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Poster display session

4155 - Identification of genomic features underlying response of muscle-invasive bladder cancer (MIBC) to neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) in an open-label, single-arm, phase 2 study

Date

10 Sep 2017

Session

Poster display session

Topics

Cytotoxic Therapy;  Translational Research;  Urothelial Cancers

Presenters

Daniele Raggi

Citation

Annals of Oncology (2017) 28 (suppl_5): v295-v329. 10.1093/annonc/mdx371

Authors

D. Raggi1, A. Paoli2, M. Dugo2, P. Giannatempo1, L. De Cecco2, M. Colecchia3, M.G. Daidone4, A. Necchi1, M.L. Sensi2

Author affiliations

  • 1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 2 Functional Genomics Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano/IT
  • 3 Pathology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano/IT
  • 4 Experimental Oncology And Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133   - Milan/IT
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Resources

Abstract 4155

Background

Genomic analyses demonstrated that MIBC can be grouped into molecular subtypes that portend different outcomes with neoadjuvant chemotherapy (NACT). SGC was active in MIBC, showing a response rate (downstaging to pT 

Methods

We analyzed 25 pts, 18 responders (R) and 7 non-responders (NR). GEP and CNV profiles were generated using Affymetrix ClariomTM D and OncoScanTM assays. Samples were assigned to claudin-low (CL), basal (B) or luminal (L) subtypes according to the BASE47 and BCL40 signatures. Genes differentially expressed or amplified/deleted between NR and R were functionally analyzed using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis.

Results

Transcriptional subtypes were robustly assigned to 24/25 pts: 13 were classified as L, 10 CL and 1 B. A significant association between subtypes and therapeutic response was observed (p = 0.002), with all L samples falling in the R group while CL were split between R and NR (5 vs 5). To avoid confounding related to the subtype we restricted the comparison of R and NR to CL samples. Through the use of IPA we identified activation of an IRF7-driven transcriptional program (p = 3.88E-12) in NR samples. In the NR group we found a positive enrichment of gene sets related to mRNA processing, cell cycle and oxidative phosphorylation and a negative enrichment of defensins. In addition, 19 genes were both significantly overexpressed and amplified in NR whereas copy number gains on chromosome 17, 18 and 20 characterized R samples. Limitations include the unassessable role of S contribution to GC.

Conclusions

Altogether, the results indicate that L tumors are responsive to SGC. Comparisons between R and NR within the CL group outlined potential genomic predictors of response. Once validated, pt selection criteria for NACT may be substantially improved. Comparison with profiling of response to NA pembrolizumab will be shown (NCT02736266).

Clinical trial identification

N/A

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori

Funding

Affymetrix

Disclosure

All authors have declared no conflicts of interest.

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