EURURO Vol. 72 No. 6

Platinum Priority – Bladder Cancer

Editorial by Cyrill A. Rentsch, David C. Mu¨ller, Christian Ruiz and Lukas Bubendorf on pp. 960–961 of this issue

Next-generation Sequencing of Nonmuscle Invasive Bladder

Cancer Reveals Potential Biomarkers and Rational

Therapeutic Targets

Eugene J. Pietzak

a ,

Aditya Bagrodia

a ,

Eugene K. Cha

a ,

Esther N. Drill

b ,

Gopa Iyer

c , d ,

Sumit Isharwal

a ,

Irina Ostrovnaya

b ,

Priscilla Baez

a ,

Qiang Li

a ,

Michael F. Berger

e ,

Ahmet Zehir

e ,

Nikolaus Schultz

d ,

Jonathan E. Rosenberg

c ,

Dean F. Bajorin

c ,

Guido Dalbagni

a ,

Hikmat Al-Ahmadie

e ,

David B. Solit

c , d ,

Bernard H. Bochner

a , *

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA;

Department of Epidemiology and Biostatistics,

Memorial Sloan Kettering Cancer Center, New York, NY, USA;

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer

Center, New York, NY, USA;

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA;

Department of

Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 5 2 – 9 5 9

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

Article info

Article history:

Accepted May 17, 2017

Associate Editor:

James Catto

Keywords:

AT-Rich interaction domain 1A

Bacillus Calmette-Gue´ rin

DNA damage repair

Genomics

Immunotherapy

Nonmuscle invasive bladder

cancer

Targeted therapy

Abstract

Background:

Molecular characterization of nonmuscle invasive bladder cancer

(NMIBC) may provide a biologic rationale for treatment response and novel therapeutic

strategies.

Objective:

To identify genetic alterations with potential clinical implications in NMIBC.

Design, setting, and participants:

Pretreatment index tumors and matched germline

DNA from 105 patients with NMIBC on a prospective Institutional Review Board-

approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory

Improvement Amendments-certified clinical laboratory.

Outcome measurements and statistical analysis:

Comutation patterns and copy number

alterations were compared across stage and grade. Associations between genomic

alterations and recurrence after intravesical bacillus Calmette-Gue´ rin (BCG) were

estimated using Kaplan-Meier and Cox regression analyses.

Results and limitations:

TERT

promoter mutations (73%) and chromatin-modifying gene

alterations (69%) were highly prevalent across grade and stage, suggesting these

events occur early in tumorigenesis.

ERBB2

FGFR3

alterations were present in 57%

of high-grade NMIBC tumors in amutually exclusive pattern. DNA damage repair (DDR)

gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar

to MIBC, and were associated with a higher mutational burden compared with

tumors with intact DDR genes (

0.001).

ARID1A

mutations were associated with

an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval:

1.51–6.51,

= 0.002).

Conclusions:

Next-generation sequencing of treatment-naive index NMIBC tumors

demonstrated that the majority of NMIBC tumors had at least one potentially actionable

alteration that could serve as a target in rationally designed trials of intravesical or

systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were

* Corresponding author. Urology Service, Department of Surgery, Kimmel Center for Prostate and

Urologic Cancers, Memorial Sloan Kettering Cancer Center, 353 East 68th Street, New York, NY 10065,

USA. Tel. +1 646 422 4387; Fax: +1 212 988 0759.

E-mail address:

bochnerb@MSKCC.org

(B.H. Bochner).

http://dx.doi.org/10.1016/j.eururo.2017.05.032

0302-2838/