Abstract 6079: Comparison of FIT and cell-free DNA analyses for detection of individuals with colorectal cancer in population based screening
Authors: Wisse Pieter Henk Abraham , Rubio-Alarcon Carmen , Schraa Suzanna J. , Mosquera Adria C. , Sausen Mark , Fijneman Remond J. , Vink Geraldine R. , de Wit Meike , Phallen Jillian , Velculescu Victor E. , Carvalho Beatriz , Meijer Gerrit A. 
Published: March 2024

Abstract
Background The fecal immunochemical test (FIT) is widely used in population based colorectal cancer (CRC) screening programs. Recently, circulating cell-free DNA (cfDNA) analyses have emerged as a new avenue for early cancer detection. The performance of cfDNA methods in comparison with FIT is currently unknown. The present study compared pre-operative cfDNA analyses to FIT for detection of patients with CRC who participated in a population-based screening program. Methods In the Dutch national CRC screening program, individuals aged 55-75 years are biennially invited to perform a single FIT. The database of the Dutch CRC screening program was queried to identify individuals with FIT data who also participated in two cfDNA studies, PLCRC-MEDOCC and PLCRC-PROVENC3 (AACR abstract C. Rubio Alarcón). Sensitivities with 95% confidence intervals (CI) for detecting individuals with CRC were determined for FIT, tumor-informed cfDNA analyses, as well as both tests combined. For FIT, sensitivities were determined at 20 µg and 47 µg hemoglobin (Hb)/g feces positivity cut-offs as these represent the most commonly used international and Dutch cut-offs, respectively. Liquid biopsy analyses were performed using next generation sequencing of cfDNA. Tumor-specific alterations were identified through parallel next generation sequence analysis of resected tumor tissues. Results The query identified 120 individuals with stage I (n=3, 2.5%), stage II (n= 57, 47.5%) and stage III (n=60, 50.0%) CRC who had participated in the Dutch CRC screening program and either PLCRC-MEDOCC or PLCRC-PROVENC3. All FIT samples were collected at a median time of 38 days before diagnosis (IQR 27-112 days). FIT sensitivity for detection of individuals with CRC was 83.3% (100/120 CRCs, 95% CI 75.4-89.5%) at a 20 µg Hb/g feces cut-off and 80.0% (96/120, 95% CI 71.7-86.7%) at a 47 µg Hb/g feces cut-off. Tumor-informed cfDNA analyses detected 75.8% (91/120, 95% CI 67.2-83.2%) of individuals with CRC in this population. The combination of cfDNA analyses and and FIT (20 µg Hb/g feces cut-off) identified almost all individuals with CRCs (119/120, sensitivity 99.2%, 95% CI 97.0-100%). The individual who was missed had a cancer that was a T3N0 microsatellite stable moderately differentiated adenocarcinoma in the ascending colon. Discussion While both FIT and cfDNA analyses identified most CRC cases (75-83%) in this series, both tests also demonstrated a substantial level of complementarity, indicating that in principle combining FIT with cell-free DNA testing would allow to increase sensitivity of CRC screening. Since the cell-free DNA tests used here are tumor-informed, which in real life screening practice is not feasible, it remains to be determined to what extent this result can be reached using non-tumor-informed approaches.
Citation Format: Pieter Henk Abraham Wisse, Carmen Rubio-Alarcon, Suzanna J. Schraa, Adria C. Mosquera, Mark Sausen, Remond J. Fijneman, Geraldine R. Vink, Meike de Wit, Jillian Phallen, Victor E. Velculescu, Beatriz Carvalho, Gerrit A. Meijer. Comparison of FIT and cell-free DNA analyses for detection of individuals with colorectal cancer in population based screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6079.