Neo-adjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase-II DeCOG trial with long-term follow-up

Abstract

PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1-PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRB signaling. This trial investigated imatinib as neo-adjuvant treatment of DFSP including long-term follow-up. EXPERIMENTAL DESIGN: The primary endpoint of this multicenter phase-II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST were eligible and received imatinib 600 mg/d until definitive surgery with histopathological proof of tumor-free margins. RESULTS: 16 patients received imatinib; 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% CR, 50.0% PR, 35.7% SD, and 7.1% PD. Toxicity was moderate with 25.0% grade 3-4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with non-response. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs. CONCLUSION: The neo-adjuvant use of imatinib 600 mg/d in DFSP is efficacious and well-tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pre-treatment, and presume that secondary resistance to imatinib might promote accelerated disease progression.