Abstract 4348
Background
Vinflunine is an antimicrotubule agent approved by the EMA for second-line treatment in p with aUC. However, no molecular biomarkers are currently available that can predict response to vinflunine in aUC. In the randomized phase II MAJA trial (NCT01529411) in p with aUC with disease control after a platinum-based regimen, maintenance vinflunine conferred a significant improvement in progression-free survival compared to best supportive care (Garcia-Donas et al. Lancet Oncol 2017). Pre-planned gene expression analyses aimed to identify biomarkers to predict response to maintenance vinflunine.
Methods
In the MAJA trial, 44 p received vinflunine. We have compared the gene expression profiles of eight poor responders to vinflunine (<4 cycles) and nine good responders (>12 cycles). RNA was isolated from FFPE tumor tissue collected during screening using the Covaris kit and gene expression levels were analyzed with Clariom S array (Thermo Fisher). Differential expression (DE), defined as p < 0.05 and |FC|>1.5, was determined with linear models for microarray data included in the limma and sva packages. Pre-ranked Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the DE genes.
Results
Hierarchical clustering of genes showed a DE between good and poor responders. DE were found in 31 genes, 13 of them were unregulated in good responders and 18 were unregulated in poor responders. In good responders, GSEA revealed overexpression of 72 genes related to G2M-checkpoint and of 61 genes related to E2F transcription factor. In poor responders, 73 genes related to epithelial-mesenchymal transition and 39 related to IL6/JAK/STAT3 were downregulated. We are currently validating these genes using qPCR to determine a gene expression profile associated with response to maintenance vinflunine.
Conclusions
Our preliminary results suggest that microarray analysis could identify a gene expression signature to predict response to maintenance vinflunine, which will be useful in selecting treatment for p with aUC. Complete results of the analyses will be reported.
Clinical trial identification
NCT01529411; EudraCT: 2011-001271-39.
Legal entity responsible for the study
Spanish Oncology Genitourinary Group.
Funding
Spanish Oncology Genitourinary Group.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.