title: A phase II trial of sorafenib in metastatic melanoma with tissue correlates.
abstract: BACKGROUND
  Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed.
  
  
  RESULTS
  Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples.
  
  
  CONCLUSIONS
  Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib.
  
  
  BACKGROUND
  Clinical Trials.gov NCT00119249.
authors.affiliation: Department of Medical Oncology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Christina
authors.initials: C
authors.lastname: Min
authors.forename: Sara
authors.initials: S
authors.lastname: Safarzadeh-Amiri
authors.forename: Lauren
authors.initials: L
authors.lastname: Goldberg
authors.forename: Joanne
authors.initials: J
authors.lastname: Yoon
authors.forename: Herman
authors.initials: H
authors.lastname: Yee
authors.forename: Michael
authors.initials: M
authors.lastname: Buckley
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christos
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: David
authors.initials: D
authors.lastname: Polsky
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000096:biosynthesis; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D019394:Ki-67 Antigen; D010671:Phenylurea Compounds; D011725:Pyridines; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf