Combination of a Novel Gene Expression Signature with a Clinical Nomogram Improves the Prediction of Survival in High-Risk Bladder Cancer

Abstract

Purpose We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. Experimental Design We evaluated microarray data from 93 bladder cancer patients managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray datasets comprising 578 additional patients, and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated post-cystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. Results Multiple markers for muscle invasive disease with highly significant expression differences in multiple datasets were identified, such as FN1, NNMT, POSTN and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent datasets, significantly improving the prediction concordance of standard staging in all datasets (mean ΔC-statistic: 0.14, 95% CI 0.01–0.27; P < 0.001). Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI −0.04–0.20; P < 0.005). Conclusions Prognostic information obtained from gene expression data can aid in post-treatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting.

Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results

“…This study is a logic follow-up to identify molecular markers in very early stage of primary NMIBC that may predict its recurrence. If we define upregulated or downregulated genes of our study, several of them are common to genes published by other authors, but in general the analogy of the genes, presented here, is not so extensive with other studies [7,8,[10][11][12][13][14][15][16]. It may be caused by unique provenance 1, 2, 3, 12, 14, 15, 16, and 22, see Table 2).…”

Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

“…In the present study, we looked exclusively for intrinsic subtypes of high-grade disease agnostic to clinical stage or outcome. We first created a meta-dataset of 262 high-grade muscleinvasive tumors, curated from four publically available datasets (12,(19)(20)(21) (SI Appendix, Table S1). In parallel, an independent set of 49 high-grade tumors from Memorial Sloan-Kettering Cancer Center (MSKCC) served as a validation set (8).…”

“…From these studies, it is apparent that low-grade noninvasive and high-grade muscle-invasive tumors harbor distinct gene expression patterns, and that further molecular subsets can be identified within low-grade and high-grade tumors (5,(11)(12)(13)(14). Moreover, a number of gene signatures have been developed that can predict tumor stage, lymph node metastases, and bladder cancer progression (11-13, 15-18).…”

“…From these studies, it is apparent that low-grade noninvasive and high-grade muscle-invasive tumors harbor distinct gene expression patterns, and that further molecular subsets can be identified within low-grade and high-grade tumors (5,(11)(12)(13)(14). Moreover, a number of gene signatures have been developed that can predict tumor stage, lymph node metastases, and bladder cancer progression (11)(12)(13)(15)(16)(17)(18). There are established gene expression patterns that differentiate lowgrade and high-grade tumors; however, there are little data identifying intrinsic subtypes specifically within high-grade disease.…”

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

“…The development of successful molecular-based therapies in bladder cancer remains challenging because of the high degree of biological diversity of bladder carcinomas. A number of large-scale molecular studies have been conducted in bladder cancer (7)(8)(9)(10)(11)(12)(13), but not with the focus of identifying a therapeutic target for a particular subgroup.…”