, do not progress into a colorectal malignancy. Colonoscopy cannot always distinguish adenomas or advanced adenomas from other polyp histology; thus, polypectomy is routinely performed for lesions identified on endoscopy. The transition rate from adenoma onset to CRC development is estimated to be 12.5 to 25 years. This slow transition from adenoma onset to CRC onset allows for multiple CRC screening opportunities over a lifetime, providing the ability to intervene along the disease development course and the potential to detect and remove adenomas, prevent colorectal cancer, and reduce CRC incidence and subsequently, disease mortality.

Once CRC has developed, tumor staging is consistent with other solid tumors and defined based on how far the cancer has spread within the body. In Stage 0 (carcinoma in situ), the cancer cells are only in the colorectal mucosa. In Stage I, the cancer has spread to the muscular layer of the colorectum but not to nearby tissue or lymph nodes. In Stage II, the cancer has grown through the wall of the colorectum and potentially to nearby tissues but has not spread to nearby lymph nodes. In Stage III, the cancer has spread to nearby lymph nodes but not to distant parts of the body. In Stage IV, the cancer has spread to one or more distant parts of the body. The estimated time frame from CRC onset to a symptomatic diagnosis of CRC is estimated to be 4-5 years, in the absence of early detection through asymptomatic cancer screening. Tumor size and location can influence the rate of transition through the stages of CRC. The 5-year survival rate for localized disease (Stage I-II) is 91%, and is 72% for regional disease (Stage III), while the 5-year survival for metastatic disease (Stage IV) is only 14%. These statistics highlight the ability to reduce CRC-related mortality by detection of early-stage (Stage I-III) disease where therapeutic intervention has the potential to result in a cure.

Eligibility Criteria:
Inclusion Criteria:

* Age 45-81 years at the time of consent
* Intending to undergo a standard of care Shield test
* Considered by a physician or healthcare provider as being of "average risk" for CRC
* Subject agrees to comply with study procedures and associated standard of care assessments, as described in Table 2

Exclusion Criteria:

* Undergoing colonoscopy for investigation of symptoms
* Has undergone colonoscopy within preceding 9 years
* Any history of a positive Shield test result
* Epi proColon/FIT/FOBT result within the previous 1 year
* Cologuard result within the previous 3 years
* History of colorectal cancer
* History of any malignancy (individuals who have undergone surgical removal of skin squamous cell cancer may be enrolled provided the procedure was completed at least 12 months prior to the date of provision of informed consent for the study)
* Known diagnosis of inflammatory bowel disease
* Currently taking any anti-neoplastic or disease-modifying anti-rheumatic drugs (DMARDs)
* Positive family history of colorectal cancer, defined as having one or more first-degree relatives (parent, sibling, or child) with CRC at any age
* Known hereditary/germline risk of colorectal cancer (for example, Lynch syndrome or Hereditary Non-Polyposis CRC \[HNPCC\], or Familial Adenomatous Polyposis \[FAP\])
* Any major physical trauma (e.g., disruption of tissue, surgery, organ transplant, blood product transfusion) within the 30 days leading up to the provision of informed consent
* Known medical condition which, in the opinion of the investigator, should preclude enrollment into the study
* Participation in a clinical research study in which an experimental medication has been administered or may be administered within the 30 days leading up to providing informed consent or may be administered through the time of colonoscopy at T3.