P0358 - Performance Evaluation of a Next-Generation Multitarget Stool DNA (mt-sDNA) Screening Test for Colorectal Cancer (CRC)

Sunday, October 22, 2023

3:30 PM – 7:00 PM PT

Location: Exhibit Hall

Has Audio

Presenting Author(s)

Thomas F. Imperiale, MD

Indiana University School of Medicine
Indianapolis, Indiana

Award: Presidential Poster Award

Thomas F.. Imperiale, MD¹, Zubin D.. Gagrat, BS², Martin Krockenberger, PhD², Marilyn C.. Olson, PhD², Kyle Porter, MAS², Paul J.. Limburg, MD²
¹Indiana University School of Medicine, Indianapolis, IN; ²Exact Sciences, Madison, WI

Introduction: The mt-sDNA test is FDA approved for average-risk CRC screening by measuring methylated DNA markers (MDMs), β-actin, KRAS gene mutations, and fecal hemoglobin. Recently, an optimized biomarker panel was developed for a next-generation (next-gen) mt-sDNA test to improve specificity while maintaining or increasing sensitivity for CRC and advanced precancerous lesions (APLs). Herein, we describe the performance of the next-gen mt-sDNA test.

Methods: The next-gen mt-sDNA panel includes novel colorectal neoplasia–associated MDMs, a reference MDM, and hemoglobin. The algorithm was trained, cross-validated, and tested using 3,011 samples combined from 2 CRC screening studies (NCT03821948; NCT03789162) that were matched on stage, index lesion distribution, and colonoscopy results of non-advanced adenomas, non-neoplastic findings, and negative exam to the DeeP-C study set (NCT01397747). Performance of the next-gen mt-sDNA panel was then evaluated on an independent test set of archived, analyzable samples from 7,662 participants from the DeeP-C study, which was conducted from 2011 to 2013. In the test set, 640 participants were positive for CRC (n=57) or APL (n=583) and 7,022 were negative for advanced neoplasia (CRC or APL). Primary endpoints were CRC sensitivity and specificity, the latter defined as non-advanced adenomas, non-neoplastic findings, or negative colonoscopy exam. Secondary endpoints were APL sensitivity and specificity, defined as non-neoplastic findings or negative colonoscopy exam. Next-gen mt-sDNA performance was compared to DeeP-C results for the currently available first-generation (first-gen) mt-sDNA assay obtained from the test set participants.

Results: In the test set, next-gen mt-sDNA sensitivity estimates were 93.0% (95% CI, 83.0-98.1) for CRC and 48.4% (95% CI, 44.2-52.5) for APL. Specificity estimates were 88.5% (95% CI, 87.7-89.2) for non-advanced adenomas, non-neoplastic findings, or negative colonoscopy exam and 90.4% (95% CI, 89.5-91.2) for non-neoplastic findings or negative colonoscopy exam; all estimates were equivalent to or higher than corresponding DeeP-C–based estimates for the first-gen mt-sDNA test (Table).

Discussion: Based on data from the independent test set of participants enrolled in the DeeP-C study, the next-gen mt-sDNA test demonstrates promising performance characteristics for average-risk CRC screening. Further validation of these results is forthcoming from the prospective BLUE-C trial (NCT04144738).

Table. Performance of the next-gen mt-sDNA test

Algorithm validation
Test set (N=7,662)^†
Most advanced colonoscopy finding	Valid DeeP-C results, n	Next-gen mt-sDNA test sensitivity, % (95% CI)	First-gen mt-sDNA test sensitivity, % (95% CI)^‡
CRC	57	93.0 (83.0-98.1)	93.0 (83.0-98.1)
Stage I	25	92.0 (74.0-99.0)	92.0 (74.0-99.0)
Stage II	21	100.0 (83.9-100.0)	100.0 (83.9-100.0)
Stage III	6	83.3 (35.9-99.6)	83.3 (35.9-99.6)
Stage IV	4	75.0 (19.4-99.4)	75.0 (19.4-99.4)
APL	583	48.4 (44.2-52.5)	41.2 (37.1-45.3)
	Valid DeeP-C results, n	Next-gen mt-sDNA test specificity, % (95% CI)	First-gen mt-sDNA test specificity, % (95% CI)^‡
All non-advanced adenomas, non-neoplastic findings, and negative results on colonoscopy	7,022	88.5 (87.7-89.2)	86.9 (86.1-87.7)
Non-neoplastic or negative results on colonoscopy	4,859	90.4 (89.5-91.2)	88.6 (87.6-89.4)
Negative results on colonoscopy	3,454	91.6 (90.7-92.5)	90.0 (89.0-91.0)

Table: †DeeP-C samples were previously described (ClinicalTrials.gov Identifier: NCT01397747). Participants were enrolled between June 2011 and November 2012. For the validation set (N=7,662), the mean (SD) age was 63.7 (8.2) years for participants who had negative results on colonoscopy and non-advanced adenomas (n=7,022) and 65.6 (8.0) years for those who were positive for CRC or APL (n=640); 56.8% (n=3,988) and 42.5% (n=272) were female, respectively.
‡Performance of the first-gen mt-sDNA test on the subset of the DeeP-C samples (N=7,662) used for validating the next-gen algorithm is included for comparative reference only.
Abbreviations: APL, advanced precancerous lesions; CI, confidence interval; CRC, colorectal cancer; first-gen, first-generation; mt-sDNA, multitarget stool DNA; next-gen, next-generation; SD, standard deviation.

Disclosures:

Thomas Imperiale: Exact Sciences Corp – Grant/Research Support.

Zubin Gagrat: Exact Sciences – Employee, Intellectual Property/Patents, Stock-privately held company.

Martin Krockenberger: ExactSciences – Employee, Stock-publicly held company(excluding mutual/index funds).

Marilyn Olson: Exact Sciences – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).

Kyle Porter: Exact Sciences – Employee, Stock-publicly held company(excluding mutual/index funds).

Paul Limburg: Exact Sciences – Consultant, Employee, Grant/Research Support, Intellectual Property/Patents, Stock-publicly held company(excluding mutual/index funds). Ironwood Pharmaceuticals – Grant/Research Support. Thorne Research – Grant/Research Support.

Thomas F.. Imperiale, MD¹, Zubin D.. Gagrat, BS², Martin Krockenberger, PhD², Marilyn C.. Olson, PhD², Kyle Porter, MAS², Paul J.. Limburg, MD². P0358 - Performance Evaluation of a Next-Generation Multitarget Stool DNA (mt-sDNA) Screening Test for Colorectal Cancer (CRC), ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.