Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition
| Autor: | Matteo S. Carlino, Richard A. Scolyer, Natalie Byrne, Russell J. Diefenbach, Helen Rizos, Elin S. Gray, John J. Park, Georgina V. Long |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Phases of clinical research PKC inhibitor lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Lactate dehydrogenase Internal medicine medicine melanoma Liquid biopsy circulating tumor DNA next generation sequencing Adaptive clinical trial response Receiver operating characteristic liquid biopsy treatment business.industry Melanoma medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Confidence interval Clinical trial 030104 developmental biology chemistry 030220 oncology & carcinogenesis uveal melanoma business |
| Zdroj: | Cancers, Vol 13, Iss 1740, p 1740 (2021) Cancers Volume 13 Issue 7 |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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