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

E.S. Gray, H. Rizos, A.L. Reid, S.C. Boyd, M.R. Pereira, J. Lo, V. Tembe, J. Freeman, J.H.J. Lee, R.A. Scolyer, K. Siew, C. Lomma, A. Cooper, Muhammad Khattak, Tarek Meniawy, G.V. Long, M.S. Carlino, Michael Millward, Melanie Ziman

    Research output: Contribution to journalArticle

    143 Citations (Scopus)

    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
    JournalOncotarget
    Volume6
    Issue number39
    Early online date22 Sep 2015
    DOIs
    Publication statusPublished - 8 Dec 2015

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