Abstract 3673: Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial
Authors: van Steijn Denise E. , Fijneman Remond J. , Vink Geraldine R. , Roodhart Jeanine M. , Koopman Miriam , Lahaye Max J. , Braat Manon N.G. , Coupé Veerle M. , Broek Daan A. van den , Meijer Gerrit A. , Wang Haoyue , Greuter Marjolein J. , Lissenberg-Witte Birgit I. , Rinaldi Lorenzo , Peters E , Konicki Alissa , Dracopoli Nicholas C. , Kok Niels F. , Velculescu Victor E. 
Published: March 2024

Abstract
Background: Accurate monitoring of treatment response in patients with metastatic colorectal cancer (mCRC) is important to decide when to adjust treatment regimen or to proceed to local therapy of metastases. At present, clinical response is determined by computed tomography (CT) imaging-based assessment of changes in tumor size. However, this monitoring approach is constrained by limited sensitivity in detecting lymph node and peritoneal metastases, as well as inter-reader variability. Detection of circulating tumor DNA (ctDNA) is indicative of the amount of neoplastic cells and may have added clinical value to CT imaging for assessment of treatment response and guidance in treatment decision making in mCRC patients. We recently developed a tumor mutation-independent ctDNA test that utilizes low-coverage whole genome sequencing to analyze the plasma cell-free DNA (cfDNA) fragmentome to measure the ctDNA tumor fraction: the DELFI-tumor fraction (DELFI-TF) score.
Aim: The DOLPHIN study aims to investigate whether the DELFI-TF ctDNA assay can provide a sensitive, affordable and broadly applicable ctDNA test to monitor treatment response of mCRC patients.
Methods: The prospective, observational, multi-center DOLPHIN study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). Clinical data, images and blood samples from 400 patients receiving systemic therapy in 8-10 Dutch hospitals will be collected. Blood samples will be drawn longitudinally in conjunction with regularly scheduled CT imaging. Plasma cfDNA will be analyzed for tumor-specific fragmentation patterns using the DELFI-TF score. Droplet digital PCR ctDNA-testing of RAS/RAF hotspot mutations will be performed as reference, when feasible. Primary endpoint is the association between ctDNA changes and clinical response. Secondary endpoints are the association between ctDNA changes and radiological response according to RECIST and to serum carcinoembryonic antigen (CEA) at various time points during systemic treatment, lead time of ctDNA-testing compared to CT imaging to detect progressive disease, and the prognostic value of longitudinal ctDNA-testing.
Results: Since the inclusion of the first patient in March 2023, 117 patients have been included in the DOLPHIN study (November 2023). Seven hospitals throughout the Netherlands are currently open for patient inclusion and more sites have been approached to participate.
Discussion: The DOLPHIN study will assess the added clinical value of longitudinal ctDNA-testing in treatment response monitoring of mCRC patients and whether imaging can be complemented and/or partly replaced by ctDNA-testing. The results of this study may lead to novel strategies for monitoring treatment response and to ctDNA-guided treatment decision making in mCRC patients.
Citation Format: Denise E. van Steijn, Remond J. Fijneman, Geraldine R. Vink, Jeanine M. Roodhart, Miriam Koopman, Max J. Lahaye, Manon N.G. Braat, Veerle M. Coupé, Daan A. van den Broek, Gerrit A. Meijer, Haoyue Wang, Marjolein J. Greuter, Birgit I. Lissenberg-Witte, Lorenzo Rinaldi, E Peters, Alissa Konicki, Nicholas C. Dracopoli, Niels F. Kok, Victor E. Velculescu. Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial [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 3673.