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

Authors

Elin S. Gray, Edith Cowan UniversityFollow
Helen Rizos
Anna L. Reid, Edith Cowan UniversityFollow
Suzanah Boyd
Michelle Pereira, Edith Cowan UniversityFollow
Johnny Lo
Varsha Tembe
James Freeman, Edith Cowan UniversityFollow
Jenny Lee
Richard Scolyer
Kelvin Siew
Chris Lomma
Adam Cooper
Muhammad Khattak
Tarek Meniawy
Georgina Long
Matteo Carlino
Michael Millward
Mel R. Ziman, Edith Cowan UniversityFollow

Author Identifier

Elin Gray

https://orcid.org/0000-0002-8613-3570

Anna Reid

https://orcid.org/0000-0002-4588-1679

James Freeman

https://orcid.org/0000-0001-8065-8416

Mel Ziman

https://orcid.org/0000-0001-7527-3538

Document Type

Journal Article

Publisher

Impact Journals LLC

School

School of Medical Sciences

RAS ID

20598

Funders

National Health and Medical Research Council

Grant Number

NHMRC Number : 1046711

Grant Link

http://purl.org/au-research/grants/nhmrc/1046711

Comments

Gray, Elin S (12.2015). "Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma.". Oncotarget (1949-2553), 6 (39), p. 42008-42018. Available here

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.

DOI

10.18632/oncotarget.5788

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.