Combining cell-free DNA fragmentomes and total tumour volume improves prognostication and tumour response evaluation in patients with colorectal cancer liver metastases

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 combined 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 models.

Results: At baseline, TTV (median=139mL, IQR=23–497mL) 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 ([Abb. 1] [2]).

Abb. 1  

Abb. 2  

Conclusion: Integrating cfDNA fragmentome-based testing with radiological tumour volume provides complementary and clinically meaningful insights for prognostication and treatment response in patients with unresectable CRLM. These findings support a multimodal biomarker approach to guide personalized treatment strategies.

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Publication History

Article published online:
04 September 2025