BRAF V600 Mutation Detection in Plasma Cell-Free DNA: NCCTG N0879 (Alliance)

Abstract

Objective: To evaluate the prognostic significance of detectable circulating cell-free DNA (cfDNA) BRAF V600E/K mutations in patients with advanced melanoma enrolled in a clinical trial without BRAF-targeted therapy.Patients and Methods: BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation. Results: In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P¼.051; OS, 9.2 vs 27.1 months; P¼.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928). Conclusion:In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials. Trial Registration: clinicaltrials.gov Identifier: NCT00976573

Predictive Performance of Serum S100B Versus LDH in Melanoma Patients: A Systematic Review and Meta-Analysis

“…Compared to tissue tumor biopsy, peripheral blood sample (liquid biopsy) is more readily available and less heterogeneous ( 13 ). Many serologic markers such as enzymes [e.g., matrix metalloproteinase-9 (MMP-9)], secreted proteins (e.g., melanoma inhibiting activity), metabolites of the melanin synthesis pathway (e.g., 5-S-cysteinyl-dopa), circulating nucleic acids (e.g., tyrosinase mRNA, circulating-free DNA BRAFV600E mutation), and peripheral blood immune markers (e.g., soluble PD-L1) have been shown to correlate with tumor progression, survival or response to treatment in patients with melanoma ( 9 – 14 , 23 , 30 , 64 , 65 ). Properly designed, conducted, analyzed and reported prediction model studies will determine how to use these markers with the greatest clinical benefit ( 11 , 31 , 66 , 67 ).…”

Cancer-cell-derived cell-free DNA can predict distant metastasis earlier in pancreatic cancer: a prospective cohort study

“… 11 , 14 cfDNA is a minimally invasive biomarker that originates from mechanisms of cell lysis, apoptosis, necrosis, and active release of DNA fragments into circulating cells during tumorigenesis 15 and may be used as a reliable method to detect tumor-specific mutations. 16 , 17 It is believed to be primarily derived from apoptotic cells in healthy individuals of hematopoietic origin. In cancer patients, it is derived from both hematopoietic and tumor origins.…”