Assessing a tumor-agnostic circulating tumor DNA assay for uveal melanoma surveillance and metastatic disease monitoring.

Abstract

e15037 Background: Uveal melanoma (UM) is a rare and aggressive intraocular malignancy, with up to half of patients developing metastatic disease. Surveillance approaches depend on gene expression profiling and radiographic imaging, but these methods do not address detection of subclinical disease. Circulating tumor DNA (ctDNA), derived from tumor nucleic acids in plasma, has emerged as a tumor marker for disease burden and treatment response, but currently limited in UM to matched tumor-informed assays in the metastatic setting. Here we assess the utility of a novel tumor-agnostic ctDNA assay, to be used for early detection in the surveillance setting as well as for metastatic disease monitoring. Methods: We conducted a prospective study of 42 UM patients at Columbia University Irving Medical Center, stratifying them into surveillance (n = 24) and metastatic (n = 18) cohorts. The Columbia University Division of Personalized Genomic Medicine developed blood based ctDNA assay using genetic alterations common to uveal melanoma (a 30 gene panel including GNAQ, GNA11, BAP1, and PLCB4). ctDNA level was measured in copies/mL and variant allele frequency (VAF %). Surveillance patients had ctDNA collected at 3-6 month intervals, while metastatic patients were sampled throughout a variety of investigational and standard treatments including liver-directed therapy. Results: In the surveillance cohort, all 24 patients had negative ctDNA at baseline and follow-up. This included two patients with undetectable ctDNA, both of whom developed radiographic evidence of liver metastasis, confirmed by biopsy within 2 weeks of a negative ctDNA. In the metastatic cohort, 10 of 18 (56%) patients had detectable ctDNA. ctDNA VAF correlated with imaging and clinical treatment responses in 6 of 7 (86%) patients in whom longitudinal samples were collected. As example, 3 patients showed rising ctDNA levels during radiographic disease progression; 1 patient exhibited decrease in ctDNA with positive treatment response on targeted clinical trial; 2 demonstrated stable disease by all metrics; and 1 exhibited stability in ctDNA levels despite rapid and overt disease progression while on trametinib. Overall, GNAQ Q209 were the most common mutations detected by ctDNA. Conclusions: Our findings show that tumor-agnostic ctDNA represents a useful biomarker for active disease monitoring in metastatic UM, in conjunction with radiographic and clinical assessment. Within the surveillance setting, our assay showed limited sensitivity for early disease detection with common false negative results. Additional development of novel, noninvasive biomarker driven assays are necessary to improve early detection of metastatic UM.