The group from MSKCC sequenced 454 patients with UBC patients using a capture-based next generation sequencing (NGS) assay (MSK-IMPACT) – the MSK Impact assay assessed for numerous common genomic alterations. Of these patients, 317 patients (123 NMIBC, 161 MIBC and 33 metastatic) had no prior h/o urothelial carcinoma (i.e. index tumors) at time of sequencing. These patients were sequenced for analysis.
Their basic findings are as follows:
1. Index tumors that harbored TP53 and/or RB1 alterations more frequently presented with advanced disease whereas tumors containing FGFR3 alterations presented with NMIBC (all p value <0.001)
2. TP53/MDM2, DNA Damage Repair (DDR) and cell cycle pathway alterations were more common in index advanced stage tumors
3. Index NMIBC had more frequent RTK/RAS/RAF pathway alterations
4. FGFR3, PBRM1 and TP53 were significant to predict both overall and metastasis free survivals in multivariate models
5. MIBC with DDR gene alterations had significantly higher pathological down-staging as well as better overall survival compared to MIBC without DDR alterations with platinum-based neoadjuvant chemotherapy (both p value =0.04)
6. Specifically, MIBC without DDR alterations, DDR alterations of unknown significance and DDR deleterious alterations had pathologic down-staging rate of 37.1%, 48% and 81.3%, respectively, with platinum-based neoadjuvant chemotherapy
7. MIBC with ERCC2 mutations exhibited a pathologic down-staging rate of 83.3% with platinum-based neoadjuvant chemotherapy.
Based on these results, authors conclude that TP53, RB1 and FGFR3 alterations as well as TP53/MDM2, DDR, cell cycle and RTK/RAS/RAF pathways alterations showed an association with index tumor stage. FGFR3, PBRM1 and TP53 were significant to predict both overall and metastasis free survivals in multivariate models. MIBC with DDR alterations had significantly higher pathological down-staging as well as better overall survival compared to MIBC without DDR alterations with platinum-based neoadjuvant chemotherapy.
Further work is obviously required. However, association does not imply causation. Many of these results have been replicated in smaller more focused studies. However, this study does provide larger series data to support those smaller data outputs.
Presented by: Sumit Isharwal, MD
Co-Authors: Francois Audenet MD, Esther Drill PhD, Eugene Pietzak MD, Irina Ostrovnaya PhD, Hikmat Al-Ahmadie MD, Eugene Cha MD, Timothy Donahue MD, Min Yuen Teo MD, Samuel Funt MD, Maria Arcila MD, Michael Berger MD, Jonathan Rosenberg MD, Dean Bajorin MD, Jonathan Coleman MD, Guido Dalbagni MD, Bernard Bochner MD, David Solit MD and Gopa Iyer MD
Affiliation: Memorial Sloan Kettering Cancer Center, New York, New York
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC