title: Sensitivity of plasma BRAFmutant and NRASmutant cell-free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non-RECIST disease progression.
abstract: 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 BRAF(mutant) 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.
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Chang
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Jyothirmayee S
authors.initials: JS
authors.lastname: Tadepalli
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA; Department of Population Health, New York University School of Medicine, New York, NY, USA.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA; Department of Population Health, New York University School of Medicine, New York, NY, USA.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Oncology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weiss
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Robinson
authors.affiliation: Molecular MD Corporation, Portland, OR, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Spittle
authors.affiliation: Digital Biology Center, Bio-Rad Laboratories, Pleasanton, CA, USA.
authors.forename: Manohar
authors.initials: M
authors.lastname: Furtado
authors.affiliation: Digital Biology Center, Bio-Rad Laboratories, Pleasanton, CA, USA.
authors.forename: Dawne N
authors.initials: DN
authors.lastname: Shelton
authors.affiliation: Digital Biology Center, Bio-Rad Laboratories, Pleasanton, CA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Karlin-Neumann
authors.affiliation: Department of Medicine, Division of Oncology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA. Electronic address: david.polsky@nyumc.org.
authors.forename: David
authors.initials: D
authors.lastname: Polsky
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D002474:Cell-Free System; D004273:DNA, Neoplasm / Q000097:blood*; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008545:Melanoma / Q000097:blood* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D007770:L-Lactate Dehydrogenase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; Biomarker; Circulating tumor DNA (ctDNA); Lactate dehydrogenase (LDH); Melanoma; NRAS