TY - JOUR
T1 - Circulating Tumor DNA Alterations in Advanced Urothelial Carcinoma and Association with Clinical Outcomes
T2 - A Pilot Study
AU - Grivas, Petros
AU - Lalani, Aly Khan A.
AU - Pond, Gregory R.
AU - Nagy, Rebecca J.
AU - Faltas, Bishoy
AU - Agarwal, Neeraj
AU - Gupta, Sumati V.
AU - Drakaki, Alexandra
AU - Vaishampayan, Ulka N.
AU - Wang, Jue
AU - Barata, Pedro C.
AU - Gopalakrishnan, Dharmesh
AU - Naik, Gurudatta
AU - McGregor, Bradley A.
AU - Kiedrowski, Lesli A.
AU - Lanman, Richard B.
AU - Sonpavde, Guru P.
N1 - Publisher Copyright:
Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - Bladder cancer
KW - Cell-free DNA
KW - Genomic alterations
KW - Outcomes
KW - Urothelial cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85092944659&partnerID=8YFLogxK
U2 - 10.1016/j.euo.2019.02.004
DO - 10.1016/j.euo.2019.02.004
M3 - Article
C2 - 31412004
AN - SCOPUS:85092944659
SN - 2588-9311
VL - 3
SP - 695
EP - 699
JO - European Urology Oncology
JF - European Urology Oncology
IS - 5
ER -