Advances in the understanding of molecular mechanisms of DFSP resulted in the implementation of targeted therapy based on PDGFR inhibition to the treatment of this sarcoma. Imatinib mesylate is a tyrosine kinase inhibitor rationally developed and specifically directed against BCR/ABL, KIT, FMS (receptor for Colony Stimulating Factor 1), ARG (ABL-related gene), and PDGFR alpha and beta. It has been also found to be the first effective systemic therapy in DFSP. Imatinib competes with adenosine triphosphate (ATP) molecule, blocking tyrosine kinase receptor ability for autophosphorylation, which in return results in inhibition of the aberrant signal transduction pathway and partial restoration of proper intracellular signaling. The observation that autocrine overproduction of PDGFB caused by gene rearrangement is a key pathogenetic factor [33
] forced the in vitro
research, which showed inhibition of DFSP cells growth in vitro
after exposure to imatinib [36
]. The further demonstration of the imatinib inhibitory effect on six different DFSP cell lines both in vitro
and in vivo
] has led to the investigation of this new therapeutic approach in the clinic. Early case reports on small series of patients suggested the usefulness of imatinib in metastatic and locally advanced DFSP [47
]. Next series of 10 patients with locally advanced and/or metastatic DFSP treated within Imatinib Target Exploration Consortium Study B2225 showed responses in all patients, including complete responses in five out of 10 of locally advanced cases and one partial response lasting seven months in metastatic case [53
]. As a consequence imatinib was registered as a therapy of choice in advanced (inoperable and/or metastatic) DFSPs (). In a phase II trial [54
] evaluating the activity of imatinib in life-threatening malignancies expressing imatinib-sensitive tyrosine kinases DFSP was the only one of five tumor types in which a notable activity was shown including extensive regression in 10/20 cases (50% partial remissions, 33,3% complete remissions).
Images of advanced dermatofibrosarcoma protuberans of the supraclavicular region before and after therapy with imatinib, and after resection of residual disease. The patient is now 3 years free of disease.
Combined analysis of prematurely closed, two phase II, single arm, open-label trials on efficacy of imatinib in advanced DFSP (European Organisation for Research and Treatment of Cancer no. 62027 and the Southwest Oncology Group no. S0345) has demonstrated the clinical benefit with rate exceeding 70% and median time to progression of 1.7 years on 25 patients with advanced DFSP [55
]. Although there were some differences in both trials' design, the observed responses' rates were similar. These results imply that the imatinib dose of 400
mg daily has similar efficacy to 800
mg daily in this entity. Rutkowski et al. [56
] have proved striking activity of imatinib mesylate in advanced DFSP in the group of 15 patients treated with imatinib in routine clinical practice outside any trial, with clinical benefit rate approaching 80% as well as median PFS and OS being not reached. In the efficacy results of imatinib in advanced DFSPs from pooled analysis of phase II trials [55
] and 15 patients treated outside clinical trials is presented [56
Table 1 The best overall responses, progression, and survival status in combined phase II clinical trials  and in group of patients treated outside clinical trials .
It has also been shown that DFSPs-FS with t(17;22) are still imatinibsensitive although responses seem to last shorter [57
] while DFSPs-FS lacking the specific aberration do not respond to the treatment [53
]. Therefore the confirmation of the molecular target (COL1A1-PDGFB
fusion) presence seems to be obligatory in every case prior to the start of imatinib therapy.
Complete, wide surgical excision is the standard treatment in localized, resectable cases, and in advanced cases it may result in cosmetic disfigurement or serious functional impairment. Thus the neoadjuvant imatinib strategy leading to tumor downstaging and decrease of excision morbidity by tissue-sparing appears to be very attractive. Kérob et al. [58
] presented report on 25 resectable DFSP (median size: 4.5
cm) treated in phase II trial with preoperative imatinib at the dose of 600
mg daily for two months. The objective partial response according to RECIST was observed in nine cases (36%). The median relative tumor volume decrease was 20% (range: 12.5–100%). Available clinical data indicate that some DFSP patients initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned out to have resectable tumor after imatinib therapy. This rational approach enabling achievement of complete remission may be potentially curative, although longer followup is needed. Further studies are required for elucidating whether preoperative imatinib therapy reduces the need for wide surgical margins or whether imatinib has activity as adjuvant therapy in cases with positive margins after excision or in other high-risk patients.
Majority of patients treated with imatinib experienced side effects during treatment, but almost all are mild and manageable. The most common were fluid retention/edema, anemia, fatigue, nausea, skin rash, thrombocytopenia, vomiting, neutropenia, and diarrhea, and they are similar to those observed in patients with gastrointestinal stromal tumor (GIST).
There are still several questions regarding imatinib mechanism of action, and possible resistance to this targeted therapy in DFSP. There is also a need to identify novel predictive molecular markers for patients' outcome. It was presumed that imatinib effect resulted from inhibition of PDGFR phosphorylation. Surprisingly, clinical activity of imatinib in DFSP is striking even in DFSP expressing relatively low amounts of activated receptor. It seems that inhibition of low-level receptor tyrosine kinase may be effective clinically if tumor cells are dependent on that signaling mechanism, what has been observed also in pigmented villonodular synovitis/tenosynovial giant-cell tumor [59
]. The better understanding of the downstream effects caused by imatinib-PDGFB interaction would allow defining additional treatment strategies for DFSP patients. In case of disease progression after initial response to imatinib the investigation of other multitargeted tyrosine kinase inhibitors seems to be justified.
To summarize, imatinib therapy is currently the gold standard in the treatment of inoperable and/or metastatic and/or recurrent cases of DFSP, and this targeted therapy may potentially facilitate resection or decrease possible disfigurement. Significant percentage of patients may be rendered free of disease by surgery of residual disease following partial imatinib responses. Current therapy of DFSP with t(17;22) translocation should be conducted by multidisciplinary team, including oncological surgeon. The use of imatinib mesylate as initial therapy should be considered to decrease possible extent of surgery and related morbidity.