Activity of sunitinib in extraskeletal myxoid chondrosarcoma.
BACKGROUND
Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, marked by NR4A3 rearrangement. Herein we report on the activity of sunitinib in a series of 10 patients, strengthening what initially observed in two cases.


METHODS
From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5mg/day, on a named-use basis. In an attempt to interpret the activity of sunitinib in EMC, genotype/phenotype correlations were carried out by fluorescence in situ hybridization (FISH) analyses. Moreover, transcriptome, immunohistochemical and biochemical analyses of a limited set of samples were performed focusing on some putative targets of sunitinib.


RESULTS
Eight of 10 patients are still on therapy. Six patients had a Response Evaluation Criteria in Solid Tumours (RECIST) partial response (PR), two were stable, two progressed. Positron emission tomography (PET) was consistent in 6/6 evaluable cases. One patient underwent surgery after sunitinib, with evidence of a pathologic response. At a median follow-up of 8.5 months (range 2-28), no secondary resistance was detected. Median progression free survival (PFS) has not been reached. Interestingly, all responsive cases turned out to express the typical EWSR1-NR4A3 fusion, while refractory cases carried the alternative TAF15-NR4A3 fusion. Among putative sunitinib targets, only RET was expressed and activated in analysed samples.


CONCLUSIONS
This report confirms the therapeutic activity of sunitinib in EMC. Genotype/phenotype analyses support a correlation between response and EWSR1-NR4A3 fusion. Involvement of RET deserves further investigation.
Adult Mesenchymal Tumor Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Electronic address: silvia.stacchiotti@istitutotumori.mi.it.
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Stacchiotti
Dipartimento di Medicina Sperimentale, Specialistica e Diagnostica, Università di Bologna, Bologna, Italy.
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Pantaleo
Centro Interdipartimentale di Ricerche sul Cancro "G. Prodi", Università di Bologna, Bologna, Italy.
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Astolfi
Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Dagrada
Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Negri
Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
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Dei Tos
Centro Interdipartimentale di Ricerche sul Cancro "G. Prodi", Università di Bologna, Bologna, Italy.
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Indio
Department of Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Morosi
Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Gronchi
Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Colombo
Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Conca
Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
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Toffolatti
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Tazzari
Department of Nuclear Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Crippa
Unit of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
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Maestro
Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Pilotti
Adult Mesenchymal Tumor Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Casali
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018204:Neoplasms, Connective and Soft Tissue / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use*; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects; D011987:Receptors, Steroid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D000077210:Sunitinib; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; C500986:EWSR1 protein, human; D007211:Indoles; C490412:NR4A3 protein, human; D011758:Pyrroles; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors; C497970:FLT3 protein, human; C000588866:KDR protein, human; D019009:Proto-Oncogene Proteins c-kit; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib
Antiangiogenic; Chemotherapy; Chondrosarcoma; Extraskeletal myxoid chondrosarcoma; Sarcoma; Sunitinib