Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder

Abstract

Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we used capture-based massively parallel sequencing to analyze 109 tumors. Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival (RFS) (hazard ratio [HR]: 0.35; p=0.014) and improved cancer-specific survival (CSS) (HR: 0.35; p=0.040) in patients treated with radical cystectomy (RC). In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR: 0.39; p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical disease (69% vs 32%, p=0.005) and lymph node-positive disease (77% vs 56%, p=0.025). Patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-altered tumors experienced worse RFS (HR: 5.76; p<0.001) and worse CSS (HR: 2.94; p=0.029) in multivariable analyses. Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes. In UCB patients treated with RC, PIK3CA mutations are associated with favorable outcomes, whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following RC.

Patient summary: Using next-generation sequencing, we identified genomic subsets of high-grade urothelial bladder cancer associated with favorable and unfavorable outcomes. These findings may aid in the selection of patients most likely to benefit from novel combined modality approaches.

Keywords: Bladder cancer; Clinical outcomes; Genomics; Mutation; PIK3CA.

Figure 1

Most commonly altered genes in 109 high-grade urothelial carcinoma of the bladder tumors analyzed by MSK-IMPACT. The number of patients with alterations is depicted on the right. Alterations were categorized by type, as recurrent missense mutations, novel missense mutations, truncating mutations (frameshift, nonsense and splice site), and copy number amplifications or deletions. The oncoprint shows the distribution of alterations across the sequenced samples. The top bar graph illustrates the number of MSK-IMPACT gene alterations per sample.

Figure 2

Associations with PI3K/AKT pathway alterations and clinical outcomes in 89 urothelial carcinoma of the bladder patients treated with radical cystectomy. Recurrence-free survival and cancer-specific survival stratified by (A) PIK3CA mutation status and (B) PI3K/AKT pathway alteration status. P values reflect log-rank test.