Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Heinrich
Michael C
MC
Oregon Health and Science University Cancer Institute and Portland VA Medical Center, Portland, OR, USA heinrich@ohsu.edu
McArthur
Grant A
GA
Demetri
George D
GD
Joensuu
Heikki
H
Bono
Petri
P
Herrmann
Richard
R
Hirte
Hal
H
Cresta
Sara
S
Koslin
D Bradley
DB
Corless
Christopher L
CL
Dirnhofer
Stephan
S
van Oosterom
Allan T
AT
Nikolova
Zariana
Z
Dimitrijevic
Sasa
S
Fletcher
Jonathan A
JA
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077214:Becaplermin; D001549:Benzamides; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D005260:Female; D018222:Desmoid Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D014057:Tomography, X-Ray Computed; D051176:beta Catenin / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; C495270:CTNNB1 protein, human; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D051176:beta Catenin; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta