title: Correlation of NRAS mutations with clinical response to high-dose IL-2 in patients with advanced melanoma.
abstract: The purpose of this study is to identify clinical and molecular characteristics of melanoma patients that predict response to high-dose interleukin-2 (HD IL-2) to improve patient selection for this approved but toxic therapy. We reviewed the records of 208 patients with unresectable stage III/IV melanoma treated with HD IL-2 at the University of Texas M.D. Anderson Cancer Center (n=100) and the Beth Israel Deaconess Medical Center (n=108) between 2003 and 2009. The BRAF and NRAS mutation status of the tumors was determined for patients with available tissue samples and the mutation status and clinical characteristics were compared with clinical outcomes. Pretreatment serum lactate dehydrogenase levels were available for most patients (n=194). Tissue was available for mutational analysis on a subset of patients (n=103) and the prevalence of mutations was as follows: BRAF 60%, NRAS 15%, WT/WT 25%. In the subset of patients for which mutational analysis was available, there was a significant difference in the response rate based on the mutation status: NRAS 47%, BRAF 23%, and WT/WT 12% (P=0.05). Patients with NRAS mutations had nonstatistically longer overall survival (5.3 vs. 2.4 y, P=0.30) and progression-free survival (214 vs. 70 d, P=0.13). Patients with an elevated lactate dehydrogenase level had a decreased progression-free survival (46 vs. 76 d, P<0.0001), decreased overall survival (0.56 vs. 1.97 y, P<0.0001), and trended toward a decreased response rate (7% vs. 21%, P=0.08). NRAS mutational status is a new candidate biomarkers for selecting patients with melanoma for HD IL-2 treatment.
authors: Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. joseph.richard@mayo.edu
authors: Richard W
authors: RW
authors: Joseph
authors: Ryan J
authors: RJ
authors: Sullivan
authors: Robyn
authors: R
authors: Harrell
authors: Katherine
authors: K
authors: Stemke-Hale
authors: David
authors: D
authors: Panka
authors: George
authors: G
authors: Manoukian
authors: Andrew
authors: A
authors: Percy
authors: Roland L
authors: RL
authors: Bassett
authors: Chaan S
authors: CS
authors: Ng
authors: Laszlo
authors: L
authors: Radvanyi
authors: Patrick
authors: P
authors: Hwu
authors: Michael B
authors: MB
authors: Atkins
authors: Michael A
authors: MA
authors: Davies
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: D054316:Biomarkers, Pharmacological; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007376:Interleukin-2; D048493:Proto-Oncogene Proteins B-raf