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

Abstract

Purpose: To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology.Experimental design: Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 na€ ve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis.Results: All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer-mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected.Conclusions: All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of na€ ve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

“…To this end, we initially compared the transcriptome profile of 5 DFSPs and of 5 FS-DFSPs. All samples expressed the COL1A1-PDGFB fusion transcript, with no significant variation in its expression levels between DFSP and FS-DFSP, as previously reported (4,8). No other recurrent fusion transcripts that may hallmark the FS-DFSP variant were detected.…”

“…Cases of fibrosarcomatous transformation occurring over time in DFSP after multiple local relapses are described in other reports (8). We cannot challenge this possibility, as the proportion of patients who relapsed was very low.…”

“…COL1A1-PDGFB rearrangement is of major help in confirming the diagnosis in those cases in which the classic component is completely lost (4,8). COL1A1-PDGFB retainment in FS-DFSP suggests that other still undetermined genetic abnormalities account for progression of DFSP to FS-DFSP.…”

Advances in sarcoma diagnostics and treatment

“…Scarce data exists on the role of imatinib specifically in these metastatic FS-DFSP tumors. A recent retrospective study evaluating 10 metastatic FS-DFSP patients treated with imatinib showed that 90% of patients achieved clinical benefit (8 partial responses and 1 stable disease) with a median of 11 months PFS [87]. However, the duration of response observed in this study was lower than that reported ina previous series containing a mix of cases with both low-grade and FS-DFSP [88].…”

Dermatofibrosarcoma Protuberans: A Rare Malignancy

“…Imatinib mesylate is also used in metastatic tumors in which resection is not possible or may have unacceptable functional and cosmetic results and radiotherapy cannot be performed. [12][13][14] This study aimed to review the literature for DFSP cases.…”