Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition.
John J ParkRussell J DiefenbachNatalie ByrneGeorgina V LongRichard A ScolyerElin Solomonovna GrayMatteo S CarlinoHelen RizosPublished in: Cancers (2021)
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.
Keyphrases
- circulating tumor
- clinical trial
- circulating tumor cells
- cell free
- squamous cell carcinoma
- ejection fraction
- end stage renal disease
- phase ii
- newly diagnosed
- prognostic factors
- double blind
- open label
- stem cells
- gene expression
- study protocol
- cross sectional
- signaling pathway
- transcription factor
- single molecule
- genome wide
- smoking cessation