Document Detail


Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).
MedLine Citation:
PMID:  16505440     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To determine the clinical efficacy of imatinib in patients with advanced aggressive fibromatosis (AF) and to identify the molecular basis of response/nonresponse to this agent. PATIENTS AND METHODS: Nineteen patients with AF were treated with imatinib (800 mg/d) as part of a phase II clinical study. Tumor specimens were analyzed for mutations of KIT, PDGFRA, PDGFRB, and CTNNB1 (beta-catenin). Tumor expression of total and activated KIT, PDGFRA, and PDGFRB were assessed using immunohistochemistry and immunoblotting techniques. We also measured plasma levels of PDGF-AA and PDGF-BB in patients and normal patient controls. RESULTS: Three of 19 patients (15.7%) had a partial response to treatment, with four additional patients having stable disease that lasted more than 1 year (overall 1 year tumor control rate of 36.8%). No mutations of KIT, PDGFRA, or PDGFRB were found. Sixteen of 19 patients (84%) had mutations involving the WNT pathway (APC or CTNNB1). However, there was no correlation between WNT pathway mutations and clinical response to imatinib. AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts. However, PDGFRB phosphorylation was not detected, suggesting that PDGFRB is only weakly activated. AF patients had elevated levels of PDGF-AA and PDGF-BB compared with normal patient controls. Notably, the plasma level of PDGF-BB was inversely correlated with time to treatment failure. CONCLUSION: Imatinib is an active agent in the treatment of advanced AF. Imatinib response in AF patients may be mediated by inhibition of PDGFRB kinase activity.
Authors:
Michael C Heinrich; Grant A McArthur; George D Demetri; Heikki Joensuu; Petri Bono; Richard Herrmann; Hal Hirte; Sara Cresta; D Bradley Koslin; Christopher L Corless; Stephan Dirnhofer; Allan T van Oosterom; Zariana Nikolova; Sasa Dimitrijevic; Jonathan A Fletcher
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of clinical oncology : official journal of the American Society of Clinical Oncology     Volume:  24     ISSN:  1527-7755     ISO Abbreviation:  J. Clin. Oncol.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-28     Completed Date:  2006-03-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8309333     Medline TA:  J Clin Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1195-203     Citation Subset:  IM    
Affiliation:
Oregon Health and Science University Cancer Institute and Portland VA Medical Center, Portland, OR, USA heinrich@ohsu.edu
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Antineoplastic Agents / pharmacology*,  therapeutic use
Clinical Trials, Phase II as Topic
Disease-Free Survival
Female
Fibromatosis, Aggressive / drug therapy*,  genetics*,  radiography,  radionuclide imaging
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immunoblotting
Immunohistochemistry
Male
Middle Aged
Mutation / drug effects
Piperazines / pharmacology*,  therapeutic use
Platelet-Derived Growth Factor / metabolism
Positron-Emission Tomography
Protein Kinase Inhibitors / pharmacology*,  therapeutic use
Protein-Tyrosine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-kit / genetics
Pyrimidines / pharmacology*,  therapeutic use
Receptor, Platelet-Derived Growth Factor alpha / genetics
Receptor, Platelet-Derived Growth Factor beta / genetics
Tomography, X-Ray Computed
beta Catenin / genetics
Grant Support
ID/Acronym/Agency:
5P30 CA69533-04/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CTNNB1 protein, human; 0/Piperazines; 0/Platelet-Derived Growth Factor; 0/Protein Kinase Inhibitors; 0/Pyrimidines; 0/beta Catenin; 0/platelet-derived growth factor A; 0/platelet-derived growth factor BB; 152459-95-5/imatinib; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Proto-Oncogene Proteins c-kit; EC 2.7.10.1/Receptor, Platelet-Derived Growth Factor alpha; EC 2.7.10.1/Receptor, Platelet-Derived Growth Factor beta
Comments/Corrections
Comment In:
J Clin Oncol. 2006 Aug 1;24(22):3714-5; author reply 3715   [PMID:  16877745 ]

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