Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma

Elin S. Gray*, Helen Rizos, Anna L. Reid, Suzanah C. Boyd, Michelle R. Pereira, Johnny Lo, Varsha Tembe, James Freeman, Jenny H J Lee, Richard A. Scolyer, Kelvin Siew, Chris Lomma, Adam Cooper, Muhammad A. Khattak, Tarek M. Meniawy, Georgina V. Long, Matteo S. Carlino, Michael Millward, Melanie Ziman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

205 Citations (Scopus)
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Abstract

Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.

Original languageEnglish
Pages (from-to)42008-42018
Number of pages11
JournalOncotarget
Volume6
Issue number39
DOIs
Publication statusPublished - 2015

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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