Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas

doi:10.4251/wjgo.v14.i11.2195

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World Journal of Gastrointestinal Oncology

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Clinical and Translational Research

World J Gastrointest Oncol. Nov 15, 2022; 14(11): 2195-2207
Published online Nov 15, 2022. doi: 10.4251/wjgo.v14.i11.2195

Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas

Manon van der Vlugt, Beatriz Carvalho, Joelle Fliers, Nahid Montazeri, Christian Rausch, Esmée J Grobbee, Manon van Engeland, Manon C W Spaander, Gerrit A Meijer, Evelien Dekker

Manon van der Vlugt, Joelle Fliers, Evelien Dekker, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam 1105 AZ, Netherlands

Beatriz Carvalho, Christian Rausch, Gerrit A Meijer, Department of Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands

Nahid Montazeri, Biostatistics Unit, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam 1105 AZ, Netherlands

Esmée J Grobbee, Manon C W Spaander, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam 3015 CN, Netherlands

Manon van Engeland, Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht 6202 AZ, Netherlands

Author contributions: van der Vlugt M, Carvalho B, Meijer GA and Dekker E contributed to the study concept and design, acquisition of data, analysis and interpretation of data; van der Vlugt M and Carvalho B contributed to drafting of the manuscript and statistical analysis; Fliers J contributed to the study concept and design; Fliers J, Montazeri N, Rausch C, Grobbee EJ, van Engeland M, Spaander MCW, Meijer GA and Dekker E contributed to critical revision of the manuscript for important intellectual content; Montazeri N and Rausch C contributed to study design and statistical analysis; Grobbee EJ, van Engeland M and Spaander MCW contributed to the study concept and acquisition of data.

Supported by Foundation of Population Screening Mid-West Netherlands, Amsterdam, The Netherlands (BoMW); Foundation of Population Screening South-West Netherlands, Rotterdam, The Netherlands (BoZW); Netherlands Comprehensive Cancer Organization (IKNL); Netherlands Organization for Health Research and Development of the Dutch Ministry of Health (ZonMW); PALGA, the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands.

Institutional review board statement: Ethics approval for performing FIT-based screening including linkage to the Netherlands Cancer Registry was provided by the Dutch National Health Council (WBO 2642467, 2832758, 3049078 and 161536-112008, The Hague, The Netherlands). No separate ethics approval was necessary for the additional molecular analysis, as judged by the scientific ethics board of the AMC University Hospital. Collection and use of tissue and patient data were performed in compliance with the ‘Code for Proper Secondary Use of Human Tissue in the Netherlands’ (www.federa.org).

Clinical trial registration statement: This study is registered at the Dutch Trial Registry. Registration number: NTR5874 (http://www.trialregister.nl).

Informed consent statement: All screenees participating in FIT screening filled in an informed consent form.

Conflict-of-interest statement: Meijer GA has research collaborations with Exact Sciences, Sysmex and Sentinel for other studies regarding early detection of colorectal cancer. The companies provide materials, equipment or (sample) analyses. Meijer GA is CSO and shareholder of CRCbioscreen BV. Carvalho B has several patents pending. Dekker E received a research grant from FujiFilm. She has received honorarium for consultancy from FujiFilm, Olympus, Tillots, GI Supply, CPP-FAP and PAION, and speakers' fees from Olympus, Roche, GI Supply and Norgine. Spaander MC received research support of Sysmex and Sentinel. All other coauthors don’t have conflicts of interest.

Data sharing statement: Raw mutation data (concerning the mutation analysis and DNA copy number analysis) have been deposited in the European Genome-Phenome Archive with the study ID: EGAS00001004683.

Corresponding author: Manon van der Vlugt, MD, PhD, Doctor, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands. m.vandervlugt@amsterdamumc.nl

Received: July 26, 2022
Peer-review started: July 26, 2022
First decision: August 19, 2022
Revised: September 6, 2022
Accepted: October 2, 2022
Article in press: October 2, 2022
Published online: November 15, 2022
Processing time: 111 Days and 19.3 Hours

ARTICLE HIGHLIGHTS

Research background

Fecal immunochemical test (FIT) is effective in reducing colorectal cancer (CRC) but FIT testing is not perfect. FIT interval cancers, i.e. CRCs diagnosed after a negative FIT but before the next FIT invitation, still occur. FIT sensitivity for CRC is approximately 75%-85% and sensitivity drops to low detection rates for adenomas and even more so for sessile serrated lesions (SSLs).

Research motivation

In order to lower the number of missed lesions, we need to understand which lesions are more often missed by FIT in order to improve the screening strategy. Previous studies have shown that FIT sensitivity for SSLs is low, but a correlation between the occurrence of FIT interval cancers and the serrated pathway has not been established.

Research objectives

Our aim was to generate more insight in the molecular features of FIT-interval CRCs, as this could help in developing a more optimal screening strategy with the aim to reduce the incidence of FIT interval cancers.

Research methods

We compared the molecular make up of screen-detected CRCs (SD-CRCs) and FIT-interval CRCs, detected in a Dutch pilot-program of FIT-based screening. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations.

Research results

FIT-interval CRCs were more often CIMP- and MSI-positive as compared to SD-CRCs. They also harbored more often BRAF and PTEN mutations as compared to SD-CRCs.

Research conclusions

The serrated pathway-associated molecular features seem to be more common in FIT-interval CRCs as compared to screen detected CRCs. This might indicate that proximal serrated lesions are overrepresented among FIT interval CRCs. Further research needs to be performed. Adding molecular markers of the serrated-pathway to the FIT needs to be further explored.

Research perspectives

These findings can provide guidance on strategies to further improve stool-based CRC screening with incorporating biomarkers for SSLs, thereby reducing the number of screening interval CRCs.