Efficacy and biological activity of imatinib in metastatic Dermatofibrosarcoma Protuberans (DFSP)

Silvia Stacchiotti, Maria A. Pantaleo, Tiziana Negri, Annalisa Astolfi, Marcella Tazzari, Gian Paolo Dagrada, Milena Urbini, Valentina Indio, Roberta Maestro, Alessandro Gronchi, Marco Fiore, Angelo P. Dei Tos, Elena Conca, Elena Palassini, Bruno Vincenzi, Federica Grosso, Silvana Pilotti, Chiara Castelli, Paolo Giovanni Casali

Research output: Contribution to journalArticle

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 nave 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 nave and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

Original languageEnglish
Pages (from-to)837-846
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 15 2016

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Dermatofibrosarcoma
Proto-Oncogene Proteins c-sis
Antigen Presentation
Imatinib Mesylate
Recurrence
Xenobiotics
Principal Component Analysis
Genes
Disease-Free Survival
Cluster Analysis
Immunoglobulins
Research Design
Phosphotransferases
Up-Regulation
Down-Regulation
Endothelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Efficacy and biological activity of imatinib in metastatic Dermatofibrosarcoma Protuberans (DFSP). / Stacchiotti, Silvia; Pantaleo, Maria A.; Negri, Tiziana; Astolfi, Annalisa; Tazzari, Marcella; Dagrada, Gian Paolo; Urbini, Milena; Indio, Valentina; Maestro, Roberta; Gronchi, Alessandro; Fiore, Marco; Dei Tos, Angelo P.; Conca, Elena; Palassini, Elena; Vincenzi, Bruno; Grosso, Federica; Pilotti, Silvana; Castelli, Chiara; Casali, Paolo Giovanni.

In: Clinical Cancer Research, Vol. 22, No. 4, 15.02.2016, p. 837-846.

Research output: Contribution to journalArticle

Stacchiotti, S, Pantaleo, MA, Negri, T, Astolfi, A, Tazzari, M, Dagrada, GP, Urbini, M, Indio, V, Maestro, R, Gronchi, A, Fiore, M, Dei Tos, AP, Conca, E, Palassini, E, Vincenzi, B, Grosso, F, Pilotti, S, Castelli, C & Casali, PG 2016, 'Efficacy and biological activity of imatinib in metastatic Dermatofibrosarcoma Protuberans (DFSP)', Clinical Cancer Research, vol. 22, no. 4, pp. 837-846. https://doi.org/10.1158/1078-0432.CCR-15-1243
Stacchiotti, Silvia ; Pantaleo, Maria A. ; Negri, Tiziana ; Astolfi, Annalisa ; Tazzari, Marcella ; Dagrada, Gian Paolo ; Urbini, Milena ; Indio, Valentina ; Maestro, Roberta ; Gronchi, Alessandro ; Fiore, Marco ; Dei Tos, Angelo P. ; Conca, Elena ; Palassini, Elena ; Vincenzi, Bruno ; Grosso, Federica ; Pilotti, Silvana ; Castelli, Chiara ; Casali, Paolo Giovanni. / Efficacy and biological activity of imatinib in metastatic Dermatofibrosarcoma Protuberans (DFSP). In: Clinical Cancer Research. 2016 ; Vol. 22, No. 4. pp. 837-846.
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AU - Stacchiotti, Silvia

AU - Pantaleo, Maria A.

AU - Negri, Tiziana

AU - Astolfi, Annalisa

AU - Tazzari, Marcella

AU - Dagrada, Gian Paolo

AU - Urbini, Milena

AU - Indio, Valentina

AU - Maestro, Roberta

AU - Gronchi, Alessandro

AU - Fiore, Marco

AU - Dei Tos, Angelo P.

AU - Conca, Elena

AU - Palassini, Elena

AU - Vincenzi, Bruno

AU - Grosso, Federica

AU - Pilotti, Silvana

AU - Castelli, Chiara

AU - Casali, Paolo Giovanni

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N2 - 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 nave 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 nave and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

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