Váraljai, R, Wistuba-Hamprecht, K, Seremet, T et al. (18 more authors) (2019) Application of circulating cell-free tumor DNA profiles for therapeutic monitoring and outcome prediction in genetically heterogeneous metastatic melanoma. JCO Precision Oncology. ISSN 2473-4284
Abstract
PURPOSE
Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneousspectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma.
MATERIALS and METHODS
We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAFV600E and NRASQ61 driver mutations as well as TERTC250T and TERTC228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase–targeted or immune checkpoint therapies.
RESULTS
Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAFV600EctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans (P < .05), with a mean lead time of 3.5 months. NRAS-mutant ctDNA was detected in a significant proportion of patients with BRAF-mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRASQ61 ctDNA in baseline samples of patients with BRAFV600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P = .01).
CONCLUSION
Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastaticmelanoma.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Copyright by American Society of Clinical Oncology. This is an author produced version of a paper published in JCO Oncology. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Funding Information: | Funder Grant number Cancer Research UK c588/A19167 |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Feb 2019 11:08 |
Last Modified: | 15 Feb 2020 01:39 |
Status: | Published online |
Publisher: | American Society of Clinical Oncology |
Identification Number: | 10.1200/PO.18.00229 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:142371 |