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Observational Study
. 2025 Mar 1;120(3):632-641.
doi: 10.14309/ajg.0000000000003043. Epub 2024 Aug 20.

Fecal Immunochemical Test to Detect Colorectal Neoplasia in Lynch Syndrome: A Prospective Multicenter Study

Elsa L S A van Liere  1   2 , Nanne K H de Boer  1   2 , Monique E van Leerdam  3   4 , Evelien Dekker  1   2   5 , Maarten A J M Jacobs  1 , Jan Jacob Koornstra  6 , Johan P Kuijvenhoven  7 , Margriet Lemmens  8 , Gerrit A Meijer  8 , Manon C W Spaander  9 , Beatriz Carvalho  8 , Dewkoemar Ramsoekh  1   2
Affiliations
Observational Study

Fecal Immunochemical Test to Detect Colorectal Neoplasia in Lynch Syndrome: A Prospective Multicenter Study

Elsa L S A van Liere et al. Am J Gastroenterol. .

Abstract

Introduction: Colonoscopy surveillance for Lynch syndrome is burdensome and postcolonoscopy colorectal cancers (CRCs) still occur. The noninvasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals.

Methods: Prospective, multicenter observational study in which individuals with Lynch syndrome performed a quantitative FIT before high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 μg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AAs] and advanced serrated lesions [ASLs]) and non-advanced adenomas (NAAs).

Results: Of the 217 included individuals (59% female, median age 51 years), 4 had CRC, 5 AA, 4 ASL, and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 μg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL, and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and negative predictive value, specificity for advanced neoplasia optimized to 94% at threshold 4.1 μg/g. Per 100 FITs at threshold 4.1 μg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia.

Discussion: FIT at thresholds ≤4.1 μg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.

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Conflict of interest statement

Guarantor of the article: Dewkoemar Ramsoekh, MD, PhD.

Specific author contributions: E.L.S.A.v.L., N.K.H.d.B., M.E.v.L., E.D., M.A.J.M.J., J.J.K., J.P.K., M.C.W.S., B.C., and D.R.: conceived the study design. M.E.v.L., E.D., M.A.J.M.J., J.J.K., J.P.K., M.C.W.S., and D.R.: invited individuals to participate in the study. M.L.: analyzed the fecal immunochemical tests. E.L.S.A.v.L: collected the data, analyzed the data and drafted the manuscript. All authors critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript, including the authorship list.

Financial support: This study was funded by Dutch Digestive Foundation (MLDS); grant number WO 19-05. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Potential competing interests: E.L.S.A.v.L., M.E.v.L., M.A.J.M.J., J.J.K., J.P.K., and M.L. declare no competing interests. N.K.H.d.B. has served as a speaker for AbbVie and MSD and has served as a consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a research grant (unrestricted) from Dr. Falk, TEVA Pharma BV, Dutch Digestive Foundation (MLDS) and Takeda. E.D. has endoscopic equipment on a loan of FujiFilm and has received a research grant from FujiFilm. She has received an honorarium for a consultancy from FujiFilm, Olympus, InterVenn and Ambu, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION and FujiFilm. G.A.M. is cofounder and board member (CSO) of CRCbioscreen BV. He has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and he has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi and Hartwig Medical Foundation; these companies provide materials, equipment, and/or sample/genomic analyses. G.A.M. is an Advisory Board member of “Missie Tumor Onbekend.” M.C.W.S. has received research support from Sysmex, Sentinel, Medtronic and Norgine. B.C. has several patents pending and/or issued. D.R. has received a research grant (unrestricted) from AbbVie. He has served as a member of the data safety monitoring board of the VIVIAD trial.

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flowchart showing the selection of the study population.
Figure 2.
Figure 2.
Receiver operating characteristic curves showing the diagnostic accuracy of the fecal immunochemical test for (a) all relevant neoplasia; CRC, advanced serrated lesions, all adenomas, (b) advanced neoplasia; CRC, advanced serrated lesions, advanced adenomas; and (c) CRC plus advanced adenomas. AUC, area under the curve; CRC, colorectal cancer.
Figure 3.
Figure 3.
Fagan's nomograms illustrating the pretest and post-test probability of colorectal cancer (CRC) and advanced adenomas (AA), following positive (blue line) and negative (red line) fecal immunochemical test (FIT) at different thresholds. The gray line represents the situation when the post-test probability remains unchanged. The figures show that a negative FIT at thresholds ≤ 4.1 μg Hb/g feces decreases the estimated probability of CRC and AA from 4% to 0.5%, while a positive FIT increases the probability of these neoplasia to 30% (2.5 μg/g threshold) or 38% (4.1 μg/g threshold). By contrast, a negative FIT at 20 μg Hb/g feces decreases the probability of CRC and AA only to 2%. NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Figure 4.
Figure 4.
Number of positive tests, lesions missed and needed to scope to detect at least 1 neoplasia per 100 individuals tested by fecal immunochemical test at different thresholds in μg Hb/g feces. Calculations are based on a prevalence of 32% for all relevant neoplasia (CRC, advanced serrated lesions, all adenomas), 6% for advanced neoplasia (CRC, advanced serrated lesions, advanced adenomas), and 4% for CRC plus advanced adenomas. CRC, colorectal cancer.
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