TY - JOUR
T1 - Combining cell-free DNA fragmentomes and total tumour volume improves prognostication and tumour response evaluation in patients with colorectal cancer liver metastases
AU - Crnovrsanin, Nerma
AU - Zeeuw, J. Michiel
AU - Ali, Mahsoem
AU - Kemna, Ruby
AU - Alipanahi, Bahar
AU - Lumbard, Keith
AU - Skidmore, Zachary L.
AU - Rinaldi, Lorenzo
AU - van 't Erve, Iris
AU - Wesdorp, Nina J.
AU - Huiskens, Joost
AU - van Steijn, Denise
AU - van Waesberghe, Jan Hein
AU - van den Bergh, Janneke
AU - Nota, Irena
AU - Moos, Shira
AU - Bond, Marinde J.G.
AU - Meiqari, Lana
AU - Huitink, Iris
AU - Giovannetti, Elisa
AU - Stoker, Jaap
AU - Verpalen, Inez
AU - van den Broek, Daan
AU - Meijer, Gerrit A.
AU - Swijnenburg, Rutger Jan
AU - Punt, Cornelis J.A.
AU - Scharpf, Robert B.
AU - Leal, Alessandro
AU - Dracopoli, Nicholas C.
AU - Velculescu, Victor E.
AU - Kok, Niels F.M.
AU - Kazemier, Geert
AU - Fijneman, Remond J.A.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2026/1
Y1 - 2026/1
N2 - Background: Treatment decisions in patients with unresectable colorectal liver metastases (CRLM) are largely guided by radiological response to induction systemic therapy. However, radiological assessment alone provides an imprecise estimate of underlying tumour biology or treatment response. Circulating tumour DNA (ctDNA) is an emerging biomarker that can support clinical decision-making. This study evaluated the independent prognostic value of radiological tumour burden and DELFI-TF, a tumour tissue- and mutation-independent cell-free DNA (cfDNA) fragmentome-based ctDNA assay. Methods: We analysed 202 plasma samples and CT scans collected at baseline and following induction systemic therapy from 101 patients with unresectable, liver-limited CRC enrolled in the phase-III CAIRO5 trial (NCT02162563), treated with FOLFOX/FOLFIRI plus bevacizumab. Total tumour volume (TTV) was centrally quantified via semi-automated segmentation of liver metastases. ctDNA was measured using the DELFI-TF score. Associations with overall survival (OS) and early recurrence were evaluated using multivariable Cox regression models. Findings: At baseline, TTV (median = 139 mL, IQR = 23–497 mL) strongly correlated with DELFI-TF (median = 0.29, IQR = 0.13–0.41; Spearman's ρ = 0.70). DELFI-TF showed a more pronounced reduction than TTV on-treatment (−97.6% vs −49.9%). Baseline levels and on-treatment changes of DELFI-TF (P = 0.001; P = 0.012) and TTV (P = 0.002; P = 0.002) were independently associated with OS in the multivariable model; their combination improved prognostic performance (Uno's C-statistic 0.78 vs 0.73; P = 0.036). Baseline (P = 0.016) and on-treatment DELFI-TF (P = 0.001) also predicted early recurrence after local therapy. Interpretation: Following further validation, integrating cfDNA fragmentome-based testing with radiological tumour volume may provide complementary and clinically meaningful insights for prognostication and treatment response in patients with unresectable CRLM. This exploratory study supports a multimodal biomarker approach to guide personalised treatment strategies. Funding:German Research Foundation (DFG,513004649),Heidelberg Medical Faculty,Dutch Cancer Society/KWF Kankerbestrijding (10438), PPP Allowance via Health ∼ Holland (LSHM22027), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer (SU2C)in-Time Lung Cancer Interception Dream Team Grant, SU2C–Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415),Gray Foundation,Commonwealth Foundation,Cole Foundation, Delfi Diagnostics (research grant), USNational Institutes of Health (CA121113,CA233259,CA271896).
AB - Background: Treatment decisions in patients with unresectable colorectal liver metastases (CRLM) are largely guided by radiological response to induction systemic therapy. However, radiological assessment alone provides an imprecise estimate of underlying tumour biology or treatment response. Circulating tumour DNA (ctDNA) is an emerging biomarker that can support clinical decision-making. This study evaluated the independent prognostic value of radiological tumour burden and DELFI-TF, a tumour tissue- and mutation-independent cell-free DNA (cfDNA) fragmentome-based ctDNA assay. Methods: We analysed 202 plasma samples and CT scans collected at baseline and following induction systemic therapy from 101 patients with unresectable, liver-limited CRC enrolled in the phase-III CAIRO5 trial (NCT02162563), treated with FOLFOX/FOLFIRI plus bevacizumab. Total tumour volume (TTV) was centrally quantified via semi-automated segmentation of liver metastases. ctDNA was measured using the DELFI-TF score. Associations with overall survival (OS) and early recurrence were evaluated using multivariable Cox regression models. Findings: At baseline, TTV (median = 139 mL, IQR = 23–497 mL) strongly correlated with DELFI-TF (median = 0.29, IQR = 0.13–0.41; Spearman's ρ = 0.70). DELFI-TF showed a more pronounced reduction than TTV on-treatment (−97.6% vs −49.9%). Baseline levels and on-treatment changes of DELFI-TF (P = 0.001; P = 0.012) and TTV (P = 0.002; P = 0.002) were independently associated with OS in the multivariable model; their combination improved prognostic performance (Uno's C-statistic 0.78 vs 0.73; P = 0.036). Baseline (P = 0.016) and on-treatment DELFI-TF (P = 0.001) also predicted early recurrence after local therapy. Interpretation: Following further validation, integrating cfDNA fragmentome-based testing with radiological tumour volume may provide complementary and clinically meaningful insights for prognostication and treatment response in patients with unresectable CRLM. This exploratory study supports a multimodal biomarker approach to guide personalised treatment strategies. Funding:German Research Foundation (DFG,513004649),Heidelberg Medical Faculty,Dutch Cancer Society/KWF Kankerbestrijding (10438), PPP Allowance via Health ∼ Holland (LSHM22027), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer (SU2C)in-Time Lung Cancer Interception Dream Team Grant, SU2C–Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415),Gray Foundation,Commonwealth Foundation,Cole Foundation, Delfi Diagnostics (research grant), USNational Institutes of Health (CA121113,CA233259,CA271896).
KW - Cell-free DNA fragmentome
KW - Colorectal liver metastases
KW - Liquid biopsies
KW - Prognosis
KW - Risk stratification
KW - Total tumour volume
KW - Treatment response
UR - https://www.scopus.com/pages/publications/105024810914
U2 - 10.1016/j.ebiom.2025.106081
DO - 10.1016/j.ebiom.2025.106081
M3 - Article
AN - SCOPUS:105024810914
SN - 2352-3964
VL - 123
JO - EBioMedicine
JF - EBioMedicine
M1 - 106081
ER -