Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.

European urology oncology. 2019 Mar 09 [Epub ahead of print]

Petros Grivas, Aly-Khan A Lalani, Gregory R Pond, Rebecca J Nagy, Bishoy Faltas, Neeraj Agarwal, Sumati V Gupta, Alexandra Drakaki, Ulka N Vaishampayan, Jue Wang, Pedro C Barata, Dharmesh Gopalakrishnan, Gurudatta Naik, Bradley A McGregor, Lesli A Kiedrowski, Richard B Lanman, Guru P Sonpavde

University of Washington, Seattle, WA, USA., Juravinski Cancer Centre, McMaster University, Hamilton, Canada., McMaster University, Hamilton, Canada., Guardant Health Inc., Redwood City, CA, USA., Weill-Cornell Medicine, New York, NY, USA., University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA., David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Karmanos Cancer Center, Wayne State University, Detroit, MI, USA., University of Arizona Cancer Center, Phoenix, AZ, USA., Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., University of Alabama at Birmingham, Birmingham, AL, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: .