Imatinib Mesylate as a Preoperative Therapy in Dermatofibrosarcoma: Results of a Multicenter Phase II Study on 25 Patients

Abstract

Aims: The treatment of dermatofibrosarcoma protuberans (DFSP) involves wide local excision with frequent need for reconstructive surgery. A t(17;22) translocation resulting in COL1A1-PDGFB fusion is present in >95% of cases. Certain patient observations and a report on nine patients suggest that imatinib mesylate, targeting platelet-derived growth factor receptor β, has clinical potential in DFSP. The primary aim of this phase II multicenter study was to define the percentage of clinical responders (Response Evaluation Criteria in Solid Tumors) to a 2-month preoperative daily administration of 600 mg of imatinib mesylate before wide local excision. The secondary aims were to determine tolerance, objective response from imaging results (ultrasound and magnetic resonance imaging), and pathologic responses observed in sequential tissue specimens.Patients and Methods: A two-stage flexible design was used with interim analysis after the recruitment of six patients. Twenty-five adults suffering from primary or recurrent DFSP were included from July 2004 to May 2006.Results: The COL1A1-PDGFB fusion gene was detected in 21 out of 25 patients following fluorescence in situ hybridization analysis (two cases were noninformative). A clinical response was achieved in nine (36%) patients (95% confidence interval, 18.9-57.5). The median relative tumoral decrease was 20.0% (range, −12.5 to 100). Apart from expected grade 1 or 2 side effects, we observed one grade 3 neutropenia, one grade 3 maculopapular rash, and one grade 4 transient transaminitis.Conclusion: Our results support the use of imatinib in a neoadjuvant setting in nonresectable DFSP, or when surgery is difficult or mutilating. These results will be useful for setting hypotheses in the evaluation of new drugs to treat primary or secondary resistance to imatinib. Clin Cancer Res; 16(12); 3288-95. ©2010 AACR.Dermatofibrosarcoma protuberans (DFSP) is a rare soft-tissue sarcoma characterized by progressive local growth of CD34+ spindle cells with a highly infiltrative pattern (1). Approximately 85% to 90% of tumors are low-grade, whereas others contain a high-grade fibrosarcomatous component (1). Wide excision is the standard therapy, but it can be difficult and mutilating (2). In less than 2% of cases, DFSP metastasizes and becomes lifethreatening.More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to fusion of COL1A1 and PDGFB genes. Transfection studies suggest that PDGFB could act as a mitogen for tumor cells, leading to platelet-derived growth factor (PDGF) receptor activation (3), which thus constitutes a therapeutic target. Indeed, three cases of DFSP with a spectacular response to imatinib mesylate (IM) were reported in 2002 (4, 5). In approximately 5% of cases, COL1A1-PDGFB fusion was not found, suggesting that other genes might be involved in DFSP pathogenesis (6).

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

“…The first two reports on IM activity in DFSP were by Rubin and colleagues (10) and by Maki and colleagues (12) in 2002 in 3 DFSP metastatic patients, with evidence of a major response in 2 cases, whereas the third patient had a transient response and eventually underwent a rapid progression (12). IM activity was further confirmed within 6 prospective phase II studies (11,(13)(14)(15)31). The largest was reported in 2010 (31) on 25 patients treated with neoadjuvant IM, but included only localized, classic DFSP.…”

“…In contrast, the role of IM in the metastatic setting is not clarified. Both the prospective and the retrospective studies reported so far analyzed locally advanced and metastatic patients together, and the efficacy of IM treatment was not investigated specifically in FS-DFSP (11)(12)(13)(14)(15). We already reported on 4 patients with advanced, translocated FS-DFSP (3 metastatic, one locally advanced) who received IM (5).…”

Fluorescence in situ hybridization analysis is a helpful test for the diagnosis of dermatofibrosarcoma protuberans

“…Therefore, for advanced cases or cases with difficult excision, a targeted therapy with tyrosine kinase inhibitor (imatinib mesylate) has been approved. [1][2][3]29 The COL1A1-PDGFB chimeric protein seems to be involved in the activation of the PDGF receptor. 2 In this context, the detection of the chromosomal rearrangement involving PDGFB is essential to favor this treatment.…”

A novel PDGFRA mutation in gastrointestinal stromal tumours, L839P, is sensitive to imatinib in vitro

“…Imatinib is now successfully used in the treatment of advanced GISTs (16,17) and chronic myelogenous leukaemia (18,19). Its clinical activity in other neoplasms has also been reported, including chordoma (20) and dermatofibrosarcoma protuberans (21).…”