ABSTRACT
PURPOSE: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
Subject(s)
Melanoma/drug therapy , Melanoma/genetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Melanoma/enzymology , Middle Aged , Molecular Targeted Therapy , Mutation , Progression-Free Survival , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Retrospective Studies , Skin Neoplasms/enzymology , Survival Rate , Translocation, Genetic , Young AdultABSTRACT
AIM: To describe the genomic characteristics of seawater-borne hemolytic Shewanella algae and its resistance genes. MATERIALS & METHODS: Whole genome sequence of S. algae SYT3 was determined using llumina MiSeq platform. Multiple-database-based analysis was performed to identify the genetic background of its hemolytic activity and the antibiotic resistance genes. RESULTS: S. algae SYT3 possesses a homolog of the hly operon involved in the synthesis of hemolysin. We also identified candidate genes associated with resistance to ß-lactam antibiotics (bla OXA-55) and fluoroquinolone (qnrA3). CONCLUSION: The study provides an insight into the hemolytic activity of S. algae. Our findings also suggested S. algae as a potential reservoir of antimicrobial resistance determinants.
