Activity of sunitinib in extraskeletal myxoid chondrosarcoma,

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Abstract

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.

Patients and methods

From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5 mg/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 EWSR1NR4A3 fusion, while refractory cases carried the alternative TAF15NR4A3 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 EWSR1NR4A3 fusion. Involvement of RET deserves further investigation.

Introduction

Extraskeletal myxoid chondrosarcoma (EMC) is an exceedingly rare sarcoma, usually arising from soft tissues of extremities [1]. EMC is marked by reciprocal translocations involving the NR4A3 gene locus on chromosome 9. In most cases, NR4A3 fuses with the EWSR1 gene located on chromosome 22, but other partner genes, namely TAF15, TCF12 and TFG, were identified [1], [2]. EMC can be subdivided into the ‘conventional well-differentiated’ and the ‘cellular high-grade’ variants [1]. ‘Dedifferentiated’ EMC was also described [3]. The natural history of the disease is usually indolent, but a more aggressive course is observed in dedifferentiated cases. Ten-year survival ranges between 85% and 65%, with a 40% risk of metastases [4], [5]. Resistance to cytotoxic chemotherapy is common [4], [5], [6], [7], which urges the need to identify alternative therapeutic strategies.

We preliminarily reported on the activity of sunitinib in two EMC patients [8]. We herein corroborate our initial observation by analysing a series of 10 patients with metastatic EMC treated with sunitinib within a named-use program. The clinical behaviour was then analysed in the light of tumour karyotype, and of transcriptome, immunohistochemical and biochemical analyses.

Section snippets

Patients

This retrospective series includes 10 consecutive metastatic EMC patients, treated with sunitinib since July 2011 at the Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Performance status (Eastern Cooperative Oncology Group (ECOG))  3, adequate bone marrow and organ function were requested. All patients provided a written informed consent to a non-conventional medical treatment, selected in the lack of any effective therapy in the disease. Approval by the Institutional Review Board was

Patients

Ten consecutive patients received sunitinib from July 2011 to December 2013. All were evaluable for response. Eight patients are still on therapy, two stopped their treatment for progression.

Table 1 summarises patient characteristics and clinical findings.

All patients displayed disease progression according to RECIST within the 6 months before starting sunitinib.

Discussion

From July 2011, 10 patients with advanced, progressive EMC have been treated with continuous-dosing sunitinib. According to RECIST, we observed six PR, two SD and two progressive disease (PD). One of the two patients with SD had a minor (<30%) dimensional response. Responses were long-lasting (median PFS not yet reached), with two patients still on treatment at 2 years. No secondary resistances were observed. Intriguingly, all responsive cases presented the most common EWSR1NR4A3 fusion. By

Conflict of interest statement

Stacchiotti S. – Pfizer: travel coverage for medical meetings, research funding. Glaxo Smith Kline: research funding.

Gronchi A. – Pfizer: honoraria, research funding.

Dei Tos A.P. – Pfizer: honoraria. Glaxo Smith Kline: honoraria, travel coverage for medical meeting.

Casali P.G. – Pfizer: advisory, honoraria, research funding. Glaxo Smith Kline: advisory, honoraria, research funding.

All remaining authors have declared no conflict of interest.

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    A small series of 10 patients treated with sunitinib (37.5 mg on a continuous daily dosing schedule) showed ORR of 60% and stable disease of 20%. All responders had EWSR1-NR4A3 fusion, whereas non-responders had TAF15-NR4A3 fusion [175]. The updated results showed a mPFS of 34 months, while OS had not been reached [176].

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Presented at 18th Connective Tissue Oncology Society (CTOS) Annual Meeting, 2013, New York, abs 1771775.

Funding: Grant from Associazione Italiana per la Ricerca sul Cancro (AIRC): IG 10300.

1

These authors equally contributed to the paper.

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