title: Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib.
abstract: OBJECTIVE
  Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity.
  
  
  METHODS
  Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.
  
  
  RESULTS
  Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. K(ep), was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028).
  
  
  CONCLUSIONS
  KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1457, USA.
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Force
authors.forename: Ariel
authors.initials: A
authors.lastname: Lopez-Chavez
authors.forename: Corrine
authors.initials: C
authors.lastname: Keen
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.forename: Yunkai
authors.initials: Y
authors.lastname: Yu
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D016207:Cytokines; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins