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


METHODS
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.


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 naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.
Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it.
Silvia
S
Stacchiotti
Dipartimento di Medicina Sperimentale, Specialistica e Diagnostica, Università di Bologna, Bologna, Italy.
Maria A
MA
Pantaleo
Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Tiziana
T
Negri
Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
Annalisa
A
Astolfi
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Marcella
M
Tazzari
Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Gian Paolo
GP
Dagrada
Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
Milena
M
Urbini
Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
Valentina
V
Indio
Unit of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
Roberta
R
Maestro
Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Alessandro
A
Gronchi
Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Marco
M
Fiore
Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
Angelo P
AP
Dei Tos
Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Elena
E
Conca
Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Elena
E
Palassini
Department Medical Oncology Campus Biomedico, Roma, Italy.
Bruno
B
Vincenzi
Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy.
Federica
F
Grosso
Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Silvana
S
Pilotti
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Chiara
C
Castelli
Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Paolo G
PG
Casali
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018223:Dermatofibrosarcoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate