Circulating tumor DNA is prognostic of patient outcome and enables therapy monitoring in metastatic uveal melanoma

Abstract Background: Circulating tumor DNA (ctDNA) refers to small DNA-fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a non-invasive tool for real-time disease monitoring. While ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. Here, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities. Objective: To assess ctDNA monitoring as a tool in evaluating therapy response and clinical outcomes in patients with mUM, using an IVDR-certified digital PCR assay targeting GNAQQ209 and GNA11Q209 mutations. Results: We analyzed 655 samples from 75 patients with mUM. Absence of detectable ctDNA in baseline samples prior to first-line therapy was associated with improved OS (HR=0.13, p=0.02) and progression-free survival (PFS) (HR=0.31, p=0.008). Similar associations were observed in patients treated with any-line of therapy (OS: HR=0.19, p=0.002; PFS: HR=0.27, p=0.02). Detection of ctDNA within 3months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF 5% any timepoint had a significantly poorer prognosis compared to patients with MAF 5% (median OS 4months vs 21months, p0.001; median PFS 2.5months vs 3.6months, p=0.004), emphasizing the added value of quantitative assessment. Conclusion: Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3months of treatment-start, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a non-invasive tool for disease monitoring.