Abstract 1965: Predictive and prognostic value of miRNA expression profile in aggressive fibromatosis treated with imatinib.
Authors: Dufresne Armelle , Paturel Marie , Penel Nicolas , Le Cesne Axel , Bui Binh , Pissaloux Daniel , Alberti Laurent , Blay Jean Yves 
Published: August 2014

Abstract
Rationale Aggressive fibromatosis (AF) is a rare fibroblastic proliferative neoplasm with locally malignant behaviour which never metastasises. Systemic treatment active in relapsing or non resectable AF include NSAIDs, antioestrogens, chemotherapy, imatinib. This study was conducted to define the predictive and prognostic value of miRNA expression profile for relapsing AF receiving imatinib for 1 year within the Desminib trial (Penel et al., Ann Oncol, 2011). Material and methods 500 ng of RNA were extracted from FFPE tissues samples of patients included in the Desminib trial: 26 of 40 patients had sufficient quantity material. The expression of 384 miRNAs for each patient was analysed using a microfluidic platform (Applied Biosystems.). Supervised and unsupervised hierarchical clustering were performed. Supervised analysis compared 1) progressive vs non progressive patients under treatment, 2) patients non progressing during imatinib but progressing within 2 years after imatinib interruption vs never progressive patients. Anova method was used to identify the statistically significant miRNAs, discriminants between the 2 groups (with p value &lt; 0.05). These miRNAs were included into the “Kyoto Encyclopedia of Genes and Genome”. Results 1) Predictive value: the expression of the 4 following miRNA was found to differ significantly between patients progressing or not during imatinib:. Wnt pathway is impacted by these miRNAs (which induces Wnt and Fz) as well as as cKIT and PDGFR, known targets of imatinib. 2) Prognostic value Among 20 patients non progressing while imatinib, 29 miRNA had a significant differential expression in progressive (n=5) vs non progressive patients (n=8) during the follow-up (7 patients had a nonsufficient follow up). 19 miR were identified as highly discriminant with a p-value ranging from 7.73.10−5 to 9.8.10−3. All these miRNA were under expressed in progressive patients. Wnt pathway is largely targeted by these miRNAs (which induces Wnt, Fz, GSK-3β, axin, APC, TCF/LEF and cyclin D1). The unsupervised hierarchical clustering of the 26 patients identified 2 groups of thirteen patients each. Median TTP in each group is 27.4 and 33.8 months, respectively. Anova study of this clustering identified 12 discriminant miRNAs, whose 9 miRNAs with p-value ranging from 6.51.10−8 to 1.24.10−4, also identified by Anova of the prognostic supervised clustering. Conclusion These results bring the first demonstration of predictive and prognostic value of miRNA expression profile in AF treated with imatinib. The next objective is 1) to confirm these results in a prospective cohort and 2) to precisely identify a miRNA signature to select patients with a non progressive disease in whom surgical resection of the primary tumor could be spared.
Citation Format: Armelle Dufresne, Marie Paturel, Nicolas Penel, Axel Le Cesne, Binh Bui, Daniel Pissaloux, Laurent Alberti, Jean Yves Blay. Predictive and prognostic value of miRNA expression profile in aggressive fibromatosis treated with imatinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1965. doi:10.1158/1538-7445.AM2013-1965