Evaluation of Stool Based Markers for the Early Detection of Colorectal Cancers and Adenomas

In recognition of the fact that novel potential biomarkers are continually being identified and will need to be validated in a rapid, efficient and scientifically rigorous manner, the NCI has made an enormous commitment to the development of a network that will facilitate biomarker development and validation in multiple organ sites. As part of the National Cancer Institute-funded Early Detection Research Network (EDRN), the Great Lakes-New England Clinical Epidemiological Center (GLNE CEC) proposes a research study that validates potential molecular markers ("biomarkers") for the detection of precancerous and cancerous conditions and cancer risk assessment. Although examples of such biomarkers are currently in clinical use (i.e. CEA, CA-125), there are limitations to all of them. Our consortium focuses on gastrointestinal neoplasia. The goals of this phase of the proposed research are:

• Assessment of the utility of individual stool-based, serum-based and urine-based biomarkers for discriminating between patients with adenocarcinomas, patients with adenomas, patients without adenomas and normal subjects both at normal and high risk for developing colon cancer.
• Construction of a panel of markers from those considered in Objective 1 to discriminate, under a number of assumptions concerning prevalence and cost of misclassification, between:

• Subjects with normal colons versus patients without adenomas, patients with adenomas and patients with cancers;
• Subjects with normal colons, patients without adenomas and patients with adenomas, versus subjects with cancers;
• Subjects with normal colons versus patients without and patients with adenomas versus patients with cancers.
• Comparison of the characteristics of individual markers and panels as discriminators to those of the established current standard, fecal immunochemical test (FIT).
• Continued support of a renewal of a bank of stool samples linked to serum, tissue, and clinical data from patients with colorectal cancer, adenomas and normal controls for validation of stool-based markers that may be developed in the future.

To build our collection, we propose to collect stool, FIT, serum, plasma, and tissue samples from 1200 new subjects. Each biomarker will be analyzed individually and considered as a potential panel marker to be used for future largescale screening longitudinal trials. (This protocol previously recruited an additional 682 subjects from January 2006 to June 2010.)

Inclusion criteria

• Willing to sign informed consent
• Able to physically tolerate removal of up to 60 ml of blood
• Adults at least 18 years old
• Willing to collect 1-2 stool samples and prepare a Fecal Immunochemical Test (FIT)
• Pregnant or nursing women who otherwise meet the eligibility criteria may participate
• Subjects with one of the following:

• Colorectal adenocarcinoma-not treated and in colon at time of stool collection (CRC bin)
• Adenoma-pathologically confirmed adenoma present in colon at time of stool collection (Adenoma Bin)
• Higher Risk Non-neoplastic Bin

• Subjects with a personal history of adenomas (confirmed by pathology) with none present on qualifying colonoscopy
• Subjects with a personal history of CRC (longer than 3 years ago because of exclusion criteria of cancer within last 3 years) with none present at time of qualifying colonoscopy
• Any family history of CRC (1st degree relative)
• Current positive screening stool test for blood, for DNA or for both within 12 months with no follow-up intervention.
• Average Risk, Non-neoplastic Bin

• No history or current finding of any colorectal neoplasia including CRC, adenomas, sessile serrated adenomas and no family history of CRC.
• Subjects who had CRC that was successfully treated at least three years ago may be considered eligible for the adenoma bin if their polyps are adenomas and there is no evidence of CRC, or for the higher risk non-neoplastic bin as noted above.
• Subjects whose screening colonoscopy shows any of these types of polyps may be included in the non-neoplastic or the higher risk non-neoplastic bin if they meet the other criteria noted above.

• Hyperplastic polyps
• Benign mucosal polyps
• Polypoid granulation tissue
• Prolapsed mucosal polyps
• Inflammatory polyp
• Transitional mucosal polyp
• Lipoma
• Gangleoneuroma
• Neuroma
• Hamartomatous polyp

Exclusion criteria

• Cancer patients who have had any surgery, radiation, or chemotherapy for their current colorectal cancer prior to collecting the baseline samples
• History of or clinically active Inflammatory Bowel Disease
• Known HNPCC or FAP
• Inability to provide informed consent.
• Other active malignancy within 3 years of enrollment except any of the following:

• Squamous cell carcinoma of the skin
• Basal cell carcinoma of the skin
• Carcinoma in situ of the cervix, Stages Ia or Ib invasive squamous cell carcinoma of the cervix treated by surgery only. (Excluded if had pelvic radiation)
• Stage Ia Grade 1 adenocarcinoma of the endometrium treated with surgery
• Patients on active chemotherapy or radiation treatment for any purpose
• Known HIV or chronic active viral hepatitis
• Women who are pregnant
• CT colonography (virtual colonoscopy) patients