Journal
MOLECULAR ONCOLOGY
Volume 10, Issue 1, Pages 157-165Publisher
WILEY
DOI: 10.1016/j.molonc.2015.09.005
Keywords
Melanoma; Circulating tumor DNA (ctDNA); Lactate dehydrogenase (LDH); BRAF; NRAS; Biomarker
Categories
Funding
- United States Food and Drug Administration Critical Path Initiative [1 U01 FD004203-01]
- United States National Cancer Institute [1 R21 CA154786-01, P30 CA16087]
- Marc Jacobs Campaign
- FOOD AND DRUG ADMINISTRATION [U01FD004203] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R21CA154786, P30CA016087] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [T32AR064184] Funding Source: NIH RePORTER
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Melanoma lacks a clinically useful blood-based biomarker of disease activity to help guide patient management. To determine whether measurements of circulating, cell-free, tumor-associated BRAF(mutant) and NRAS(mutant) DNA (ctDNA) have a higher sensitivity than LDH to detect metastatic disease prior to treatment initiation and upon disease progression we studied patients with unresectable stage IIIC/IV metastatic melanoma receiving treatment with BRAF inhibitor therapy or immune checkpoint blockade and at least 3 plasma samples obtained during their treatment course. Levels of BRAFmutant and NRAS(mutant\) ctDNA were determined using droplet digital PCR (ddPCR) assays. Among patients with samples available prior to treatment initiation ctDNA and LDH levels were elevated in 12/15 (80%) and 6/20 (30%) (p = 0.006) patients respectively. In patients with RECIST scores <5 cm prior to treatment initiation, ctDNA levels were elevated in 5/7 (71%) patients compared to LDH which was elevated in 1/13 (8%) patients (p = 0.007). Among all disease progression events the modified bootstrapped sensitivities for ctDNA and LDH were 82% and 40% respectively, with a median difference in sensitivity of 42% (95% confidence interval, 27%-58%; P < 0.001). In addition, ctDNA levels were elevated in 13/16 (81%) instances of non-RECIST disease progression, including 10/12 (83%) instances of new brain metastases. In comparison LDH was elevated 8/16 (50%) instances of non-RECIST disease progression, including 6/12 (50%) instances of new brain metastases. Overall, ctDNA had a higher sensitivity than LDH to detect disease progression, including non-RECIST progression events. ctDNA has the potential to be a useful biomarker for monitoring melanoma disease activity. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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