Validation of Biomarkers for the Early Detection of Colorectal Adenocarcinoma (GLNE 010)

Abbreviated Name

GLNE 010

Lead Investigator

— University of Michigan

Coordinating Investigator

Zheng, Yingye — Fred Hutchinson Cancer Center

Involved Investigators

Abstract

We propose a Phase 2 (large cross-sectional) PRoBE-compliant validation trial of stool-based and serum-based tests for the detection of colorectal neoplasia (1). The trial is powered to detect early stage colorectal adenocarcinoma or high grade dysplasia. This is the most stringent, conservative approach to the early diagnosis of colonic neoplasia and addresses the most important endpoint of identifying individuals with curable, early stage cancer and those with very high risk non-invasive neoplasia (high grade dysplasia).

Aims

Aim 1 a. To estimate the sensitivity and specificity for 1) colorectal adenocarcinoma and high grade dysplasia, or 2) screen relevant neoplasms (colorectal adenocarcinoma, high grade dysplasia, and adenomas>1cm) of the following individual colorectal neoplasia early detection biomarkers using colonoscopy as the gold standard: • stool vimentin methylation • serum galectin-3 ligand, • fecal immunochemical tests (FIT) • Exact Sciences stool DNA panel • Other currently unspecified biomarkers b. To test the null hypotheses that the sensitivities are 50% or lower versus the alternative hypotheses that sensitivities are higher than 50% for the early detection of colorectal adenocarcinoma and high grade dysplasia; and the null that sensitivities are 25% or lower versus the alternative that they are higher than 25% for the detection of screen relevant neoplasia, using colonoscopy as the gold standard and for both outcomes, to test the null hypotheses that the specificities of the above early detection biomarkers are 70% or lower versus the alternative hypotheses that specificities are higher than 70%. Aim 2: To determine if the sensitivities of the above early detection biomarkers are greater than that for fecal immunochemical testing (FIT) for the detection of the combined endpoint of colorectal adenocarcinoma or adenomas with high grade dysplasia. Aim 3 a. To estimate the sensitivity and specificity of the above individual binary biomarkers, in combination with FIT for 1) colorectal adenocarcinoma and high grade dysplasia, and for 2) screen relevant neoplasms (SRN). The combinatory rule defines a test positive if either individual test is positive. b. To test the null hypothesis that the sensitivities of the combined tests described Aim 3a are equal or lower than a minimally acceptable value (MAV) versus the alternative that they are higher than the MAV, with the MAV set as 70% for the detection of colorectal adenocarcinoma and high grade dysplasia and 45% or higher for SRN with the assumption that the specificity is maintained at 70% or higher using colonoscopy as the gold standard. c. To construct a combined early detection biomarker score using the above individual biomarkers using logistic regression, and describe its performance for 1) colorectal adenocarcinoma and high grade dysplasia, and for 2) SRN. Aim 4 To establish an archive of appropriately preserved stool, serum, plasma, urine, and DNA human biospecimens to be used by EDRN investigators for future validation and biomarker discovery research.

Analytic Method

7.1 Vimentin methylation (Colosure) This assay will be performed at LabCorp under a sublicense from Exact Sciences according to previously published method described in the background. Assay qualitatively tests for presence of methylated vimentin gene. Result is positive or negative. The vimentin methylation assay will be performed blinded without knowledge of clinical source or results of other assays. 7.2 Fecal immunochemical Test (FIT) The FOBT-CHEKOC®, Polymedco, Inc product will be used according to manufacturer’s instructions. The threshold for a positive test is 100 ng/ml. The Central Biomarker Laboratory will process the samples using equipment provided by Polymedco, Inc. Technicians will undergo tutorial and quality assessment with Polymedco, Inc support technicians prior to study launch. A quantitative result will be generated and recorded in the database. If either stool result is above Polymedco, Inc recommended cut-off, that subject will be called positive. 7.3 Galectin-3 Ligand The analytically validated ELISA method described in the preliminary data will be transferred to an EDRN Biomarkers Reference Laboratory. Serum aliquots will be provided to the analytical sites in a blinded fashion. The Bresalier laboratory will assay 20% of the samples to ensure quality control. All of the samples will be assayed by the Biomarker Reference Laboratory that will be selected by the NCI-EDRN program staff. 7.4 Exact Sciences DNA Stool Biomarker Panel: Potential improved Exact Sciences DNA Stool Biomarker Panel The Exact Sciences panel consists of a panel of genetic biomarkers from DNA isolated from human stool. The panel consists of: 1. qInvader (an automated, multiplexed rtPCR assay) reactions of: a. methylated vimentin and MM2 multiplexed b. K-Ras multiplex, 1 amplicon, 7 mutations c. APC panel 1, 3 amplicons, 3 mutations. d. APC panel 2, 3 amplicons, 3 mutations 2. Immuno-hemoglobin (ELISA based) assay or stool supernatant.

Publications

No publications available at this time for this protocol.

Biomarkers

Data Collections

No data collections available at this time for this protocol.

Start Date

Aug 1 2010

Estimated Finish Date

Jul 31 2015

Finish Date

Apr 12 2019

Protocol ID

320

Protocol Type

Validation

Fields of Research

Other
Proteomics

Collaborative Group

G.I. and Other Associated Cancers Research Group

Cancer Types

Malignant neoplasm of colon

Phased Status