Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e264">Background</h5> <p id="P1">Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e269">Objective</h5> <p id="P2">To identify genetic alterations with potential clinical implications in NMIBC.</p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e274">Design, setting, and participants</h5> <p id="P3">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. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e279">Outcome measurements and statistical analysis</h5> <p id="P4">Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. </p> </div><div class="section"> <a class="named-anchor" id="S5"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e284">Results and limitations</h5> <p id="P5"> <i>TERT</i> promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. <i>ERBB2</i> or <i>FGFR3</i> alterations were present in 57% of high-grade NMIBC tumors in a mutually 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 ( <i>p</i> &lt; 0.001). <i>ARID1A</i> mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, <i>p</i> = 0.002). </p> </div><div class="section"> <a class="named-anchor" id="S6"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e308">Conclusions</h5> <p id="P6">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 associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. <i>ARID1A</i> mutations were associated with an increased risk of recurrence after BCG therapy. Whether <i>ARID1A</i> mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. </p> </div><div class="section"> <a class="named-anchor" id="S7"> <!-- named anchor --> </a> <h5 class="section-title" id="d4281426e319">Patient summary</h5> <p id="P7">Analysis of frequently mutated genes in <i>superficial</i> bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. </p> </div>