Abstract
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. 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 naïve 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. 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. 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 naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.
Highlights
Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma [1], arising from the skin and marked by rearrangement ofNote: Supplementary data for this article are available at Clinical Cancer Research Online.Prior presentation: The abstract (10553) was presented at the 2015 ASCO Annual Meeting in Chicago.Ó2015 American Association for Cancer Research.chromosomes 17 and 22, which results in the COL1A1–PDGFB fusion gene [2]
Three of these patients were among the 4 previously reported [5]. We describe their clinical behavior and we report on the gene expression profile (GEP) analysis performed in few na€ve and imatinib mesylate (IM)-pretreated FS-dermatofibrosarcoma protuberans (DFSP) tumor samples
We retrospectively reviewed all consecutive adult patients treated with IM for metastatic relapse from DFSP or FS-DFSP at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (INT), and within the Italian Rare Cancer Network (IRCN) from 2007 to 2014
Summary
Clinical findings Out of 52 patients who requested a treatment with IM for a DFSP or an FS-DFSP from January 2007 to March 2015, 10 cases with metastatic disease were identified. We detected changes consistent with early signs of response to IM, marked by a variable inflammatory component and intermingled with scattered viable tumor cells (Supplementary Fig. S1, corresponding to patient 4, Tables 1 and 2, whose matched cryopreserved halve was used for RNAseq analysis). Immunohistochemistry failed to highlight decrease of PDGFRB expression in the viable tumor cells surrounding the regressed areas (data not shown) This is consistent with our previous reports on the lack of evidence of PDGFRB decrease/switch-off in IM-responsive DFSP patients, as assessed by both IHC and immunoblot [5]. IHC analysis performed in post-IM samples (Table 1, patient 4) using anti-CD20 and CD57-specific antibodies confirmed the presence of tumor-infiltrating lymphoid cells expressing B- and NK-specific markers (Fig. 2). Pathway enrichment analysis confirmed the modulation of genes related to the immune response, with genes involved in antigen processing and presentation and in NK-mediated cytotoxicity being overrepresented in IM-treated samples (Table 3; Fig. 1C)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
