Longitudinal ctDNA Analysis Identifies Patients With Poorer Outcomes in Metastatic Colorectal Cancer
Clinical Summary:
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Design/Population: This retrospective biomarker analysis of the phase 2 VALENTINO trial evaluated longitudinal circulating tumor DNA (ctDNA) in 154 patients with RAS wild-type metastatic colorectal cancer (mCRC) treated with first-line panitumumab plus FOLFOX using the METER ctDNA detection workflow.
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Key Outcomes: Detectable baseline ctDNA and persistent ctDNA after 8 weeks of treatment were independently associated with significantly worse progression-free and overall survival. Conversely, ctDNA clearance correlated with greater depth of tumor response.
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Clinical Relevance: These findings support longitudinal ctDNA assessment using the METER workflow as a potential cost-effective tool for prognostication and treatment monitoring in metastatic colorectal cancer, complementing conventional radiographic response assessment.
Exploratory biomarker analyses from the phase 2 VALENTINO trial demonstrated that baseline circulating tumor DNA (ctDNA) detection and early ctDNA dynamics were strongly associated with clinical outcomes in patients with RAS wild-type 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 retrospective biomarker analysis, investigators evaluated 154 patients with RAS wild-type mCRC receiving first-line panitumumab plus FOLFOX. ctDNA was assessed at baseline and after 8 weeks of treatment using METER, a computational workflow designed to estimate ctDNA presence and fraction from low-pass whole-genome bisulfite sequencing. Performance was compared with the established ichorCNA method.
At baseline, ctDNA was detected in 72.7% of patients and was associated with significantly shorter progression-free survival (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.13 to 2.42; P = .010) and overall survival (HR, 2.24; 95% CI, 1.37 to 3.66; P < .001).
Among patients with detectable baseline ctDNA, 80.2% achieved ctDNA clearance after 8 weeks of treatment. Persistent ctDNA was associated with significantly worse progression-free survival (HR, 2.70; 95% CI, 1.63 to 4.49; P < .001) and overall survival (HR, 3.37; 95% CI, 2.00 to 5.69; P < .001). Patients with ctDNA clearance also experienced a greater median depth of response than those with persistent ctDNA (48.4% vs 41.2%; P = .023), although rates of early tumor shrinkage were similar between groups.
Compared with conventional copy number– and variant allele frequency–based approaches, the METER workflow identified a greater proportion of patients with detectable ctDNA.
“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
