Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients

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Abstract

Background

Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients’ overall metabolic tumour burden (MTB).

Methods

Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).

Results

CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB ( p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.

Conclusions

We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.

Electronic supplementary material

The online version of this article (10.1186/s12885-018-4637-6) contains supplementary material, which is available to authorized users.

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Most cited references 12

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

Elin Gray, Helen Rizos, Anna L. Reid … (2015)

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.

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Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma.

J. Lee, G. Long, S. Boyd … (2017)

Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information.

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Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.

Anne-Marie Martin, P Ascierto, Niki Arya … (2013)

Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients. Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies.

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Author and article information

Contributors

Ashleigh C. McEvoy: a.mcevoy@ecu.edu.au

Lydia Warburton: lydia.warburton@health.wa.gov.au

Zeyad Al-Ogaili: zeyad.al-ogaili@health.wa.gov.au

Liesl Celliers: liesl.celliers@health.wa.gov.au

Leslie Calapre: l.calapre@ecu.edu.au

Michelle R. Pereira: m.pereira@ecu.edu.au

Muhammad A. Khattak: muhammad.khattak@health.wa.gov.au

Tarek M. Meniawy: tarek.meniawy@health.wa.gov.au

Michael Millward: michael.millward@health.wa.gov.au

Melanie Ziman: m.ziman@ecu.edu.au

Elin S. Gray:

ORCID: http://orcid.org/0000-0002-8613-3570

e.gray@ecu.edu.au

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 9 July 2018

Publication date PMC-release: 9 July 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 726

Affiliations

[1 ]ISNI 0000 0004 0389 4302, GRID grid.1038.a, School of Medical and Health Sciences, , Edith Cowan University, ; 270 Joondalup Drive, Joondalup, WA 6027 Australia

[2 ]ISNI 0000 0004 0437 5942, GRID grid.3521.5, Department of Medical Oncology, , Sir Charles Gairdner Hospital, ; Hospital Avenue, Nedlands, WA 6009 Australia

[3 ]ISNI 0000 0004 4680 1997, GRID grid.459958.c, Department of Molecular Imaging and Therapy Service, , Fiona Stanley Hospital, ; Murdoch, WA 6150 Australia

[4 ]ISNI 0000 0004 4680 1997, GRID grid.459958.c, Department of Medical Oncology, , Fiona Stanley Hospital, ; 11 Robin Warren Drive, Murdoch, WA 6150 Australia

[5 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Medicine and Pharmacology, , The University of Western Australia, ; 35 Stirling Highway, Crawley, WA 6009 Australia

[6 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Biomedical Sciences, , University of Western Australia, ; 35 Stirling Highway, Crawley, WA 6009 Australia

[7 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, Centre for Opthalmology and Visual Science, , University of Western Australia, ; 35 Stirling Highway, Crawley, Western Australia 6009 Australia

Author information

Elin S. Gray http://orcid.org/0000-0002-8613-3570

Article

Publisher ID: 4637

DOI: 10.1186/s12885-018-4637-6

PMC ID: 6038195

PubMed ID: 29986670

SO-VID: e5f5e918-745e-42af-b1cb-3f06f2825a5b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 February 2018

Date accepted : 26 June 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 1119791

Award Recipient : Melanie Ziman

Funded by: FundRef http://dx.doi.org/10.13039/100009860, Ramaciotti Foundations;

Funded by: FundRef http://dx.doi.org/10.13039/501100001170, Cancer Council Western Australia;

Award ID: 1100249

Award Recipient : Elin S. Gray

Funded by: FundRef http://dx.doi.org/10.13039/501100006065, Department of Health, Government of Western Australia;

Funded by: Spinnaker Health Research Foundation

Funded by: Cancer Research Trust

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circulating tumour dna,ctdna,metabolic tumour burden,tumour lesion glycolysis,melanoma,droplet digital pcr

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circulating tumour dna, ctdna, metabolic tumour burden, tumour lesion glycolysis, melanoma, droplet digital pcr

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients

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Karger: Dermatology

Most cited references 12

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

Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma.

Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.

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