ctDNA Dynamics to Predict Survival Outcomes in Patients With Metastatic Colorectal Cancer

Clinical Summary:

• Design/Population: This retrospective biomarker analysis evaluated longitudinal ctDNA in 154 patients with RAS wild-type mCRC who received first-line panitumumab plus FOLFOX in the VALENTINO trial using the METER workflow.
• Key Outcomes: Baseline ctDNA detection and persistence at 8 weeks were associated with significantly worse survival outcomes and ctDNA clearance correlated with deeper tumor response. 
• Clinical Relevance: Longitudinal ctDNA monitoring using a cost-effective sequencing approach may serve as a prognostic treatment-monitoring tool, complementing radiographic assessment in mCRC.

Exploratory longitudinal circulating tumor DNA (ctDNA) analysis results from the phase 2 VALENTINO trial demonstrated that baseline detection and early ctDNA dynamics are strongly associated with clinical outcomes among patients with metastatic colorectal cancer (mCRC). 

“Longitudinal measuring of [ctDNA] during systemic treatment of [mCRC] is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness,” stated Paolo Manca, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, and coauthors. 

In this study, 154 ctDNA evaluable patients with RAS wild-type mCRC receiving first-line panitumumab plus FOLFOX were analyzed. Using METER, a computational workflow built to infer ctDNA presence and fraction, investigators assessed ctDNA at baseline and at 8 weeks using low-pass whole-genome bisulfite sequencing. IchorCNA was used as a benchmark method. 

At analysis, baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of disease progression (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.13 to 2.42; P = .010) and death (HR, 2.24; 95% CI, 1.37 to 3.66; P < .001). Among patients with detectable baseline ctDNA, 80.2% achieved ctDNA clearance at 8 weeks. Persistence of ctDNA was associated with a significantly higher risk of disease progression (HR, 2.70; 95% CI, 1.63 to 4.49; P < .001) and death (HR, 3.37; 95% CI, 2.00 to 5.69; P < .001). Median depth of response was 48.4% in patients with ctDNA clearance and 41.2% in patients with ctDNA persistence (P = .023). Early tumor shrinkage was achieved in 72% and 73.7% of patients, respectively (P = 1). 

METER identified a higher proportion of ctDNA-positive patients compared with traditional copy-number and variant allele frequency-based approaches.

“ctDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiologic assessment of response dynamics,” concluded Dr Manca et al. 

Source:

Manca P, Paoli M, Galardi F, et al. ctDNA detection with low-pass whole-genome bisulfite sequencing in RAS wild-type metastatic colorectal cancer: An exploratory objective of the VALENTINO trial. Clin Cancer Res. Published online: March 2, 2026. doi:10.1158/1078-0432.ccr-25-2773