Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition.

John J Park,Helen Rizos,Elin S Gray,Georgina V Long,Natalie Byrne,Matteo S Carlino,Russell J Diefenbach,Richard A Scolyer

doi:10.3390/cancers13071740

Abstract

Simple SummaryUveal melanoma (UM) is a rare cancer, with no effective standard systemic therapy in the metastatic setting. Over 95% of UM harbor activating driver mutations that can be detected in the circulation. In this study, circulating tumor DNA (ctDNA) was measured in 17 metastatic UM patients treated with protein kinase C inhibitor (PKCi)-based therapy. ctDNA predicted response to targeted therapy and increasing UM ctDNA preceded radiological progression with a lead-time of 4–10 weeks. Next generation sequencing (NGS) of ctDNA also identified prognostic and treatment resistance mutations. Longitudinal ctDNA monitoring is useful for monitoring disease response and progression in metastatic UM and is a valuable addition to adaptive clinical trial design.The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

Highlights

Uveal melanoma (UM) is the most common primary intraocular malignancy [1].The tumor arises from melanocytes within the uveal tract, with more than 90% of cases involving the choroid followed by iris and ciliary body [2]
We examined the circulating tumor DNA (ctDNA) of these patients using a targeted next generation sequencing (NGS) panel that included gene alterations shown to be prognostic in UM (Table 2)
We explored the utility of ctDNA as an early marker of Phase I drug efficacy and resistance in metastatic UM [28]

Summary

Introduction

Uveal melanoma (UM) is the most common primary intraocular malignancy [1].The tumor arises from melanocytes within the uveal tract, with more than 90% of cases involving the choroid followed by iris and ciliary body [2]. UM will develop metastatic disease [6] with over 90% of metastases occurring in the liver [7]. There is no effective systemic treatment in metastatic UM and the median progression free survival (PFS) and overall survival (OS) are 3.3 months and. Additional hot spot mutations affecting the EIF1AX and SF3B1 genes are associated with better prognosis whereas loss of function BAP1 gene alterations are correlated with the development of UM metastases and poor prognosis [9,16]. The specific and defined mutation profile of UM provides an excellent opportunity to investigate the utility of circulating tumor DNA (ctDNA) as a biomarker to detect the presence of metastatic disease and to rapidly monitor response to early-phase drug therapies

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