title: In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours.
abstract: BACKGROUND
  Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting.
  
  
  METHODS
  We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration.
  
  
  RESULTS
  Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2-10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs 2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration.
  
  
  CONCLUSIONS
  The pharmacodynamic assessment of RAF transduction may identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted.
authors: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Suite 5-718, Toronto, Ontario, Canada M5G2M9.
authors: M
authors: M
authors: Quintela-Fandino
authors: M
authors: M
authors: Krzyzanowska
authors: G
authors: G
authors: Duncan
authors: A
authors: A
authors: Young
authors: M J
authors: MJ
authors: Moore
authors: E X
authors: EX
authors: Chen
authors: A
authors: A
authors: Stathis
authors: R
authors: R
authors: Colomer
authors: J
authors: J
authors: Petronis
authors: M
authors: M
authors: Grewal
authors: S
authors: S
authors: Webster
authors: L
authors: L
authors: Wang
authors: L L
authors: LL
authors: Siu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D011446:Prospective Studies; D000077157:Sorafenib; D015996:Survival Rate; D014018:Tissue Distribution; D048490:raf Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D009536:Niacinamide; D003520:Cyclophosphamide; D000077157:Sorafenib; D048490:raf Kinases