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Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC's).

ABSTRACT: BACKGROUND:Desmoplastic small round cell tumor (DSRCT) is a very rare mesenchymal tumor that mainly affects teenagers and young adults with a mean age at diagnosis around 20-25 years. Although initial management still needs standardization, many centers will use multimodal treatment including intensive chemotherapy, extensive surgical resection followed by radiotherapy. Despite this, prognosis remains very poor and the median overall survival is 25 months. Recurrent disease is mainly treated by chemotherapy. Recently, due to the unmet medical need for recurrent disease, targeted therapies were explored for DSRCT. METHODS:In this study, we assessed the response rate and progression free survival in nine cases of progressive DSRCT included in the OUTC's registry and treated with antiangiogenics targeted agents (sunitinib, sorafenib and bevacizumab). OUTC's, a French national registry, collects data about the use of off-label targeted therapy in sarcoma. RESULTS:Eight males and one woman were included, with median age at diagnosis of 27.3 years (range from 9 to 48 years). They received a mean 3 lines (2-5) of treatment before antiangiogenic agent initiation. Six patients received sunitinib, two received sorafenib and one bevacizumab. Median progression free survival was 3.1 months (range 2-5.5 months) and best response observed was 5.5 months stable disease. Most patients had manageable low-grade toxicities, mainly fatigue, abdominal pain and skin toxicity. CONCLUSIONS:Despite very limited activity of antiangiogenics in our study, prospective collection of cases of these rare tumors together with molecular data should guide therapeutic decision and enhance outcome.

SUBMITTER: Betrian S

PROVIDER: S-EPMC5424317 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC's).

Bétrian Sarah S Bergeron Christophe C Blay Jean-Yves JY Bompas Emmanuelle E Cassier Philippe A PA Chevallier Laure L Fayette Jérome J Girodet Magali M Guillemet Cécile C Le Cesne Axel A Marec-Berard Perrine P Ray-Coquard Isabelle I Chevreau Christine C

Clinical sarcoma research 20170510

<h4>Background</h4>Desmoplastic small round cell tumor (DSRCT) is a very rare mesenchymal tumor that mainly affects teenagers and young adults with a mean age at diagnosis around 20-25 years. Although initial management still needs standardization, many centers will use multimodal treatment including intensive chemotherapy, extensive surgical resection followed by radiotherapy. Despite this, prognosis remains very poor and the median overall survival is 25 months. Recurrent disease is mainly tre ...[more]

PMID: 28491276

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Project description:Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1-WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1-WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1-WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study. IMPLICATIONS: These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.

Project description:BACKGROUND:Facioscapulohumeral muscular dystrophy is a rare inherited neuromuscular disease with an estimated prevalence of 1/20,000 and France therefore harbors about 3000 FSHD patients. With research progress and the development of targeted therapies, patients' identification through registries can facilitate and improve recruitment in clinical trials and studies. RESULTS:The French National Registry of FSHD patients was designed as a mixed model registry involving both patients and physicians, through self-report and clinical evaluation questionnaires respectively, to collect molecular and clinical data. Because of the limited number of patients, data quality is a major goal of the registry and various automatic data control features have been implemented in the bioinformatics system. In parallel, data are manually validated by molecular and clinical curators. Since its creation in 2013, data from 638 FSHD patients have been collected, representing about 21% of the French FSHD population. The mixed model strategy allowed to collect 59.1% of data from both patients and clinicians; 26 and 14.9% from respectively patients and clinicians only. With the identification of the FSHD1 and FSHD2 forms, specific questionnaires have been designed. Though FSHD2 patients are progressively included, FSHD1 patients still account for the majority (94.9%). The registry is compatible with the FAIR principles as data are Findable, Accessible and Interoperable. We thus used molecular standards and standardized clinical terms used by the FILNEMUS French network of reference centers for the diagnosis and follow-up of patients suffering from a rare neuromuscular disease. The implemented clinical terms mostly map to dictionaries and terminology systems such as SNOMED-CT (75% of terms), CTV3 (61.7%) and NCIt (53.3%). Because of the sensitive nature of data, they are not directly reusable and can only be accessed as aggregated data after evaluation and approval by the registry oversight committee. CONCLUSIONS:The French National Registry of FSHD patients belongs to a national effort to develop databases, which should now interact with other initiatives to build a European and/or an international FSHD virtual registry for the benefits of patients. It is accessible at www.fshd.fr and various useful information, links, and documents, including a video, are available for patients and professionals.

Dataset Information

Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC's).

Publications

Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC's).

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