ESMO 2017: Identification of genomic features underlying response of muscle-invasive bladder cancer to neoadjuvant sorafenib, gemcitabine, and cisplatin in an open-label, single-arm, phase 2 study

Madrid, Spain (UroToday.com) Dr. Daniele Raggi and colleagues presented results of a clinical study assessing genomic features of muscle invasive bladder cancer (MIBC) with regards to response to neoadjuvant chemotherapy at today’s ESMO 2017 poster session. Genomic analyses demonstrated that MIBC can be grouped into molecular subtypes that portend different outcomes with neoadjuvant chemotherapy (NAC). Sorafenib, gemcitabine, and cisplatin were active in MIBC, showing a response rate (downstaging to pT < 2) of 54.3% in 46 patients in a phase 2 trial [1]. The objective of this study was to analyze gene expression profiles and copy number variations of transurethral resections (TURB) from these patients.

For this study, the authors analyzed 25 patients, 18 responders and 7 non-responders. Gene expression profiles and copy number variation profiles were generated using Affymetrix Clariom D and OncoScan assays. Samples were assigned to claudin-low, basal or luminal subtypes according to the BASE47 and BCL40 signatures. Genes differentially expressed or amplified/deleted between non-responders and responders were functionally analyzed using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis.

Transcriptional subtypes were robustly assigned to 24 of 25 patients: 13 were classified as luminal, 10 claudin-low, and one as basal. A significant association between subtypes and therapeutic response was observed (p = 0.002), with all luminal samples falling in the responder group while claudin-low were split between responders and non-responders (5 vs 5). To avoid confounding related to the subtype, the authors restricted the comparison of responders and non-responders to claudin-low samples. Using IPA, they identified activation of an IRF7-driven transcriptional program (p<0.001) in non-responder samples. Furthermore, in the non-responder group, they 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 non-responders whereas copy number gains on chromosome 17, 18 and 20 characterized responder samples.

In summary, the results indicate that luminal tumors are responsive to sorafenib, gemcitabine, and cisplatin NAC. Comparisons between responders and non-responders within the claudin-low group outlined potential genomic predictors of response. Once validated, patient selection criteria for NAC may be substantially improved.

Speaker: Daniele Raggi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain

References:

Necchi A, Lo Vullo S, Raggi D, et al. Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single arm, phase II study. J Clin Oncol 2017;35(suppl 6S; abstr 345).
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