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Application of circulating cell-free tumor DNA profiles for therapeutic monitoring and outcome prediction in genetically heterogeneous metastatic melanoma

Lookup NU author(s): Dr Jérémie Nsengimana, Batool Shannan



This is the final published version of an article that has been published in its final definitive form by American Society of Clinical Oncology, 2019.

For re-use rights please refer to the publisher's terms and conditions.


© 2019 American Society of Clinical Oncology.PURPOSE Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum 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 BRAFV600E ctDNA, 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 progressionfree 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 metastatic melanoma.

Publication metadata

Author(s): Varaljai R, Wistuba-Hamprecht K, Seremet T, Diaz JMS, Nsengimana J, Sucker A, Griewank K, Placke J-M, Horn PA, Neuhoff N, Shannan B, Chauvistre H, Vogel FCE, Horn S, Becker JC, Newton-Bishop J, Stang A, Neyns B, Weide B, Schadendorf D, Roesch A

Publication type: Article

Publication status: Published

Journal: JCO Precision Oncology

Year: 2019

Volume: 3

Online publication date: 15/02/2019

Acceptance date: 02/04/2016

Date deposited: 25/06/2020

ISSN (electronic): 2473-4284

Publisher: American Society of Clinical Oncology


DOI: 10.1200/PO.18.00229


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