Circulating Tumor DNA Is Prognostic of Patient Outcome and Enables Therapy Monitoring in Metastatic Uveal Melanoma.

Abstract

Circulating tumor DNA (ctDNA) refers to small DNA fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a noninvasive tool for real-time disease monitoring. Although ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. In this study, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities. 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. 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 3 months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF > 5% any time point had a significantly poorer prognosis compared with patients with MAF < 5% (median OS 4 months vs. 21 months, P < 0.001; median PFS 2.5 months vs. 3.6 months, P = 0.004), emphasizing the added value of quantitative assessment. Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3 months of starting of treatment, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a noninvasive tool for disease monitoring.